NPC Natural Product Communications

2009
NPC Natural Product Communications Vol. 4

No. 11
1511 - 1532
Chemical and Functional Diversity of Natural Products
from Plant Associated Endophytic Fungi
Vijay C. Vermaa, Ravindra N. Kharwara* and Gary A. Strobelb
a
Centre of Advanced Study in Botany, Banaras Hindu University, Varanasi-221005, India
b
Department of Plant Sciences, Montana State University, Bozeman MT 59717, USA
rnkharwar@yahoo.com
Received: March 30th, 2009; Accepted: June 30th, 2009
This review describes examples of naturally occurring bioactive compounds obtained from fungal endophytes from various
host plants. The main topics addressed are sources, identification, biological activity, biosynthesis, and ecological and
chemosystematic significance of those bioactive compounds whose sources were well defined.
Keywords: Endophytic fungi, bioactive natural products, anti-microbial, endophyte-host interaction.
1. Introduction 1% of earth’s bacterial species and less than 5 % of

Rationale for a search for novel natural products: fungal species are currently known [1]. While aspects
Presently, many large pharmaceutical companies of the soil environment have been studied over the
have abandoned their search for new anti-infectious years by the pharmaceutical industry it still appears
drugs despite an enormous upsurge in infections and that less than 1% of these microbes have been
deaths caused by drug resistant bacteria. cultured and characterized. Thus, even with this
Furthermore, the threat of human infecting fungi important microbial niche, challenges to find novel
remains an ever increasing problem especially in microbes remain. It appears that the ‘marine
AIDS patients and others who are immuno- ecosystem’ supports an array of novel microbial
compromised. Over the years, drug discovery has diversity that includes everything from the aqueous
focused on microbial sources where nearly 80% of environment to the deep ocean sediments [2,3]. Other
the world’s antibiotics have their origins [1]. These habitats housing microbes are numerous and varied.
sources have almost entirely been from soils It seems that any place on earth having the proper
collected from around the world, but new microbial support systems, even ones that are unusual or
habitats need to be examined for microbiota that unsuspected, will provide a niche for microbes,
produce useful bioactive compounds. Recent deaths including ones that are unseemly, such as those in
in the USA resulting from E. coli and other which the environment is extreme in temperature,
pathogens and the use of pesticides that may be pressure or salinity.
harmful to the environment suggest that new
processes and biologically derived products are Other promising habitats are the internal tissues of
needed to cope with the emerging problems in plants that supply protection and nutritional support
agriculture and food processing, storage and for microbes. The microbiota that live within plant
shipment. tissues are called “endophytes”, and cause no overt
symptoms of pathogenicity and bear no signs of their
While it may appear that the pharmaceutical industry presence in host plant tissues [4]. They live in inter or
has completely exhausted the hidden treasures of the intracellular spaces of the host plant including roots,
microbial world to find solutions to the infectious stems, leaves, flowers, and fruits. In most cases they
diseases of the last century, a report by the American are viewed as having a symbiotic relationship with
Academy of Microbiology estimates that less than the host, but, depending on conditions, they may also
1512 Natural Product Communications Vol. 4 (11) 2009 Verma et al.
eventually revert to some form of pathogenesis [5,6]. complexity of the interaction is believed to be
The most frequently isolated microbes from plant variable from host to host and microbe to microbe.
tissues are fungi, but bacteria, including the For example, the endophytic fungus, Helianthimum
actinomycetes, can exist as endophytes. Although chamaecistus, passes from one generation to another
these microbes can be easily obtained from most through the seeds, which remain dormant for a long
plant sources, the effectiveness of their recovery is time [12]. The fungus enters the developing plant
not known and thus many remain non-cultured. from the seed and spreads throughout the plant
systemically entering new tissues as they arise, and
The existence of endophytes has been known for over thus, in many cases the growth of host and the
a hundred years, but studies on these organisms endophytes become synchronous. The presence of
and their bioactive products is relatively sparse, endophytes supports germination and subsequent
until recently [7]. A great deal of the work on development of the seedling without which the plant
plant/endophyte relationships has been carried out on ceases to grow beyond a certain stage. In return, the
grasses, such as tall fescue [8]. Anti-herbivory was plant digests the swollen hyphae of the fungus that
noted in tall fescue grazed by livestock A major are found in the roots. In this case, the relationship is
international research effort focused on the behavior truly mutualistic in that the fungus must derive
of grazing animals in these areas. For many years nourishment from the host plant since it does not
work on endophyte biology and biochemistry was have direct contact with the environment. Similarly,
almost entirely dedicated to the fescue/endophyte endophytes that inhabit foraging grasses (e.g.
problem. Endophyte biology had a negative ryegrass) never leave their plant host and can only
connotation, since livestock were negatively affected reproduce by invading seed tissue of the plant [13].
by an endophyte, Neotyphodium sp., that produced a On the other hand, fungi that reside solely in the
toxin which discourages insects and other animals mycorrhizae of a plant always enter from the soil,
from feeding on this pasture grass [9]. generally causing no damage to the root system [14].
In the past decade endophytes have been studied as Some workers have suggested that in certain
sources of bioactive natural products. The primary instances, the host/plant relationship may be more
rationale for this approach is that since endophytes akin to a balanced pathogen-host antagonism than a
live in association with a eukaryotic host, they are truly symbiotic one [15]. Endophytic fungi might
less likely to make products that are toxic or contribute to the process of nutrient recycling by
otherwise harm host tissues [10]. Thus, the bioactive initiating the biological degradation of the dying host
products that they make to protect the host may prove plant [5]. There is some evidence that endophytes do
useful in human medicine, agriculture and industry. elicit a chemical reaction from the host plant despite
It is also the case that endophytes are numerous, and their largely benign relationship. As in Douglas-fir
many are undiscovered. In fact, of 135 endophytic seedlings, the plant produces resveratrol, which is a
fungi isolated in an upper Amazonian rainforest known anti-fungal agent in response to endophyte
nearly 10% were widely divergent from already infection [16]. Endophytes, of course, can be
know fungal genera and most were biologically involved in pathogenicity of host plants. The
active [11]. Thus, the chance for finding novel endophyte population in abnormally developed plant
bioactive endophytes is great. Generally, it seems to tissues, such as in galls and cysts, is often quite
be true that novel taxonomy may hold promise for different from other endophyte/host relationships
novel chemistry. [17]. Overall, it seems there is no question that both
the endophyte and its host govern the outcome of the
2. The complexities of the host-endophyte relationship by virtue of the products made by both
relationship organisms.
Some understanding of the biology of the
endophyte/host relationship is instructive before 3. Endophytes, natural products, and bioactive
launching into an endophyte discovery program. compound discovery
Overall, the host/endophyte relationship seems to be Probably humans have always relied on various
highly integrated and specialized since a foreign remedies for treating maladies. Nature has
microorganism lives within and between the cells of traditionally been the ultimate source of substances
the tissues of a higher plant. Generally, the endophyte that reduce human suffering. Aspirin, the world’s
is restricted in some manner by the host. The best known and most universally used medicinal
Bioactive natural products from fungal endophytes Natural Product Communications Vol. 4 (11)2009 1513
agent, is analogous to ‘salicin’ having its origins in [25]. The hypothesis proposed to explain why T.
the plant genera Salix and Populus. [18]. Today, andreanae produced taxol was a genetic
many of the world’s tribal peoples have a better recombination of the endophyte with the host that
understanding of native medicinal flora than that in occurred during a long evolutionary symbiosis. Thus,
modern medical textbooks. if endophytes can produce the same rare and
important bioactive compounds as their host plants,
Some of the most erudite peoples in this regard are this would not only reduce the need to harvest slow-
those in the Amazon basin, the highlands of Papua growing and possibly rare plants, but also help to
New Guinea, and the Aborigines of Australia, each of preserve the world’s ever-diminishing biodiversity.
which have their own pharmacopeia of medicinal Taxol interacts with tubulin during the mitotic phase
knowledge [19]. Thus, this basic tribal knowledge of the cell cycle, and prevents the disassembly of the
can serve as a starting point for modern drug microtubules and thereby interrupts cell division [26].
discovery. Natural products are now rapidly finding a The original target diseases for this compound were
place in modern drug development. About 40% of ovarian and breast cancers, but now it is used to treat
prescription drugs are based on natural products. a number of other human tissue proliferating diseases
Furthermore, over 50% of the new chemical products (carcinomas) as well [18]. The discovery of
registered by the FDA from 1981-2002 as anticancer, endophytic fungi making taxol sparked interest in the
anti-migraine, and antihypertensive agents are either prospects and possibilities that some of the world’s
natural products or their derivatives [20]. Excluding medicinal plants may possess biological activities
the biologicals, from 1989-1995, 60% of approved that are more related to their endophytes than the
drugs and pre-new drug application (pre-NDA) plant itself. However, in the case of taxol, both the
candidates were of natural origin [21]. From 1983 to endophyte and the plant make this important drug.
1994, over 60% of all approved and pre-NDA stage This original report was followed up with at least 30
cancer drugs were of natural origin, and so too were additional reports in which numerous cases were
78% of all newly approved antibacterial agents. At found of various endophytic fungi making taxol
least 21 natural products and natural product-derived [27-30]. While to-date, none has been domesticated
drugs have been launched onto the market in the to serve as a source of this important drug, the future
United States, Europe or Japan since 1998 and there holds promise that eventually fungi will serve as a
are many natural product-derived compounds in source of taxol.
either Phase III or under registration that may be
launched in the coming years [22]. Several years ago, with the advent of new competing
methodologies for drug discovery, such as
O
combinatorial chemistry and high throughput
O
O O OH screening, natural products discovery began to be
dismissed as a source of new bioactive compounds.
NH O
Now, however, there is a resurgence of interest in
O
O
O
natural product based discoveries. These compounds
HO
OH
O
are now finding world-wide interest because of their
O
O low toxicity, their complete biodegradability, their
availability from renewable sources, and, in most
Taxol (1) cases, their low cost when compared with those of
compounds obtained by total chemical synthesis [31].
Examples that illustrate the significance of natural Certainly, one source of novel bioactive natural
products from plants and microorganisms in modern products is the world’s endophytes and the report on
civilization include taxol (1), the world’s first billion taxol, described above, was a key example. For
dollar anticancer drug [23,24]. Some plants instance, Tan and Zau point out that, in comparison
generating bioactive natural products have associated with fungal plant pathogens and fungal soil isolates,
endophytes that produce the same natural products. relatively few secondary metabolites have been
This is the case with taxol (1), a highly functionalized isolated from endophytic fungi and there are
diterpenoid that is found in each of the world’s yew immense opportunities for finding new bioactive
tree species (Taxus sp.) [23]. In 1993, a novel taxol- metabolites [32]. Currently, endophytic fungi and
producing endophytic fungus, Taxomyces andreanae, bacteria are viewed as outstanding sources of
from Taxus brevifolia, was isolated and characterized bioactive natural products because so many of them
are occupying literally millions of unique biological endophytic fungi and their potential in the
niches (higher plants) growing in many unusual pharmaceutical and agrochemical arenas. Each
environments. Each plant has been reported to compound is listed with some aspect of its chemistry
harbor one or more endophytes [33,34], thus having and biological activity.
unique endophytic microbial suites. Furthermore,
endophytes commonly produce bioactive secondary 5. Earlier work on bioactive metabolites from
metabolites when placed in culture. endophytes
A large number of secondary metabolites have been
4. Chemical footprints of natural bioactive extracted, isolated and characterized from endophytic
products from endophytes microbes, especially from fungal endophytes, and
Since the discovery of endophytes in Darnel, some of these have been discussed in detail in earlier
Germany, in 1904, there has been a general search for reviews [32,35,36]. Many of these compounds are
them, mostly in plants in temperate regions, with the bioactive, and include alkaloids, steroids, terpenoids,
majority of the literature dealing with the isolation peptides, polyketones, flavonoids, quinols and
and identification of these organisms from various phenols, as well as some chlorinated compounds.
plants. Until 15-20 years ago, only limited and
infrequent attempts had been made to isolate any Cryptocandin A (2) is an antifungal lipopeptide that
secondary products from these organisms that may was isolated and characterized from the endophytic
have potential for either medicine or agriculture. fungus, Cryptosporiopsis quercina [40]. This
Endophytic fungi are a unique treasure of bioactive compound contains a number of unusual
compounds, because so many of them inhabit hydroxylated amino acids and a novel amino acid, 3-
literally millions of unique biological hosts growing hydroxy-4-hydroxymethylproline. Cryptocandin A is
in unusual environments. While some plants active against some important human fungal
generating bioactive natural products have associated pathogens including Candida albicans and
endophytes that produce the same natural products, Trichophyton sp. and also against a number of plant
such as taxol described above, endophytes do pathogenic fungi, including Sclerotinia sclerotiorum
produce many bioactive compounds that are unique and Botrytis cinerea. Cryptocin (3), a tetramic acid, is
and useful. A search is underway to find, and an antifungal compound also obtained from C.
describe endophytes and their products. The greatest quercina. This unusual compound possesses potent
potential for success is to search in areas of high activity against Pyricularia oryzae, the causal
biological diversity, such as the tropics and organism of one of the nastiest plant diseases in the
semitropical areas of the earth. world, as well as a number of other plant pathogenic
fungi [41].
New organisms and many novel natural products
from endophytic fungi inhibit or kill a wide variety of Pestalotiopsis spp. exist in most of the world’s
harmful microorganisms like bacteria, fungi, viruses, rainforests and are extremely biochemically diverse.
and protozoans that affect humans and animals [32]. Thus, isolating any given strain does not imply that it
Endophytes do produce secondary metabolites in will produce the same products as any other strain or
culture, but the temperature, the composition of the isolate. Some examples of products coming from this
medium, and the degree of aeration will affect the group of endophtyes are herein described. Ambuic
amount and kinds of compounds produced [18], acid (4) is a highly functionalized cyclohexenone
including steroids, xanthones, phenols, isocoumarins, possessing antifungal activity, and is produced by a
perylene derivatives, quinines, furandiones, number of isolates of P. microspora [42]. A strain of
terpenoids, depsipeptides, and cytochalasines P. microspora, isolated from the tree, Torreya
[32,35,36]. taxifolia, produces several compounds having
antifungal activity, including the glucosylated
Some of these represent novel structural groups, aromatic compound pestaloside (5) [43]. P. jesteri is
for example, the palmarumycins [37,38] and a newly described endophytic fungal species from the
benzopyranones [39]. Endophytes may contribute to Septik river area of Papua New Guinea, and produces
their host plant by producing a plethora of bioactive the highly functionalized cyclohexenone epoxides,
substances to provide protection which ultimately jesterone (6) and hydroxyjesterone. These epoxides
aids in the survival of the host plant. Described below exhibit antifungal activity against a variety of plant
are some examples of bioactive products from pathogenic fungi [44].
OH H3C CH3
HO
CH3
H
OH
O
O
HO H H
HO OH H2C
O O O
H OH
CH3
N O
N OH
H 2N
H OH HO
OH
O N
N O O OH O
O
HO H
H
O O
HO H
OH NH OH
HN
Pestacin (8) Isopestacin (9) Subglutinol A (10)
OH NH
OH
O
OHC OHC
(CH 2 ) 14
O O
Cryptocandin A (2)
O Me
N H OH
HO HO
O O
O
Me Me Periconicin A (11) Periconicin B (12)
H
O OH
O
Me
Me
The endophytic fungus, Fusarium subglutinans,
H OH produces the immunosuppressive, but non-cytotoxic
Cryptocin (3) Ambuic acid (4) diterpene pyrones, subglutinols A (10) and B. Two
HO new fusicoccane diterpenes, named periconicin A
O
O
(11) and B (12) with anti-fungal as well as
HO
HO OH
O
O
antibacterial activities were isolated by bioassay
H3C
OH guided fractionation from an endophytic fungus
OH HO Periconia sp., collected from small branches of Taxus
Pestaloside (5) Jesterone (6) cuspidata [48]. Periconicins have an array of
Me
HO2C
biological properties including antimycotic activities
HO2C O
Me O
O against the agents of human mycoses, Candida
O
H
Me
albicans, Trichophyton mentagrophytes, and T.
O
rubrum. These compounds also possess plant growth
O
O
O H
H
regulatory activities, inhibition of hypocotyl
H elongation and root growth of Brassica campestris
and Raphanus sativus [49].
Me
Torreyanic acid (7) Camptothecin (13) was first isolated from the wood
of Camptotheca acuminata Decne (Nyssaceae),
Torreyanic acid (7), a selectively cytotoxic quinone which is a plant native to mainland China [50].
dimer and potential anticancer agent, was isolated Camptothecin and its derivatives show strong
from a P. microspora strain obtained from T. antineoplastic activity. The drug is already used in
taxifolia (Florida torreya) [42,45]. After being tested China for the treatment of skin diseases. Recently,
against several cancer cell lines, torreyanic acid camptothecin (13) has been obtained from fungal
demonstrated 5 to 10 times more potency in those endophytes isolated from the inner bark of the plant
cell-lines that are sensitive to protein kinase C Nothapodytes foetida from the western coast of India.
agonists and caused cell death by apoptosis. Pestacin The endophytic fungus, which belongs to the family
(8) and isopestacin (9) have been obtained from Phycomycetes, produced camptothecin when grown
culture fluids of P. microspora, an endophyte isolated in a synthetic liquid medium (Sabouraud broth) under
from the Combretaceaous tree, Terminalia shake flask and bench scale fermentation conditions.
morobensis [46,47]. Both pestacin (8) and isopestacin The biological activity of this compound was tested
(9) display antimicrobial as well as antioxidant using an in-vitro cytotoxicity assay against human
activities. It is suspected that many additional cancer cell lines (A-549 for lung cancer, HEP-2 for
biologically active compounds are to be discovered in liver cancer, OVCAR-5 for ovarian cancer) in
the Pestalotiopsis group of endophtyic fungi. comparison with the standard authentic example and
shown to be identical [51].
O
N O O O
N O
OH
OH O
O
CH3 OMe
H3 C O N O
H O OH OH O
HO
O O CH3
O
Camptothecin (13) Cytochalasins (14) OH O
MeO
H3C O OH O
Guignardic acid (19) Xanthoviridicatin E (20)
H3C O O O
CH3 O
OCH3
H3C O O CH3
OH O OH OH O OH
O CH3 HO O
O
OH O O
H3CO O OH O HO
MeO O
Rubrofusarin B (15) Fonsecinone A (16) Xanthoviridicatin F (21) Phomol (22)

H3C H3C O OH O
OH
H3C O O
OH
O H3C O O CH3
OH O OH
H3C O O CH3 O
H3C O OH
H3C O O CH3 OH
O O
O CH3 O O
OH OH O
O
Microcarpalide (23) Paranolin (24)
OH O H3C
Asperpyrone B (17) Asperpyrone A (18) OH
O
Some alkaloids produced by endophytic fungi are
HO
also anticancer agents. Wagenaar et al. isolated three O
novel cytochalasins (14) from an endophyte

Rhinocladiella sp. with potential antitumor activity OH
Phomosine G (25) Vincristine (26)

against selected neoplastic cell lines [52] Song et al.
reported that they obtained four known naphtho-γ-
pyrones, rubrofusarin B (15) fonsecinone A (16), two novel quinine related metabolites produced by an
asperpyrone B (17), and aurasperone A (18) by endophytic Penicillium chrysogenum colonizing an
fractionation of the extract of Aspergillus niger unidentified plant. These metabolites inhibit the
IFB-E003, an endophyte of Cynodon dactylon. cleavage reaction of HIV-1 integrase with IC50 values
Rubrofusarin B (15) is cytotoxic to the colon of 6 and 5 uM, respectively [55]. Phomol (22)
cancer cell line SW1116 (IC5O: 4.5 µg mL-1), and is a novel polyketide lactone from Phomopsis sp.,
aurasperone A (18) is inhibitory to xanthine oxidase present in the medicinal plant Erythrina crista-galli
(XO) (IC50: 10.9 µM). Moreover, the four naphtho-γ- [56]. Microcarpalide (23), a novel microfilament-
pyrones exhibited growth inhibition against the five disrupting agent with weak cytotoxicity to
test microbes with MICs ranging between 1.9 and mammalian cells, was characterized from an
31.2 µg mL-1. The recognition of rubrofusarin B and unidentified fungus in Ficus microcarpa L [57]. A
aurasperone A as strong co-inhibitors of the XO, new xanthene based metabolite, paranolin (24) was
colon cancer cell line, and some microbial pathogens characterized from an endophytic strain of
is of significance since it signals the relevance of Paraphaeosphaeria nolinae IFB-E011 from
endophytic compounds as potential therapeutic Artemisia annua, (Asteraceae) [58].
agents [53].
Recently, a novel compound from a Phomopsis sp.
Guignardic acid (19) was detected in the culture endophytic on Adenocarpus foliolosus was isolated
broth of an endophytic Guignardia sp. obtained from and identified as phomosine G (25) [59]. Two
Spondias mombin [54]. The oxidative deamination anticancer indole derivatives, vincristine (26) and
products of L-valine and L-phenylalanine chaetoglobosin A (27), have been purified from
(dimethylpyruvic acid and phenylpyruvic acid Fusarium oxysporum, an endophyte of Catharanthus
respectively) are biogenetic precursors of this roseus (L.) G. Don, and Chaetomium globosum
metabolite. Xanthoviridicatin E (20) and F (21) are in Maytenus hookeri [60,61]. Thus, this is another
HO
example of an endophytic fungus producing an OH HO OH
O
O
O
important drug (the anticancer drug vincristine) that H3CO
HO
O
OH
OCH3 H3CO
O OH
OH
OCH3
had already been identified from its plant host. (-)-

Oocydin A (28) is a unique chlorinated macrocyclic O
O
O
O
lactone isolated from an endophytic bacterial strain of OH

OH
OH
OH
Serratia marcescens occurring both as an endophyte Cytoskyrin A (34) Cytoskyrin B (35)

and as an ephiphyte of the aquatic plant Rhyncholacis
antibacterial activity. The bisanthrones cytoskyrin A
penicillata. The potential of oocydin A as an
(34) and B (35), have been obtained from Cytospora
agrochemical to control oomyceteous fungi,
sp. CR200, a fungal strain endophytic in Conocarpus
including Pythium and Phytopthora spp., is currently
erecta. Of these, only cytoskyrin A (34) was active in
being evaluated [62].
the biochemical induction assay (BIA), a rapid
colorimetric bacterial assay used to identify
The previously known macrolide fungal metabolite
compounds that either damage DNA or inhibit DNA
brefeldin A (29), with a wide range of biological
synthesis and thus have potential as natural product
activities, occurs in Aspergillus clavatus and
anticancer agents [67].
Paecilomyces sp. endophytic in Chinese Taxus mairei
and Torreya grandis [63]. Mutualism developed Three new preussomerins, including preussomerin L
between these organisms and it has been suggested (36), have been reported from Mycelia sterilia, a
that brefeldin A is used to protect the host plant from fungus endophytic in Atropa belladonna [68]. A new
bacterial infection and from predation by insects and benzophenone, named rhizoctonic acid (37), together
animals. It was proposed that this compound may with three known compounds, monomethylsulochrin,
also affect the normal function of the secretory ergosterol, and 3β,5α,6β-trihydroxyergosta-7,22-
system of plant cells by inhibiting vesicle formation diene, were isolated through bioassay-guided
at the Golgi apparatus [64]. Graphislactone A fractionation from the culture of Rhizoctonia sp.
(30), botralin (31) and ulocladol (32) are (Cy064), an endophytic fungus in the leaves of
acetylcholinesterase (AChE) inhibitors, isolated from Cynodon dactylon [69]. Trichodion (38), a novel
an endophytic Microsphaeropsis olivacea, originally bioactive pyrone antibiotic, was isolated from an
obtained from Pilgerodendron uviferum, a endophytic Trichoderma sp. This novel bioactive
gymnosperm [65]. New octaketides, termed pyrone has a wide range of activity against potential
cytosporones (33), have been reported from two pathogenic microbes [70]. Methyltriacetic lactone
endophytic fungal strains CR 200 (Cytospora sp.) (39) and altersolanol A (40) were isolated from
and CR 146 (Diaporthe sp.) isolated and collected in endophytic Ampelomyces sp., obtained from the
Costa Rica [66,67]. Of these, only those metabolites medicinal plant Urospermum picroides and exhibited
with a trihydroxybenzene lactone moiety exhibited considerable cytotoxic activity when tested in vitro
H3C
O Me
against L5178Y mouse lymphoma cells [71,72].
H3C
O
H
OAc O H
H
CH3
H
HH
OH
Me
Enfumafungin (41) is a new antifungal triterpenoid
N COOH
NH H O O
H
CH3
glucoside produced by Hormonema sp. (ATCC
O H
O OH
Cl
H 74360), a fungus endophytic in Juniperus communis
Chaetoglobosin A (27) (-)-Oocydin A (28) [73]. The interesting antifungal spectrum exhibited
OH O
by ergosterol (42) and its effect on the morphology of
OH Aspergillus fumigatus was shown to be comparable to
H O O
O
Me OH
that of the glucan synthase inhibitor pneumocandin
HO
H
H3CO B. This finding has led to an extensive search for
H Me OMe other Hormonema isolates from different geographic
Brefeldin A (29) Graphislactone A (30) locations and potential producers of enfumafungin
O
(41) and helvolic acid (43). Colletorin B (44) and its
OH O
O OH
HO
chlorinated analogue, colletochlorin B, are
O
Me CO2R1
acetylcholinesterase (AChE) inhibitors. These
R2
H3CO
HO OMe MeO
compounds were isolated from Nectria galligena, a
OH OMe
O OH OH O fungus endophytic in Malus domestica [74].
Botralin (31) Ulocladol (32) Cytosporones (33)
O
latest advances in the area of bioactive natural
OH
products from endophytic microbes.

HO
OH O CO2R2
O O O H3C
R1 O O CH3
OH
6.1 Antimicrobial compounds from fungal
OH endophytes
O OMe O O
Preussomerin L (36) Rhizoctonic acid (37) Trichodion (38) Many new natural products are reported to have
bioactivity against pathogenic microbes (fungi,
O OH
H3C O
OH bacteria, protozoa and human pathogens) and might
OH
CH3
serve as novel lead compounds for new drugs.
OH
OH O OH
O O
6.1.1 Anti-fungal
Methyltriacetic lactone (39) Altersolanol A (40)
CO2H
Me
An endophytic fungal strain from Torreya mairei
OH
Me
Me
was identified as Aspergillus clavatonanicus by
Ac H
OH
O
Me
Me analysis of its morphological characteristics and
O
HO O
O Me the sequences of the internal transcribed spacers
HO OH
Me HO
(ITS) of rDNA. When grown in surface culture, the
fungus produced clavatol (46) (2′,4′-dihydroxy-3′,5′-
Enfumafungin (41) Ergosterol (42)
dimethylacetophenone) and patulin (47) (2-hydroxy-
HOOC
Me
3,7-dioxabicyclo [4.3.0] nona-5,9-dien-8-one) as
Me
OH
shown by NMR, MS, X-ray, and EI-MS analysis.
Me Me OAc OHC Both exhibited inhibitory activity in vitro against
H Me several plant pathogenic fungi, i.e., Botrytis cinerea,
O
H
OAc OH
Didymella bryoniae, Fusarium oxysporum f. sp.
Me O R
cucumerinum, Rhizoctonia solani, and Pythium
Helvolic acid (43) Colletorin B (44)
ultimum [77]. Pestafolide A (48), a new reduced
O
spiroazaphilone derivative, and pestaphthalides A
(49) and B (50), two new isobenzofuranones, have
O
been isolated from solid cultures of an endophytic
H
HO
isolate of Pestalotiopsis foedan. Its organic solvent
Nodulisporic acid A (45) extract displayed antifungal activity against Candida
albicans (ATCC 10231), Geotrichum candidum
Reinvestigation of Nodulisporium sp., endophytic in (AS2.498), and Aspergillus fumigatus (ATCC 10894)
Bontia daphnoides and known to produce the indole [78].
terpenoid nodulisporic acid A (45), has afforded two
O
novel insecticides, nodulisporic acid A1 and A2 that OH O
H3C
H3C
are structurally related to nodulisporic acid [75]. The CH3 O
HO O
nematicidal alkaloid peniprequinolone, first isolated O

O HO
O
from the soil fungus Penicillium cf. simplicissimum HO

CH3 CH3
OH
[76] has been found in P. janczewskii, a fungal
endophyte of the Chilean gymnosperm Prumnopitys Clavatol (46) Patulin (47) Pestafolide A (48)
andina. OH
O
OH
O
H3C H3C
6. Recent discoveries of bioactivities in endophytic O O
microbes HO HO
CH3 CH3
HO
We began this review using specific examples of HO
endophytes that produce biological active compounds Pestaphthalides A (49) and B (50)
from years past. Recently, workers world-wide have
shown interest in this field with implications in Four new 10-membered lactones (51-54) were
medicine, agriculture and industry. It is desirable to isolated from the broth extract of an endophytic
identify the products of the organism and its host fungus Phomopsis sp. YM 311483, obtained from the
plant. It is also desirable to have these organisms stem of Azadirachta indica. These lactones were
available locally or nationally. Below are some of the evaluated for their antifungal activity against seven
O CH3
CH3 OH OH
O O
O O OH
OH
O
O R2
O O O
O
CH3 O O
H2N R1
O CH3 O CH3 O CH3
7-amino-4-methylcoumarin (59) Xylarosides (60-61)

(51) (52) (53)
R1 R2
O CH3 60 OH O glu
CH3
N
61 O glu OH
O
H
O NH2 O O O O
Me H OH
OH O O O
H3C O
O OH
O O H3C H H
H3C
O
O O
CH3
O Me
O CH3 CH3 CH3 OH CH3
CHO Me H3C O
(54) solanapyrone N (55) solanapyrone O (56)
Sordaricin (62) Monocerin (63)
O
typhi (20 μg mL−1), Salmonella typhimurium (15 μg

O NH
OH
mL−1), Salmonella enteritidis (8.5 μg mL−1),
O
Aeromonas hydrophila (4 μg mL−1), Yersinia sp.
H3C H CH3
(12.5 μg mL−1), Vibrio anguillarum (25 μg mL−1),
H3C
O
O Shigella sp. (6.3 μg mL−1), Vibrio parahaemolyticus
CH3 H (12.5 μg mL−1), Candida albicans (MIC, 15 μg
Solanapyrone C (57) Nigrosporalactone (58) mL−1), Penicillium expansum (40 μg mL−1), and
Aspergillus niger (25 μg mL−1) [81].
plant pathogens, Aspergillus niger, Botrytis cinerea,
Fusarium avenaceum, F. moniliforme, The glucoside derivatives, xylarosides A (60) and B
Helminthosporium maydis, Penicillium islandicum, (61), were isolated from the broth extract of the
and Ophiostoma minus, using the dose-dependent endophytic fungus Xylaria sp. PSU-D14, along with
paper-disk diffusion method, and all five compounds two known compounds, sordaricin (62) and 2,3-
showed weak antifungal activities. Compound 52 was dihydro-5-hydroxy-2-methyl-4H-1-benzopyran-4-
the most potent, with MIC values in the range 31.25- one. Sordaricin (62), one of the known metabolites,
500 μg mL-1. Interestingly, compound 52 was more exhibited moderate antifungal activity against
active than compound 51, even though their Candida albicans ATCC 90028 with a MIC value of
structures differed only in the position of the acetoxy 32 µg mL-1 [82]. An endophytic fungus,
substituent [79]. Microdochium bolleyi (strain no. 8880), isolated from
Fagonia cretica, a herbaceous plant of the semiarid
Two new solanapyrone analogues, solanapyrones coastal regions of Gomera was investigated for
N and O (55-56) and three known compounds, biologically active secondary metabolites. The crude
solanapyrone C (57), nigrosporalactone (58) and ethyl acetate extract of the culture showed very good
phomalactone (59), were isolated from the antifungal activity against Microbotryum violaceum
fermentation culture of Nigrospora sp. YB-141, an and moderate algicidal activity against Chlorella
endophytic fungus isolated from Azadirachta indica fusca. Fractionation led to the known monocerin (63),
A. Juss. Most of the compounds exhibited either no together with two new analogues and a ring-opened
or only weak antifungal activities [80]. derivative [83]. Blennolides A-G, seven unusual
chromanones, were isolated together with secalonic
An endophytic Xylaria sp., having broad spectrum acid B from Blennoria sp., an endophytic fungus
antimicrobial activity, was isolated and characterized from Carpobrotus edulis. Preliminary studies showed
from Ginkgo biloba L. From the culture extracts of strong antifungal and antibacterial activities of these
this fungus, a bioactive compound, P3, was isolated compounds against Microbotryum violaceum and
by bioactivity guided fractionation and identified as Bacillus megaterium, respectively. They were also
7-amino-4-methylcoumarin (59). The compound active against the alga Chlorella fusca and the
showed strong antibacterial and antifungal activities bacterium Escherichia coli [84]. The metabolites of
in-vitro against Staphylococcus aureus (MIC,16 μg an endophytic Penicillium sp. from the leaf of
mL−1 ), Escherichia coli (10 μg mL−1 ), Salmonella Hopea hainanensis, obtained by bioassay-guided
OH
fractionation of the EtOAc extract of a solid-matrix O
CH3
steady culture of the fungus, afforded six compounds, H3C
identified as monomethylsulochrin (64), rhizoctonic O
CH3
acid (37), asperfumoid (65), physcion (66), 7,8- O OH O
dimethyl-iso-alloxazine (67) and 3,5-dichloro-p- Javanicin (68)

anisic acid. Compounds 66 and 67 were obtained
from a Penicillium sp. for the first time. The in vitro HO
O
bioactive assays showed significant bioactivity H
against three human pathogenic fungi, Candida HO
H
HO
O
albicans, Trichophyton rubrum and Aspergillus niger O OCH3

H3CO H3CO
and cytotoxic activity against the human
OH O
Botryomaman (69) Primin (70) Mellein (71)

nasopharyngeal epidermoid tumor KB cell line, and
the human liver cancer HepG2 cell line. Compounds CH3 O OH O
NH +
64-67 inhibited the growth of C. albicans with H3C NH
CH3 HO O N
O
-
MICs of 40, 20, 50 and 15 µg mL-1. In addition, 67 OH O CH3 O

exhibited cytotoxic activities against KB cell line Phomoenamide (72) Phomonitroester (73)
with an IC50 value of 30-5.0 µg mL-1 and against
HepG2 cell line with an IC50 value of 30-10 µg mL-1
O
OH HO O CH3
[85]. HO O OH
O O OH O CH3
OH
CH3
O O O OH
MeO OH O
O O H3C OH O
OH OH OH
H3C O
OMe O H3C R O
H3C O OH
O
O CH3
O O
H3C OH OMe
O O
H3C CH3 Me N
H
O (74-75) Dicerandrol A (76)
74 R= H
monomethylsulochrin (64) Asperfumoid (65) 75 R=COCH3
OH O OH OH H
H3C OH
Me N N O
HO
N
H3COC Me Me N H
O O H3C
OH
Physcion (66) 7,8-dimethyl-iso-alloxazine (67)
H3C
(77)
6.1.2 Anti-bacterial
The endophytic fungus Chloridium sp., produces methicillin-resistant S. aureus SK1. Primin (70)
javanicin (68) under liquid and solid media showed the activity against both strains with equal
culture conditions. This highly functionalized MIC values of 8 µg mL-1 [88]. Three metabolites
naphthaquinone exhibits strong antibacterial activity named phomoenamide (72), phomonitroester (73)
against Pseudomonas spp., pathogens to both humans and deacetylphomoxanthone B (74), have been
and plants. The compound was elucidated by X-ray reported from an endophytic fungus Phomopsis sp.
crystallography to confirm the structure determined PSU-D15, together with four known compounds,
by standard spectroscopic methods [86]. phomoxanthone B (75), dicerandrol A (76),
(1S,2S,4S)-p-menthane-1,2,4-triol (77) and uridine.
New octaketide, cytosporone A (33), has been Phomoenamide (72) exhibited moderate in vitro
reported from two endophytic fungal strains CR 200 antimycobacterial activity against Mycobacterium
(Cytospora sp.) and CR 146 (Diaporthe sp.) [66,87]. tuberculosis H37Ra [89]. The crude ethyl acetate
One new dihydrobenzofuran derivative, extract of the broth showed interesting
botryomaman (69), was isolated from the broth antimycobacterial activity against M. tuberculosis
extract of the endophytic fungus Botryosphaeria H37Ra, with a minimum inhibitory concentration
mamane PSU-M76 along with six known (MIC) value of 0.195 µg mL-1. Only compound 76
compounds, 2,4-dimethoxy-6-pentylphenol, primin was tested for this activity and exhibited an MIC
(70), mellein (71), cis-4-hydroxymellein, trans-4- value of 6.25 µg mL-1. Phomoxanthone B (75), the
hydroxymellein and 4,5-dihydroxy-2-hexenoic acid. diacetate analogue of (74), had the same MIC value
All compounds demonstrated antibacterial activity as phomoenamide (72) [90].
against Staphylococcus aureus ATCC 25923 and
6.2 Anti-cancer OH
O O
Two novel benzoquinone metabolites, 2-chloro-5- O

methoxy-3-methylcyclohexa-2,5-diene-1,4-dione OH
O
(78) and xylariaquinone A (79), together with the O O
O OH O
known compound 80, were isolated from an O
endophytic Xylaria sp. Compounds 78 and 79 OH
OH
showed in vitro activity against Plasmodium O O OH O
falciparum K1 strain, with IC50 values of 1.84 and Nigerasperone A (89) Nigerasperone B (90)
6.68 μM and cytotoxicity against African green
OH O
monkey kidney fibroblasts (Vero cells) with IC50 O
values of 1.35 and >184 μM, respectively [91]. Six OH
new tetramic acids derivatives, penicillenols A1, A2, O O

O
HO O
B1, B2, C1, and C2 (81-86), together with citrinin, OH OH
OH O
phenol A acid, phenol A and dihydrocitrinin were OH O
identified from Penicillium sp. GQ-7, an endophytic O
fungus associated with Aegiceras corniculatum. All O O
the new compounds were evaluated for their O
cytotoxic effects in four cell lines by the MTT Nigerasperone C (91) Excelsione (92)
bioassay. Penicillenols A1 (81) and B1 (83) showed

cytotoxicity against the HL-60 cell line with IC50 Two new cyclic depsipeptides, 1962A (87) and
values of 0.76 mM and 3.20 mM, respectively [92]. 1962B (88), along with three known cyclodipeptides,
O
cyclo-(Leu-Tyr), cyclo-(Phe-Gly), and cyclo-(Leu-
O Me O Me
O Leu), were isolated from the fermentation broth of
Me Me
OMe
HO
OMe
the mangrove endophytic fungus (No. 1962) isolated
Cl H
H
HO H from an old leaf of Kandelia candel collected in
O
O H OMe O Hong Kong. Both of these new cyclo-depsipeptides
(78) Xylariaquinone A (79) (80) were found to contain one D-amino acid. In the MTT
Me
O O bioassay, 1962A (87) showed weak activity against
Me
N OH N OH human breast cancer MCF-7 cells [93].
Me Me
OH
O Me
OH
O Me Three new naphtho-γ-pyrones, nigerasperone A-C
Penicillenols A1 (81) Penicillenols A2 (82) (89-91), together with nine related known compounds
O were characterized from Aspergillus niger EN-13, an
Me
O H3C OH
CH3 endophytic fungus isolated from the marine brown
N
N OH
alga Colpomenia sinuosa. In the cytotoxic assay,
Me H O these compounds did not show remarkable inhibitory
O Me
H CH3
effects against A549 and SMMC-7721 tumor cell
Penicillenols B1 (83) Penicillenols B2 (84) lines. However, 91 and several known compounds
O
O showed weak antifungal activity against Candida
Me
Me
N OH N OH albicans and moderate activity for DPPH scavenging
[94]. A new tetracyclic depsidone, excelsione (92),
HO Me
Me
O Me
OH
O Me was isolated from the extract of an unidentified
fungal endophyte obtained from the New Zealand
Penicillenols C1 (85) Penicillenols C2 (86)
endemic tree Knightia excelsa. Structurally,
D-Leu
D-Leu excelsione (92) belongs to the depsidones, a group of
O
H
N
O
Gly-2
H O
Gly-2
secondary metabolites more commonly found in
lichens than in fungi lacking an association with
O N
phytobionts. Excelsione (92) was inactive against

O
O
O
NH
L-Tyr P388 murine leukemia cells at 12.5 µg mL-1 and in
S-O-Leu O
disk agar diffusion assays against various bacterial

NH
HN S-O-Leu O
HN
O
and fungal strains using 40 µg of the compound per

N
H OH O
N
H
O
L-Phe
disk [95].
O
Gly-1
L-Val Gly-1 L-Val
1962A (87) 1962B (88)

O OH O OH HO O
O OH
(CH2)6 CH3
MeO OEt
O O O O O O O O O
CH2
OH O CH3
Phomopsin C (104)
H3C
O O O
CH2
O
Preussomerin EG1 (93), Preussomerin EG2 (94) Preussomerin EG3 (95)
HO
O O
O
OH O CH3 O CH3 H
HO O O
CH3 HO
H H
O H H H
OH H3C O
H3C O OH OH H
O O H
Leptosphaerone C (96) Penicillenone (97)

Xyloketal B (105) Xyloketal J (106)
H O O
O
OH HO OH
O CH2
O OH
O HO O
O
O
O O O
CHO H OH
O H2C
OH OH O
CH3
Arugosin I (98) FR-901235 (99) Nectriapyrone (100) Xyloester A (107) Xyloallenolid B (108)
OH O OH OH
O
O O O HO
O O CH2OH
OH O
O CH3 O
O OH O
HO
HO HO O
R1
Tyrosol (101) Phomopsin A (102) Phomopsin B (103) H3C
H
CH3 R2
Chemical investigation of the mycelium of Edenia (109) (110) (111-114)

R1 R2
gomezpompae, a newly discovered endophytic 111 H2 H
fungus isolated from the leaves of Callicarpa 112 O H
acuminata (Verbenaceae) collected from the 113 α-OH β-H, H
114 H2 OH
ecological reserve El Eden in Mexico, produced four
T leukemia cells and B16F10 melanoma cells.
naphthoquinone spiroketals, three new ones
It is noteworthy that nectriapyrone (100) showed
preussomerin EG1 (93), preussomerin EG2 (94) and
higher activity than methotrexate on both tumor
preussomerin EG3 (95) and the known palmarumycin
cell lines. Nectriapyrone also showed selectivity to
CP2 [96].
the tumor cells, because it did not show a remarkable
cytotoxic effect towards normal peripheral blood
Four polyketides, leptosphaerone C (96),
mononuclear cells (PBMC) (IC50 = 2667 μg mL−1)
penicillenone (97), arugosin I (98) and 9-demethyl
between those of the positive controls methotrexate
FR-901235 (99), were isolated from the Penicillium
(IC50 = 3709 μg mL−1) and gemcitabine (IC50 =
sp. JP-1, an endophytic fungus isolated from
1381 μg mL−1). The higher activity of the crude
Aegiceras corniculatum. Leptosphaerone C (96)
extract VA1A (IC50 249 μg mL−1) compared with that
shows cytotoxicity against A-549 cells with an IC50
observed for nectriapyrone (476.4 μg mL−1) towards
value of 1.45 μM, while penicillenone (97) showed
JURKAT cells could be related to synergistic activity
cytotoxicity against P388 cells with an IC50 value of
between fatty acid derivatives present in the extract
1.38 μM [97]. Glomerella cingulata was the most
and nectriapyrone [98]. Three metabolites,
common endophytic fungus associated with Viguiera
phomopsin A (102), B (103) and C (104), together
arenaria. For this reason, the cytotoxic extract was
with two known compounds, cytosporone B and C,
selected for chemical studies, leading to the isolation
were isolated from the mangrove endophytic fungus,
and identification of the bioactive compound
Phomopsis sp. ZSU-H76 obtained from the South
nectriapyrone (100) and also of tyrosol (101) [98].
China Sea [99]. Metabolites, named xyloketal B
(105), xyloketal J (106), xyloester A (107), and
Tyrosol (101) was inactive, but nectriapyrone had
xyloallenolid B (108), were isolated from the
significant cytotoxic activity against both JURKAT
mangrove endophytic fungus Xylaria sp. [100].
OH O
OCH3
OH
CH3
6.4 Anti-viral metabolites
N
NO Four new cyclohexadepsipeptides, pullularins A–D
R O OCH3 H O
OH
O
OH
O (120-123), were isolated from the endophytic fungus
N
N
H
O H3CO
Pullularia sp. BCC 8613. Pullularin A exhibited
O
OH
H
OCH3 activities against the malaria parasite Plasmodium
Trichodermamide A (115) B (116) Trichodermamide C (117) falciparum K1 (IC50 3.6 μg mL-1) and herpes simplex
115 R= OH virus type 1 (HSV-1; IC50 3.3 μg mL-1), whereas it
116 R= Cl
showed weak cytotoxicity to Vero cells (IC50 36 μg
mL-1) [106]. Two novel human cytomegalovirus
(+)-(5S,10S)-4′-Hydroxymethylcyclozonarone (109), protease inhibitors, cytonic acids A and B, have been
and phyllospinarone (110), together with tauranin isolated from the solid-state fermentation of the
(111), 3-ketotauranin (112), 3α-hydroxytauranin endophytic fungus Cytonaema sp. [107].
(113) and 12-hydroxytauranin (114), were isolated
from Phyllosticta spinarum, a fungal endophyte in H R3
Platycladus orientalis. All were evaluated for in vitro N N
antiproliferative activity against a panel of five O Me

O O N
sentinel cancer cell lines, NCI-H460 (non small cell O O O
lung), MCF-7 (breast), SF-268 (CNS glioma), PC-3 O
M (prostate), and MIA Pa Ca-2 (pancreatic). Only N

N
H R2
tauranin (111) showed antiproliferative activity R1 Me
against the cancer cell lines tested [101]. Chemical

O
investigations of a culture broth from the endophytic
Pullularins A–D (120-123)
fungus Eupenicillium sp., afforded the new R1 R2 R3
modified dipeptides trichodermamides A-C (115- 120 H Me OH
121 Me Me OH
117). Trichodermamide C (117) displayed 122 H H OH
cytotoxicity towards the human colorectal carcinoma 123 H Me H
HCT116 and human lung carcinoma A549 with IC50
values of 0.68 and 4.28µg mL-1, respectively [102]. 6.5 Nematicidal / insecticidal metabolites
From the endophytic fungal strain Geotrichum sp.
6.3 Anti-inflammatory
AL4 , cultivated from the leaves of neem tree
A new anti-inflammatory compound, 5, 7-dimethoxy- (Azadirachta indica), four compounds (124-127)
4-p-methoxylphenylcoumarin (118), and 5, 7- were isolated from the ethyl acetate extract, including
dimethoxy-4-phenylcoumarin (119) were isolated two new, chlorinated, epimeric 1,3 oxazinane
from endophytic Streptomyces aureofaciens derivatives. All compounds were assessed for their
CMUAc130 [103,104]. nematicidal activity against the nematodes
Bursaphelenchus xylophilus and Panagrellus
These two compounds were investigated for their redivivus and showed noticeable bioactivities [108].
effects not only on the formation of nitric oxide
O O
(NO), PGE2, TNF-α, IL-6 and IL-1β, but also on O O
Cl Cl
inducible NO synthase and cyclooxygenase-2 (COX- NH NH
2) in lipopolysaccharide (LPS)-induced murine
macrophage RAW 264.7 cells. They significantly (124) (125)
reduced the formation of TNF-α. These findings O O
support the application of 118 and 119 as anti-

inflammatory agents [105]. OH HO OH
(126) (127)
H3CO O O
The nematicidal alkaloid peniprequinolone, first

OCH3 isolated from the soil fungus Penicillium cf.
simplicissimum, has been found in P. janczewskii, a
fungal endophyte of the Chilean gymnosperm
R
Prumnopitys andina [109].
118 R= OMe
119 R= H
O
6.6 Immunosuppressant HO
O
H
N
(CH2)10CH3
R1
H
N O
N O
Three compounds (A-C) produced by an O
NH
H O
NH2
H 2N
HN
O
O O
endophytic Pestalotiopsis leucothës, isolated from NH O O
N
O NH
Tripterygium wilfordii, were evaluated for their O O
HN
N
H
OH
immunomodulatory effects. The IC50 value of A, in O
R2 O N
H O
NH2 R3
the proliferative assay, in combination with various Epichlicin (128) (129-131)
stimulating agents such as phytohemagglutinin-M R1 R2 R3
(PHA-M), phorbol myristate acetate 31
O
(PMA)/ionomycin, mixed lymphocyte reaction NH2
Fusaristatins A 129 H CH3
(MLR) and poke weed mitogen (PWM) was 0.35, 34
OH
1.6, 0.8 and 5.4 μg mL-1, respectively. Compound (B)
Fusaristatins B 130 O H CH3
significantly inhibited the production of cytokines O
like interleukin (IL)-1β, IL-2, interferon (IFN)-γ and NH2

tumor necrosis factor (TNF)-α, by peripheral blood Topostatin 131 OSO3H CH3 H
mononuclear cells (PBMNC) and soluble IL-2 OR' OR' O
H
OH
H
receptor expression at concentrations greater than 1
μg mL-1. Inhibition of PHA stimulated PBMNC
H
HO
proliferation and IL-2 and sIL-2R production by this O O OR O O OH
compound suggest that it is a T-cell specific

immunosuppressant. The third compound, C,
exhibited both suppression and enhancement of (132-133) (134)
PBMNC proliferation in the presence of various 132 R= R’= H
stimulants. All three fungal compounds altered the 133 R= H, R’= 4-Br-Benzoyl
percentage of T-lymphocyte subpopulations only at OCH3 OH Me

Me OH Me
high concentrations [110]. O
H3COC
O O O
6.7 Miscellaneous bioactive compounds Me
CH2OH
H
OH
The novel cyclic peptide epichlicin (128) was Papyracillic acid C (135) microsphaeropsins A (136)
isolated from Epichloe typhina, an endophytic fungus O OH
H
from the timothy plant (Phleum pretense L.).
Epichlicin (128) shows inhibitory activity towards HO OH OCH3
Me
spore germination of Cladosporium phlei, a HO
O O OH O
H3COC
pathogenic fungus of timothy plant at an IC 50 value Me
O O
of 22 nM [111]. Two new cyclic lipopeptides, Me
Me
fusaristatins A (129) and B (130), and topostatin 137 Decaspirone (138) Papyracillic acid A (139)
(131) were isolated from rice cultures of Fusarium
sp. YG-45 in the course of a screening of endophytic
A chemical examination of the endophytic fungus
fungi. Fusaristatin B (130) showed a moderate
Penicillium sp., isolated from the mangrove plant
inhibitory effect on topoisomerases I (IC50: 73 μM)
Aegiceras corniculatum resulted in the isolation
and II (IC50: 98 mM) without cleavable complexes.
and characterization of eight new indole triterpenes
Furthermore, fusaristatin A and B showed growth-
named shearinines A, D–K (140-148), along
inhibitory activity toward lung cancer cells LU-65
with paspalitrem A (149) and paspaline (150).
with IC50 values of 23 and 7 mM, respectively [112].
Shearinines D (140) and E (141) exhibit significant
Five new metabolites, palmarumycin M1 (132) and in vitro blocking activity on large-conductance
M2 (134), papyracillic acid C (135) and the calcium-activated potassium channels [114]. A novel
microsphaeropsins A (136) and B (137) were isolated CYP3A4 inhibitor, diaporthichalasin (151), together
from the fungus Microsphaeropsis sp. together with with pycnidione (152), were isolated from an
the known decaspirone (138) and the papyracillic endophytic fungus, Diaporthe sp. Diaporthichalasin
acids A and C (139,135). The absolute configuration (151) exhibited significantly potent inhibition of
of palmarumycin M1 (132) was determined by CYP3A4 with an IC50 value of 0.626 µM, while the
single-crystal X-ray analysis of the bis-4- IC50 value of pycnidione (152) was 465 µM [115].
bromobenzoate (133) [113].
H
R
OH
Koninginins A (153), E (154) and F (155) (KonA,
O KonE and KonF, respectively) isolated from
O
N
H
O
Trichoderma koningii inhibited the edema-inducing,
O
myotoxic and enzymatic activities of the total venom
140 R= OH
141 R= OMe
of the Bothrops jararacussu snake, as well as one of
142 R=H its homolog forms of phospholipases A2 and human
R2
H
secreted PLA2 protein fusion. KonE (154) and KonF
R1 OH
O
(155) structures are similar to vitamin E and possibly,
O
N
H the mode of action of these molecules is similar
O
O [116].
143 R1=R2=H
OH O OH
144 R1+R2=O
H
O
H3C H3C OH OH O OH
H3C OH
H3C O
H3C OH
N O
O CH3
H
O
H3C O CH3 OH
H3C
CH3 CH3 OH O OH O
(145)
H
Hypericin (156) Emodin (157)
O OH
H3C H H3C OH
H3C O O
O H3C O
N O HO
O CH3 H3C O
H
O OCH3
H3C O CH3
HO O
CH3 CH3
(146) OH
Cl
CH3 OCH3
H
CH3 H3C
O
H3C OH
H3C O Chloropupukeananin (158)
H3C O
N CH3
H
O
CH3
For the first time, an endophytic fungus has been

O CH3
CH3
(147)
isolated from the stems of the medicinal herb
H
CH3
H3C OH
Hypericum perforatum. The fungus produced the
H3C
H3C
O
napthodianthrone derivative hypericin (156) in rich
N
CH3
H
CH3
O
O
CH3
mycological medium (potato dextrose broth) under
CH3
shake flask and bench scale fermentation conditions.
(148) Emodin (157) was also produced simultaneously by
H
the fungus under the same culture conditions [117].
Chloropupukeananin (158), the first pupukeanane
H3C OH
O
H3C CH3
N
H
CH3
O
chloride with a highly functionalized tricyclo-
[4.3.1.03,7]-decane skeleton, and pestheic acid have
O CH3
CH3
(149)
H been isolated from the plant endophyte Pestalotiopsis
H3C CH3 fici, obtained from branches of an unidentified tree in
N CH3
H
CH3
China. Chloropupukeananin (158) was tested for in
H
O
H OH
vitro activity against HIV-1 replication in C8166
CH3
cells, and showed an inhibitory effect with an IC50
(150)
CH3
value of 14.6 μM (the positive control indinavir
H3C H3C sulfate showed an IC50 value of 8.18 nM). The
compound also displayed antimicrobial activity
CH3
H3C
H HO
H O HO H
H3C H
O
O against Staphylococcus aureus (ATCC 6538), with
CH3
H3C
NH O H H3C O IC50 and MIC values of 21.8 and 97.3 μM,
H3C
H OH
CH3
CH3
respectively (the positive control AMP showed IC50
OH HO O and MIC values of 1.2 and 3.9 μM at the same
(151) (152) concentration) [118].
OH O O HO
HO
O
Pestalotheols A-D (159-162) have been isolated from
O O
OH O CH3
OH OH OH
the plant endophytic fungus Pestalotiopsis theae
(153) (154) (155) (LN560), obtained from branches of an unidentified
CH3
O OH O O OH
Phomodione (163), a furandione with similarities in
HO O
H3C O
OH
CH3
structure and activity to cercosporamide (164) and
H3C OH the closely related derivative (-)-pseudoplacodiolic
O CH3
CH3
HO
Cl
OCH3 acid (165), was produced in submerged cultures of a
OH
Phoma sp. isolated from Saurania scaber, a New
Pestalotheol A (159) Pestalotheol B (160)
Guinea plant [120]. Pestaloficiols A–E (166-170),
O
HO CH3
H3C O CH3 five new cyclopropane derivatives, have been
H3C OH
H3C
O
OH
CH3 O CH3
isolated from cultures of the plant endophyte
H3C O Pestalotiopsis fici [121]. None of the compounds was
Pestalotheol C (161) Pestalotheol D (162) effective against Escherichia coli at 500 μg or lower,
but minimum inhibitory concentrations (MICs) of all
H3C
H3C
these compounds were approximately the same on
O
OMe
O
O
Staphylococcus aureus, indicating that they may be
OCH3 O
H3C H3C
H3C H3C
O
more effective against Gram positive bacteria. The
OH
antimycotic activity was tested using a representative
HO
O
O CH3 HO
O
O CH3 species from three classes of fungi. The
O CH3 O CH3 representative oomycete, ascomycete and
(163) (164) basidiomycete were Pythium ultimum, Sclerotinia
H3C sclerotiorum, and Rhizoctonium solani, respectively.
O
O RO In each case, usnic acid was less effective than either
OH
H3C H3C H
cercosporamide (164) or phomodione (163).
OH
O OH
O
O CH3
Chrysogenamide A, a new member of the macfortine
HO
CH3
OH
group of alkaloids, along with four known
O O
(165) 166 R= H compounds, was identified from Penicillium
167 R= CH3 chrysogenum No. 005, an endophytic fungus asso-
H
H3C
CH3
OR ciated with Cistanche deserticola. Chrysogenamide
H
A exhibited a neurocyte protection effect against
H3C
O O
O OH oxidative stress-induced cell death in SH-SY5Y cells
H3C [122]. Four new aromatic allenic ethers, (7E)-3-(4-
OH
O
OH
buta-2,3-dienyloxy-3-methoxy-phenyl)-acrylic acid
O
methyl ester (171), (7E)-3-[4-(4-buta-2,3-dienyloxy-
168 R= H (170)
169 R= CH3 benzyloxy)-phenyl]-acrylicacid methyl ester (172), 4-
(4-buta-2,3-dienyloxy-benzyloxy)-benzoic acid
tree on Jianfeng Mountain, Hainan Province, methyl ester (173), (7E)-3-[4-(4-buta-2,3-dienyloxy-
People’s Republic of China. These metabolites have benzyloxy)-3-methoxy-phenyl]-acrylic acid methyl
antifungal as well as anti-HIV activity. Pestalotheols ester (174) were isolated from the endophytic fungus
A-D, were tested for in vitro activity against HIV-1. Xylaria sp. No. 2508 [123].
Pestalotheol C (161) showed an inhibitory effect on The endophytic fungus Alternaria sp. (UFMGCB55)
HIV-1 replication in C8166 cells, with EC50 and was isolated from the plant Trixis vauthieri DC
CC50 values of 16.1 and 163 μM, respectively (Asteraceae), known to contain trypanocidal
(selectivity index, SI ); the positive control indinavir compounds. The organic extract of the culture of
sulfate showed an EC50 value of 8.18 μM). Alternaria sp. was able to inhibit Trypanosoma by
Pestalotheols A-D were also evaluated for activity 99%, when tested at 20 µg mL-1. Fractionation of the
against a panel of bacteria including Staphylococcus extract resulted in the identification of altenusin, a
aureus (ATCC 6538), Streptococcus mutans (ATCC biphenyl derivative with an IC50 value of 4.3+/-0.3
25175), Enterococcus faecalis (ATCC 19433), and mM in the TR bioassay. This compound is the first in
Sarcina lutea (CMCC B28001), and the fungi its class to have shown TR inhibitory activity,
Geotrichum candidum (AS2.498), Candida albicans opening new perspectives for the design of more
(ATCC 10231), and Aspergillus fumigatus (ATCC effective derivatives that could serve as drug leads
10894) [119]. for new chemotherapeutic agents to treat
trypanosomiasis and leishmaniasis [124].
H3CO
become diseased. Indeed, some natural products
C COOCH3 made by plants can also be made by the endophytes
O
associated with them. Has there been genetic transfer
(171) from the plant to the endophyte or visa versa? Do
COOCH3
secondary products of the host regulate product
C O formation by the endophyte? Are the same products
O
made by the endophyte in culture as when in the
(172)
host? If so, what role do these products play in the
C O COOCH3
host? Furthermore, how are these products
O synthesized and what genetic controls exist for
(173) product formation? The answers to questions such as
H3CO these will lead to a better understanding of the
interactions between the endophyte and its host.
C O COOCH3
O
The greatest diversity of endophytes is likely to occur
(174) in the tropical and temperate rainforests [125]. It has
been noted that the search for novel endophytes and
8. Conclusions their products is an opportunity for undergraduate
Endophytes and novel endophytic fungal and students to become involved in scientific discovery
bacterial species are excellent sources of novel, [126].
bioactive natural products. Although the
antimicrobial bioactivities are the most easily 9. Acknowledgement - We are thankful to the Head
assayed, other activities include anticancer, (Prof. BR Chaudhary) of the Dept. of Botany, BHU,
insecticidal, antiviral, anthelmintic, anti-plasmodial Varanasi for providing the existing facilities. VCV
and immunomodulatory. Questions remain as to how owes his thanks to CSIR New Delhi, for financial
endophytes take up residence in a plant, form a help. The financial help to RNK, from DST New
relationship with it and generally not cause it to Delhi, is gratefully acknowledged.
References
[1] Osburne MS, Grossman TH, August PR, MacNeil IA. (2000) Tapping into microbial diversity for natural products drug discovery.
American Society of Microbiologists News, 66, 411-426.
[2] Bernan VS, Greenstein M, Maiese WM. (1997) Marine microorganisms as a source of new natural products Advances in Applied
Microbiology, 43, 57-90.
[3] Castantino V, Fattorusso E, Menna M, Taglialatela-scafati O. (2004) Chemical diversity of bioactive marine natural products: an
illustrative case study. Current Medicinal Chemistry, 11, 1671-92.
[4] Bacon CW, White JF. (2000) In: Microbial Endophytes, Bacon CW, White JF. (Eds.), Marcel Dekker Inc., New York & Basel, p.
237.
[5] Petrini O. (1991) Fungal endophytes of tree leaves. In: Microbial Ecology of Leaves. Andrews J, Hirano S. (Eds.), Springer-Verlag,
New York, p. 179-197.
[6] Strobel GA. (2002) Rainforest endophytes and bioactive products. Critical Reviews in Biotechnology, 22, 315-333.
[7] De Bary A (1866) Morphologie und Physiologie der Plize, Flechten, und Myxomyceten (Hofmeister’s Handbook of Physiological
Botany). Vol. 2, Leipzig.
[8] Bischoff JF, White JF. (2005) In: The Fungal Community (3rd ed.), Dighton J, White JF, Oudemans P. (Eds.), Taylor & Francis.
[9] Bultman TL, Murphy JC. (2000) Do fungal endophytes mediate wound-induced resistance? In: Microbial Endophytes, Bacon CW,
White JF. (Eds.) Marcel Dekker: New York, Chapter 16, p. 421-452.
[10] Schulz B, Boyale C. (2005) The endophytic continuum. Mycological Research, 109, 661-686.
[11] Smith SA, Tank DC, Boulanger LA, Bascom-Slack CA, Eisenman K, Kingery D, Babbs B, Fenn K, Greene JS, Hann BD, Keehner
J, Kelley-Swift EG, Kembaiyan V, Lee SJ, Li P, Light DY, Lin EH, Ma Cong, Moore E, Schorn MA, Vekhter D,Nunez PV,
Strobel GA, Donoghue MJ, Strobel SA (2008) Bioactive endophytes warrant intensified exploration and conservation. PLoS ONE,
3, 3052-3059.
[12] Boursnell JG. (1950) The symbiotic seed borne fungus in the Cistaceae. In: Distribution and function of the fungus in the seedling
and in the tissues of mature plants. Annals of Botany, 14, 217-243.
[13] Clay K. (1988) Fungal endophytes of grasses: a defensive mutualism between plants and fungi. Ecology, 69, 10-16.
[14] Kyde MM, Gould AB. (2000) Mycorrhizal symbiosis. In: Microbial Endophytes, Bacon CW, White JF. (Eds.) Marcel Dekker,
New York, p. 161.
[15] Schultz B, Rommert AK, Dammann U, Aust HJ, Strack D. (1999) The endophyte-host interaction: a balanced antagonism.
Mycological Research, 105, 1275-1283.
[16] Sylvia DM, Sinclair WA. (1983) Phenolic compounds and resistance to fungal pathogens are induced in primary roots of Douglas-
fir seedlings by the ectomycorrhizal fungus Laccaria laccata. Phytopathology, 73, 390-397.
[17] Stone JK, Polishook JD, White JF. (2004) In: Endophytic fungi. Mueller GM, Bills GF, Foster MS. (Eds.),.Biodiversity of fungi
inventory and monitoring methods, Elsevier, Amsterdam, p.241–270.
[18] Strobel GA, Daisy B, Castillo U, Harper J. (2004) Natural products from endophytic fungi. Journal of Natural Products, 67, 257-
268.
[19] Isaacs J. (1994) Bush Food Aboriginal Food and Herbal Medicine. Lansdowne Publishing Pty. Ltd., Sydney.
[20] Newman DJ, Cragg GM. (2007) Natural products as sources of new drugs over the last 25 years. Journal of Natural Products, 70,
461-477.
[21] Grabley S, Thiericke R. (1999) In: Drug Discovery from Nature, Grabley S, Thiericke R, (Eds.), Springer-Verlag, Berlin, p. 3.
[22] Concepcion GP, Lazaro JE, Hyde KD. (2001) In: Bio-exploitation of Filamentous Fungi, Pointing SB, Hyde KD. (Eds.), Fungal
Diversity Press, Hong Kong, p. 93.
[23] Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. (1971) Plant antitumor agents. VI. The isolation and structure of taxol, a
novel antileukemic and antitumor agent from Taxus brevifolia. Journal of American Chemical Society, 93, 2325-2327.
[24] Bills GF, Dombrowski A, Pelaez F, Polishook J, An Z. (2002) In: Tropical Mycology: Micromyceyes, Watling R, Frankland
JC,Ainsworth AM, Isaac S, Robinson CH. (Eds.), CABI Publishing, New York, 2, p.165.
[25] Stierle A, Strobel G, Stierle D. (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew.
Science, 260, 154-155.
[26] Koskinen A. (1993) In: Asymmetric Synthesis of Natural Products, John Wiley & Sons Ltd, West Sussex, p. 28
[27] Guo BH, Wang YC, Zhou XW, Hu K, Tan F, Miao ZQ (2006) An endophytic taxol-producing fungus BT2 isolated from Taxus
chinensis var. mairei. African Journal of Biotechnology, 10, 875–877.
[28] Ji Y, Bi JN, Yan B, Zhu XD. (2006) Taxol-producing fungi: a new approach to industrial production of taxol. Chinese Journal of
Biotechnology, 1, 1–6.
[29] Gangadevi V, Muthumary J. (2008) Taxol, an anticancer drug produced by an endophytic fungus Bartalinia robillardoides Tassi,
isolated from a medicinal plant, Aegle marmelos Correa ex Roxb. World Journal of Microbiology and Biotechnology, 24, 717-724.
[30] Gangadevi V, Muthumary J. (2009) Taxol production by Pestalotiopsis terminaliae, an endophytic fungus of Terminalia arjuna
(arjun tree). Biotechnology and Applied Biochemistry, 52, 9–15.
[31] Tringali C. (2001) In: Bioactive Compounds from Natural Sources, Taylor & Francis, London, p.9
[32] Tan RX, Zau WX. (2001) Endophytes: A rich source of functional metabolites. Journal of Natural Products, 18, 448-459.
[33] Verma VC, Gond SK, Kumar A, Kharwar RN, Strobel GA. (2007) Endophytic mycoflora of bark, leaf and stem tissues of
Azadirachta indica A Juss. from Varanasi, India. Microbial Ecology, 54, 119-125.
[34] Kharwar RN, Verma VC, Strobel GA, Ezra D. (2008) The endophytic fungal complex of Catharanthus roseus (L.) G. Don.
Current Science, 95, 228-232.
[35] Gunatilaka, AAL. (2006) Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity and
implications of their occurrence. Journal of Natural Products, 69, 509-526.
[36]. Guo B, Y. Wang Y, Sun X, Tang K. (2008) Bioactive natural products from endophytes: A review. Applied Biochemistry and
Microbiology, 44, 136-142.
[37] Krohn K, Beckmann K, Flörke U, Aust HJ, Draeger S, Schulz B, Bringmann G, Busemann S. (1997) New palmarumycins CP4a,
and CP5 from Coniothyrium palmarum: Structure elucidation, crystal structure analysis and determination of the absolute
configuration by CD calculations. Tetrahedron, 53, 3101-3108.
[38] Krohn K, Bahramsari R, Flörke U, Ludewig K, Kliche-spory C, Michel A, Aust HJ, Draeger S, Schulz B, Antus S. (1997)
Dihydroisocoumarins from fungi: Isolation, structure elucidation, circular dichroism and biological activity. Phytochemistry, 45,
313-320.
[39] Krohn K, Biele C, Drogies KH, Steingröver K, Aust HJ, Draeger S, Schulz B. (2002) Fusidilactones, a new group of polycyclic
lactones from an endophyte, Fusidium sp. European Journal of Organic Chemistry, 2331-2335.
[40] Strobel GA, Miller RV, Miller CM, Condron MM, Teplow DB, Hess WH. (1999) Cryptocandin, a potent antimycotic from the
endophytic fungus Cryptosporiopsis cf. quercina. Microbiology, 145, 1919-24.
[41] Li JY, Strobel G, Harper J, Lobkovsky E, Clardy J. (2000) Cryptocin, a potent tetramic acid antimycotic from the endophytic
fungus Cryptosporiopsis cf. quercina. Organic Letters, 2, 767-770.
[42] Ding G, Li Y, Fu S, Liu S, Wei J, Che Y. (2009) Ambuic acid and torreyanic acid derivatives from the endolichenic fungus
Pestalotiopsis sp. Journal of Natural Products, 72, 182–186.
[43] Lee JC, Yang X, Schwartz M, Strobel G, Clardy J. (1995) The relationship between an endangered North American tree and an
endophytic fungus. Chemical Biology, 2, 721-727.
[44] Li JY, Strobel GA. (2001) Jesterone and hydroxy-jesterone anti-oomycete cyclohexenenone epoxides from the endophytic fungus
Pestalotiopsis jesteri. Phytochemistry, 57, 261-265.
[45] Lee JC, Strobel GA, Lobkovsky E, Clardy JC. (1996) Torreyanic acid: a selectively cytotoxic quinone dimer from the endophytic
fungus Pestalotiopsis microspora. Journal of Organic Chemistry, 6, 13232-33.
[46] Strobel GA, Ford E, Worapong J, Harper JK, Arif AM, Grant DM, Fung PCW, Chan K. (2002) Ispoestacin, an isobenzofuranone
from Pestalotiopsis microspora, possessing antifungal and antioxidant activities. Phytochemistry, 60, 179-183.
[47] Harper JK, Ford EJ, Strobel GA, Arif A, Grant DM, Porco JD, Tomer DP, K. Oneill K. (2003) Pestacin: a 1,3-dihydro
isobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimycotic activities. Tetrahedron, 59, 2471-76.
[48] Kim S, Shin DS, Lee T, Oh KB. (2004) Periconicins, two new fusicoccane diterpenes produced by an endophytic fungus Periconia
sp. with antibacterial activity. Journal of Natural Products, 67, 448-450.
[49] Shin DS, Oh MN, Yang HC, Oh KB. (2005) Biological characterization of periconicins, bioactive secondary metabolites produced
by Periconia sp. OBW-15. Journal of Microbiology and Biotechnology, 15, 216-220.
[50] Wall ME, Wani MC, Cooke CE, Palmer KT, McPhail AT, Sim GA. (1966) Plant antitumor agents. I. The isolation and structure of
camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminate. Journal of American Chemical
Society, 88, 3888-3890.
[51] Puri SC, Verma V, Amna T, Qazi GN, Spiteller MJ. (2005) An endophytic fungus from Nothapodytes foetida that produces
camptothecin. Journal of Natural Products, 68, 1717–1719.
[52] Wagenaar M, Corwin J, Strobel GA, Clardy J. (2000) Three new chytochalasins produced by an endophytic fungus in the genus
Rhinocladiella. Journal of Natural Products, 63, 1692-1695.
[53] Song YC, Li H, Ye YH, Shan CY, Yang YM, Tan RX. (2004) Endophytic naphthopyrone metabolites are co-inhibitors of xanthine
oxidase, SW1116 cell and some microbial growths. FEMS Microbiology Letters, 241, 67-72.
[54] Rodrigues-Heerklotz KF, Drandarov K, Heerklotz J, Hesse M, Werner C. (2001) Guignardic acid, a novel type of secondary
metabolite produced by endophytic fungus Guignardia sp.: isolation, structure elucidation and asymmetric synthesis Helvetica
Chimica Acta, 84, 3766
[55] Singh SB, Zink DL, Guan Z, Collado J, Pelaez F, Felock PJ, Hazuda DJ. (2003) Isolation, structure, and HIV-1 integrase inhibitory
activity of xanthoviridicatin E and F, two novel fungal metabolites produced by Penicillium chrysogenum. Helvetica Chimica Acta,
86, 3380-3385.
[56] Weber DO, Sternere O, Anke T, Gorzalczancy S, Martino V, Acevedo C. (2004) Phomol, a new antiinflammatory metabolite from
an endophyte of the medicinal plant Erythrina crista-galli. Journal of Antibiotics, 57, 559-565.
[57] Ratnayake S, Yoshida WY, Mooberry SL, Hemscheidt T. (2001) The structure of macrocarpilide: A microfilament disrupting agent
from an endophytic fungus. Organic Letters, 3, 3479-3481.
[58] Ge HM, Song YC, Chen JR, Hu S, Wu JY, Tan RX. (2006) Paranolin: a new xanthene-based metabolite from Paraphaeosphaeria
nolinae. Helvetica Chimica Acta, 89, 502-506.
[59] Dai JQ, Krohn K, Florke U, Gehle D, Aust HJ, Drarger S, Schulz B, Rheinheimer J. (2005) Novel highly substituted biraryl ethers,
phomosines D-G, isolated from the endophytic fungus Phomopsis sp. from Adenocarpus foliolosus. European Journal of Organic
Chemistry, 5100-5105.
[60] Zhang LQ, Guo B, Li HY, Zeng SR, Shao H, Gu S, Wei RC. (2000) Chinese Traditional Herbal Drugs, 31, 805-811.
[61] Zhang LQ, Wang HK, Shao H, Shen YM, Zeng SR, Xu CD, Xuan Q, Wei RC. (2002) Chinese Pharmaceutical Journal, 37,
172-176.
[62] Strobel G, Li JY, Sugawara F, Koshino H, Harper J, Hess WM. (1999) Oocydin A, a chlorinated macrocyclic lactone with potent
anti-oomycete activity from Serratia marcescens. Microbiology, 145, 3557-3564.
[63] Wang J, Huang Y, Fang M, Zhang Y, Zheng Z, Zhao Y, Su W. (2002) Brefeldin A, a cytotoxin produced by Paecilomyces sp. and
Aspergillus clavatus isolated from Torreya grandis. FEMS Immunology and Medical Microbiology, 34, 51-57.
[64] Ritzenthaler C, Nebenfu¨hr A, Movafeghi A, Garaud SC, Behnia L, Pimpl P, Staehelin LA, Robinson DG. (2002) Reevaluation of
the effects of brefeldin A on plant cells using tobacco bright yellow 2 cells expressing golgi-targeted green fluorescent protein and
COPI antisera. Plant Cell, 14, 237-261.
[65] Hormazahal E, Schmeda-Hirschmann G, Astudillo L, Rodriguez J, Theoduloz C. (2005) Metabolites from Microsphaeropsis
olivacea, an endophytic fungus of Pilgerodendron uviferum. Zeitschrift fuer Naturforschung,C, Journal of Biosciences, 60, 11-21.
[66] Brady SF, Wagenaar MM, Singh MP, Janso JE, Clardy J. (2000) The cytosporones, new octaketide antibiotics isolated from an
endophytic fungus. Organic Letters, 2, 4043-4046.
[67] Brady SF, Singh MP, Janso JE, Clardy J. (2000) Cytoskyrins A and B, new BIA active bisanthraquinones isolated from an
endophytic fungus. Organic Letters, 2, 4047-4049.
[68] Krohn K, Flörke U, John M, Root N, Steingröver K, Aust HJ, Draeger S, Schulz B, Antus S, Simonyi M, Zsila F. (2001)
Biologically active metabolites from fungi. Part 16: New preussomerins J, K and L from an endophytic fungus: structure
elucidation, crystal structure analysis and determination of absolute configuration by CD calculations. Tetrahedron, 57, 4343-4348.
[69] Ma YM, Li Y, Liu JY, Song YC, Tan RX. (2004) Anti-Helicobacter pylori metabolites from Rhizoctonia sp. Cy064, an endophytic
fungus in Cynodon dactylon. Fitoterapia, 75, 451-456.
[70] Erkel G, Rrather J, Anke T, Sterner O. (2000) Trichodion, a new bioactive pyrone from a Trichosporiella species. Journal of
Antibiotics, 53, 1401-1404.
[71] Aly AH, Edrada-Ebel R, Wray V, Werner EGM, Müller FT, Kozytska S, Hentschel U, Proksch P, Ebel R. (2008) Bioactive
metabolites from the endophytic fungus Ampelomyces sp. isolated from the medicinal plant Urospermum picroides.
Phytochemistry, 69, 1716-1725.
[72] Aly AH, Edrada-Ebel R, Indriani ID, Wray V, Werner EGM, Müller FT, Zirrgiebel U, Schächtele C, Kubbutat MHG, Lin WH,
Proksch P, Ebel R. (2008) Cytotoxic metabolites from the fungal endophyte Alternaria sp. and their subsequent detection in its host
plant Polygonum senegalense. Journal of Natural Products, 71, 972-980.
[73] Pelaez F, Cabello A, Platas G, Diez MT, del Val AG, Basilio A, MartanI, Vicente F, Bills GF, Giacobbe RA, Schwartz RE, Onishi
JC, Meinz MS, Abruzzo GK, Flattery AM, Kong L, Kurtz MB. (2000) The discovery of enfumafungin, a novel antifungal
compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms.
Systematic and Applied Microbiology, 23, 333-343.
[74] Gutierrez M, Theoduloz C, Rodriguez J, Lolas M, Schmeda-Hirschmann G. (2005) Bioactive metabolites from the fungus Nectria
galligena, the main apple canker agent in Chile. Journal of Agriculture and Food Chemistry, 53, 7701-7708.
[75] Ondeyka JG, Helms GL, Hensens OD, Goetz MA, Zink DL, Tsipouras A, Shoop WL, Slayton L, Dombrowski AW, Polishook JD,
Ostlind DA, Tsou NN, Ball RG, Singh SB. (1997) Nodulisporic acid A, a novel and potent insecticide from a Nodulisporium sp.
Isolation, structure determination, and chemical transformations. Journal of American Chemical Society, 119, 8809-8816.
[76] Kusano M, Koshino H, Uzawa J, Fujioka S, Kawano T, Kimura Y. (2000) Nematicidal alkaloids and related compounds produced
by the fungus Penicillium cf. simplicissimum. Bioscience Biotechnology and Biochemistry, 64, 2559-2568.
[77] Zhang CL, Zheng BQ, Lao JP, Mao LJ, Chen SY, Kubicekand CP, Lin FC. (2008) Clavatol and patulin formation as the
antagonistic principle of Aspergillus clavatonanicus, an endophytic fungus of Taxus mairei. Applied Microbiology and
Biotechnology, 78, 833-840.
[78] Ding G, Liu S, Guo L, Zhou Y, Che Y. (2008) Antifungal metabolites from the plant endophytic fungus Pestalotiopsis foedan.
Journal of Natural Products, 71, 615–618.
[79] Wu SH, Chen YW, Shao HC, Wang LD, Li ZY, Yang LY, Li SL, Huang R. (2008) Ten-membered lactones from Phomopsis sp.,
an endophytic fungus of Azadirachta indica. Journal of Natural Products, 71, 731-734.
[80] Wu SH, Chen YW, Shao SC, Li-Dong Wang , Ying Yu , Zhi-Ying Li , Li-Yuan Yang , Shao-Lan Li , Rong Huang. (2008) Two new
solanapyrone analogues from the endophytic fungus Nigrospora sp. YB-141 of Azadirachta indica. Chemistry and Biodiversity, 6,
79-85.
[81] Liu X, Dong M, Chen X, Jiang M, Lv X, Zhou J. (2008) Antimicrobial activity of an endophytic Xylaria sp.YX-28 and
identification of its antimicrobial compound 7-amino-4-methylcoumarin. Applied Microbiology and Biotechnology, 78, 241-247.
[82] Pongcharoen W, Rukachaisirikul V, Phongpaichit S, Kühn T, Pelzing M, Sakayaroj J, Taylor WC. (2008) Metabolites from the
endophytic fungus Xylaria sp. PSU-D14. Phytochemistry, 69, 1900-1902.
[83] Zhang W, Krohn K, Draeger S, Schulz B. (2008) Bioactive isocoumarins isolated from the endophytic fungus Microdochium
bolleyi. Journal of Natural Products, 71, 1078–1081.
[84] Zhang W, Krohn K, Ullah Z, Flörke U, Pescitelli G, Bari LD, Antus S, Kurtán T, Rheinheimer J, Draeger S, Schulz B. (2008) New
mono- and dimeric members of the secalonic acid family: blennolides A-G isolated from the fungus Blennoria sp. Chemistry-An
European Journal, 14, 4913-4923.
[85] Wang FW, Hou ZM, Wang CR, Li P, Shi DH. (2008) Bioactive metabolites from Penicillium sp., an endophytic fungus residing in
Hopea hainanensis. World Journal of Microbiology and Biotechnology, 24, 2143-2147.
[86] Kharwar RN, Verma VC, Kumar A, Gond SK, Harper JK, Hess WM, Lobkovosky E, Ma C, Ren Y, Strobel GA. (2009) Javanicin,
an antibacterial naphthaquinone from an endophytic fungus of neem, Chloridium sp. Current Microbiology, 58, 233-238.
[87] Singh MP, Janso JE, Brady SF. (2007) Cytoskyrins and cytosporones produced by Cytospora sp. CR200: taxonomy, fermentation
and biological activities. Marine Drugs, 5, 71-84.
[88] Pongcharoen W, Rukachaisirikul V, Phongpaichit S, Sakayaroj J. (2007) A new dihydrobenzofuran derivative from the endophytic
fungus Botryosphaeria mamane PSU-M76. Chemical and Pharmaceutical Bulletin, 55, 1404-1405.
[89] Rukachaisirikul V, Sommart U, Phongpaichit S, Sakayaroj J, Kirtikara K. (2008) Metabolites from the endophytic fungus
Phomopsis sp. PSU-D15. Phytochemistry, 69, 783-787.
[90] Isaka M, Jaturapat A, Rukseree K, Danwisetkanjana K, Tanticharoen M, Thebtaranonth Y. (2001) Phomoxanthones A and B, novel
xanthone dimers from the endophytic fungus Phomopsis sp. Journal of Natural Products, 64, 1015-1018.
[91] Tansuwan S, Pornpakakul S, Roengsumran S, Petsom A, Muangsin N, Sihanonta P, Chaichit N. (2007) Antimalarial
benzoquinones from an endophytic fungus, Xylaria sp. Journal of Natural Products, 70, 1620-1623.
[92] Lin ZJ, Lu ZY, Zhu TJ, Fang YC, Gu QQ, Zhu WM. (2008) Penicillenols from Penicillium sp. GQ-7, an endophytic fungus
associated with Aegiceras corniculatum. Chemical and Pharmaceutical Bulletin, 56, 217-221.
[93] Huang H, She Z, Lin Y, Vrijmoed LLP, Lin W. (2007) Cyclic peptides from an endophytic fungus obtained from a mangrove leaf
(Kandelia candel). Journal of Natural Products, 70, 1696-99.
[94] Zhang Y, Ming LX, Wang BG. (2007) Nigerasperones A-C, new monomeric and dimeric naphtho-γ-pyrones from a marine alga-
derived endophytic fungus Aspergillus niger EN-13. Journal of Antibiotics, 60, 204-210.
[95] Lang G, Cole ALG, Blunt JW, Robinson WT, Munro MHG. (2007) Excelsione, a depsidone from an endophytic fungus isolated
from the New Zealand endemic tree Knightia excelsa. Journal of Natural Products, 70, 310-311.
[96] Macías-Rubalcava ML, Hernández-Bautista BE, Jiménez-Estrada M, González MC, Glenn AE, Hanlin RT, Hernández-Ortega S,
Saucedo-García A, Muria-González JM, Anaya AL. (2008) Naphthoquinone spiroketal with allelochemical activity from the newly
discovered endophytic fungus Edenia gomezpompae. Phytochemistry, 69, 1185-1196.
[97] Lin Z, Zhu T, Fang Y, Gu Q, Zhu W. (2008) Polyketides from Penicillium sp. JP-1, an endophytic fungus associated with the
mangrove plant Aegiceras corniculatum. Phytochemistry, 69, 1273-1278.
[98] Guimarães DO, Borges WS, Kawano CY, Ribeiro PH, Goldman GH, Nomizo A, Thiemann OH, Oliva G, Lopes NP, Pupo MT.
(2008) Biological activities from extracts of endophytic fungi isolated from Viguiera arenaria and Tithonia diversifolia. FEMS
Immunology and Medical Microbiology, 52, 134-144.
[99] Huang Z, Cai X, Shao C, She Z, Xia X, Chen Y, Yang J, Zhou S, Lin Y. (2008) Chemistry and weak antimicrobial activities of
phomopsins produced by mangrove endophytic fungus Phomopsis sp. ZSU-H76. Phytochemistry, 69, 1604-1608.
[100] Xu F, Zhang Y, Wang J, Pang J, Huang C, Wu X, She Z, Vrijmoed LLP, Jones EBG, Lin Y. (2008) Benzofuran derivatives from
the mangrove endophytic fungus Xylaria sp. (#2508). Journal of Natural Products, 71, 1251–1253.
[101] Kithsiri Wijeratne EM, Paranagama PA, Marron MT, Gunatilaka MK, Arnold AE, Gunatilaka AAL. (2008) Sesquiterpene
quinones and related metabolites from Phyllosticta spinarum, a fungal strain endophytic in Platycladus orientalis of the Sonoran
Desert. Journal of Natural Products, 71, 218-222.
[102] Davis RA, Longden J, Avery VM, Healy PC. (2008) The isolation, structure determination and cytotoxicity of the new fungal
metabolite, trichodermamide C. Bioorganic and Medicinal Chemistry Letters, 18, 2836-2839.
[103] Taechowisan T, Lu C, Shen Y, Lumyong S. (2007) Antitumor activity of 4-arylcoumarins from endophytic Streptomyces
aureofaciens CMUAc130. Journal of Cancer Research and Therapy, 3, 86-91.
[104] Taechowisan T, Lu C, Shen Y, Lumyong S. (2005) Secondary metabolites from endophytic Streptomyces aureofaciens
CMUAc130 and their antifungal activity. Microbiology, 151, 1691-1695.
[105] Taechowisan T, Lu C, Shen Y, Lumyong S. (2007) 4-arylcoumarin inhibits immediate-type allergy. Food and Agricultural
Immunology, 18, 203-211.
[106] Isaka M, Berkaew P, Intereya K, Komwijit S, Sathitkunanon T. (2007) Antiplasmodial and antiviral cyclohexadepsipeptides from
the endophytic fungus Pullularia sp. BCC 8613. Tetrahedron, 63, 6855-6860.
[107] Guo B, Dai JR, Ng S, Huang Y, Leong C, Ong W, Carte BK. (2000) Cytonic Acids A and B: Novel tridepside inhibitors of hCMV
protease from the endophytic fungus Cytonaema species. Journal of Natural Products, 63, 602-606.
[108] Li GH, Yu ZF, Li X, Wang XB, Zheng LJ, Zhang KQ. (2007) Nematicidal metabolites produced by the endophytic fungus
Geotrichum sp. AL4. Chemistry and Biodiversity, 4, 1520-1524.
[109] Schmeda-Hirschmann G, Hormazabal E, Astudillo L, Rodriguez J, Theoduloz C. (2005) Secondary metabolites from endophytic
fungi isolated from the Chilean gymnosperm Prumnopitys andina Lleuque. World Journal Microbiology and Biotechnology, 21,
27-32.
[110] Kumar DSS, Lau CS, Wan JMF, Yang D, Hyde KD. (2005) Immunomodulatory compounds from Pestalotiopsis leucothës, an
endophytic fungus from Tripterygium wilfordii. Life Sciences, 78, 147-156.
[111] Yoshiya S, Kosaku T, Hideyuki M, Yasunori K, Hiroshi Y, Teruhiko Y, Kensuke N. (2007) Novel cyclic peptide, epichlicin, from
the endophytic fungus, Epichloe typhina. Bioscience Biotechnology and Biochemistry, 71, 1470-1475.
[112] Shiono Y, Tsuchinari M, Shimanuki K, Miyajima T, Murayama T, Koseki T, Laatsch H, Funakoshi T, Takanami K, Suzuki K.
(2007) Fusaristatins A and B, two new cyclic lipopeptides from an endophytic Fusarium sp. Journal of Antibiotics, 60, 309-316.
[113] Dai J, Krohn K, Elsässer B, Flörke U, Draeger S, Schulz B, Pescitelli G, Salvadori P, Antus S, Kurtán T. (2005) Metabolic
products of the endophytic fungus Microsphaeropsis sp. from Larix deciduas. Journal of Organic Chemistry, 29, 4845-4854.
[114] Xu M, Gessner G, Groth I, Lange C, Christner A, Bruhn T, Deng Z, Li X, Heinemann SH, Grabley S, Bringmann G, Sattler I, Lin
W. (2007) Shearinines D–K, new indole triterpenoids from an endophytic Penicillium sp. (strain HKI0459) with blocking activity
on large-conductance calcium-activated potassium channels. Tetrahedron, 63, 435-444.
[115] Pornpakakul S, Roengsumran S, Deechangvipart S, Petsom A, Muangsin N, Ngamrojnavanich N, Sriubolmas N, Chaichit N, Ohta
T. (2007) Diaporthichalasin, a novel CYP3A4 inhibitor from an endophytic Diaporthe sp. Tetrahedron Letters, 48, 651-655.
[116] Souza ADL, Rodrigues E, Souza AQL, Pereira JO, Calgarotto AK, Maso V, Marangoni S, Da Silva SL. (2008) Koninginins,
phospholipase A2 inhibitors from endophytic fungus Trichoderma koningii. Toxicon, 51, 240-250.
[117] Kusari S, Lamshöft M, Zühlke S, Spiteller M. (2008) An endophytic fungus from Hypericum perforatum that produces hypericin.
Journal of Natural Products, 71, 159-162.
[118] Liu L, Liu S, Jiang L, Chen X, Guo L, Che Y. (2008) Chloropupukeananin, the first chlorinated pupukeanane derivative, and its
precursors from Pestalotiopsis fici. Organic Letters, 10, 1397-1400.
[119] Li W, Tian R, Liu S, Chen X, Guo L, Che Y. (2008) Pestalotheols A-D, bioactive metabolites from the plant endophytic fungus
Pestalotiopsis theae. Journal of Natural Products, 71, 664-668.
[120] Hoffman AM, Mayer SG, Strobel GA, Hess WM, Sovocool GW, Grange AH, Harper JK, Arif AM, Grant DM, Kelley-Swift EG.
(2008) Purification, identification and activity of phomodione, a furandione from an endophytic Phoma species. Phytochemistry,
69, 1049-1056.
[121] Liu L, Tian R, Liu S, Chen X, Guo L, Che Y. (2008) Pestaloficiols A-E, bioactive cyclopropane derivatives from the plant
endophytic fungus Pestalotiopsis fici. Journal of Natural Products, 16, 6021-6026.
[122] Lin Z, Wen J, Zhu T, Fang Y, Gu Q, Zhu W. (2008) Chrysogenamide A from an endophytic fungus associated with Cistanche
deserticola and its neuroprotective effect on SH-SY5Y Cells. Journal of Antibiotics, 61, 81-85.
[123] Wang SY, Xu ZL, Mao WW, She ZG, Tan N, Li CR, Lin YC. (2008) Four new aromatic allenic ethers from the fungus Xylaria sp.
No. 2508. Natural Product Research, 22, 612-617.
[124] Betania BC, Luiz HR, Rachel BC, Lúcia TR, Tânia MAA, Carlos AR, Carlos LZ. (2008) Altenusin, a biphenyl isolated from the
endophytic fungus Alternaria sp., inhibits trypanothione reductase from Trypanosoma cruzi. FEMS Microbiology letters, 285, 177-
182.
[125] Strobel GA, Daisy B. (2003) Bioprospecting for microbial endophytes and their natural products. Microbiology and Molecular
Biology Reviews, 67, 491-502.
[126] Strobel SA, Strobel GA. (2007) Plant endophytes as a platform for discovery-based undergraduate science education. Nature-
Chemical Biology, 3, 356-359.

NPC Natural Product Communications

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

NPC Natural Product Communications

Uploaded by

Copyright:

Available Formats

2009

NPC Natural Product Communications Vol. 4

Received: March 30th, 2009; Accepted: June 30th, 2009

Keywords: Endophytic fungi, bioactive natural products, anti-microbial, endophyte-host interaction.

1. Introduction 1% of earth’s bacterial species and less than 5 % of

Rubrofusarin B (15) Fonsecinone A (16) Xanthoviridicatin F (21) Phomol (22)

Asperpyrone B (17) Asperpyrone A (18) OH

novel cytochalasins (14) from an endophyte

Phomosine G (25) Vincristine (26)

had already been identified from its plant host. (-)-

lactone isolated from an endophytic bacterial strain of OH

Serratia marcescens occurring both as an endophyte Cytoskyrin A (34) Cytoskyrin B (35)

products from endophytic microbes.

nematicidal alkaloid peniprequinolone, first isolated O

from the soil fungus Penicillium cf. simplicissimum HO

6. Recent discoveries of bioactivities in endophytic O O

7-amino-4-methylcoumarin (59) Xylarosides (60-61)

typhi (20 μg mL−1), Salmonella typhimurium (15 μg

dimethyl-iso-alloxazine (67) and 3,5-dichloro-p- Javanicin (68)

albicans, Trichophyton rubrum and Aspergillus niger O OCH3

Botryomaman (69) Primin (70) Mellein (71)

MICs of 40, 20, 50 and 15 µg mL-1. In addition, 67 OH O CH3 O

Two novel benzoquinone metabolites, 2-chloro-5- O

endophytic Xylaria sp. Compounds 78 and 79 OH

values of 1.35 and >184 μM, respectively [91]. Six OH

new tetramic acids derivatives, penicillenols A1, A2, O O

fungus associated with Aegiceras corniculatum. All O O

the new compounds were evaluated for their O

bioassay. Penicillenols A1 (81) and B1 (83) showed

phytobionts. Excelsione (92) was inactive against

disk agar diffusion assays against various bacterial

and fungal strains using 40 µg of the compound per

1962A (87) 1962B (88)

Leptosphaerone C (96) Penicillenone (97)

Chemical investigation of the mycelium of Edenia (109) (110) (111-114)

Platycladus orientalis. All were evaluated for in vitro N N

antiproliferative activity against a panel of five O Me

M (prostate), and MIA Pa Ca-2 (pancreatic). Only N

against the cancer cell lines tested [101]. Chemical

support the application of 118 and 119 as anti-

The nematicidal alkaloid peniprequinolone, first

like interleukin (IL)-1β, IL-2, interferon (IFN)-γ and NH2

compound suggest that it is a T-cell specific

percentage of T-lymphocyte subpopulations only at OCH3 OH Me

For the first time, an endophytic fungus has been

You might also like