South African Journal of Botany 132 (2020) 226"241

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South African Journal of Botany

journal homepage: www.elsevier.com/locate/sajb

A review on the diversity, chemical and pharmacological potential of the

green algae genus Caulerpa
Mohammed I. Rushdia, Iman A.M. Abdel-Rahmana, Eman Zekry Attiab,
Wedad M. Abdelraheemc, Hani Saberd, Hashem A. Madkoure, Elham Aminf,g,
Hossam M. Hassanf,h, Usama Ramadan Abdelmohsenb,i,j,*
a
Department of Pharmacognosy, Faculty of Pharmacy, South Valley University, 83523, Qena, Egypt
b
Department of Pharmacognosy, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt
c
Department of Medical Microbiology and Immunology, Faculty of Medicine, Minia University, 61519 Minia, Egypt
d
Department of Botany and Microbiology, Faculty of Science, South Valley University, 83523, Qena, Egypt
e
Department of Marine and Environmental Geology, National Institute of Oceanography and Fisheries, Red Sea Branch, 84511 Hurghada, Egypt
f
Department of Pharmacognosy., Faculty of Pharmacy, Beni-Suef University, 62514 Beni-Suef, Egypt
g
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, 51452, Kingdom of Saudi Arabia.
h
Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, 62514 Beni-Suef, Egypt.
i
Arabia Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, 61111 New Minia City, Egypt
j
Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia

A R T I C L E I N F O A B S T R A C T

Article History: The seaweed Genus Caulerpa is still chemically and pharmacologically underexplored. This sea vegetable is of
Received 14 November 2019 nutritional interest where some species are considered a source of food, such as sea grapes C. lentillifera. Con-
Revised 8 April 2020 versely, C. taxifolia is toxic. Therapeutic potentials of pure compounds isolated from the Genus Caulerpa are
Accepted 14 April 2020
promising as antiviral, antimicrobial, cytotoxic, immunostimulatory, hypolipidemic, anti-obesity, cardio-pro-
Available online 8 June 2020
tective, hepatoprotective and anti-proliferative agents. This review covers the literature on Genus Caulerpa
Keywords: during the period 1978 to 2019 and highlights the chemical and pharmacological potential of the genus Cau-
Marine lerpa with their mechanism of action whenever applicable.
Natural products © 2020 SAAB. Published by Elsevier B.V. All rights reserved.
Green algae
Caulerpa
Caulerpaceae
Sea grapes
Bioactivities

1. Introduction infraspecific names. Ninety-seven of the species names are flagged as

Green algae of the family Caulerpaceae, represented by the genus
Caulerpa, occur worldwide, typically in shallow-water tropical and
subtropical marine habitats. Caulerpa prolifera (Forsskal) J. V. Lamour-
!
accepted taxonomically and are supported by the listed literature
below the species name (Guiry 2019). The thallus is composed of a
horizontal stolon connected by colorless rhizoids, connecting erect
photosynthetic fronds (assimilators) of diverse morphology including

oux was the first species from genus Caulerpa discovered in 1809
(Guiry 2019). Caulerpa has a dual advantage of providing a better
alternative food with therapeutic potential. They are salty and pun-
gent in style and are consumed by several marine cultures around
the world. C. lentillifera and C. racemosa are the most generally edible
with the common names viz. sea grapes, green caviar (England),
Bulung boni (Indonesea), Limu-fuafua (Hawaii), Lelato (Philippines),
and Kumejima (Japan) (Robledo and Pelegrin 1997). There are cur-
rently 163 species names within the literature, similarly to 228
* Corresponding author: Usama Ramadan. Minia University, Faculty of Pharmacy,
Minia 61519, Egypt. Tel.: +2-86-2347759, Fax: +2-86-2369075.
E-mail address: usama.ramadan@mu.edu.eg (U.R. Abdelmohsen).
spongy, thread-like, pinnate, blade-like and vesicular structures.
Radial branching is regarded as primitive and bilateral branching as
more recent based on interpretations which are supported by ultra-
structure of chloroplasts. The reduction of light leads to the modifica-
tion of erect parts from radial to bilateral symmetry. The thallus is
composed of coenocytic filament walls principally of 1,3 xylan, with
various trabeculae traversing the lumen. Caulerpa is wide spread and
considered as invasive marine algae due to its ability for rapid plug
formation after wounding to prevent the loss of cell content. When
wounded by grazing fish, the blade or rhizome exude a yellowish
sticky mass which hardens to a wound plug in a few minutes to pre-
vent the loss of cell content (Weissflog et al. 2013). Meiosis occurs at

https://doi.org/10.1016/j.sajb.2020.04.031
0254-6299/© 2020 SAAB. Published by Elsevier B.V. All rights reserved.
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 1. Caulerpa racemosa from Hurghada City coast line, Red Sea (Egypt).
gametogenesis with the formation of gametes in unmodified areas of
the thallus, without separation by cross walls. The gametes are liber-
ated in gelatinous extrusions through superficial papillae. C. okamurai
is monoecious with both sexes separated throughout thallus whereas
C. prolifera is dioecious (Guiry 2019).
Caulerpa is resistant to herbivorous fishes due to its high content
of sesquiterpenes and other phytochemicals that act as a chemical
defense against herbivorous fishes (Paul et al. 1987). Although Cau-
lerpa has not attracted the most attention of researchers, therapeutic
potency of pure compounds isolated from Caulerpa are promising as
antiviral, antimicrobial, cytotoxic, immunostimulatory, anti-obesity,
cardioprotective, hepatoprotective and hypolipidemic agents. Some
metabolites such as caulerpin, caulersin, and caulerpenyne have
brought great attention in structure elucidation and total synthesis
attributable to their uncommon structural complexity and interesting
pharmacological properties. This review covers the literature on the
genus Caulerpa, focusing on its chemical and medicinal potency.
Fig. 1
1.1. Caulerpa ashmeadii Harvey 1858
Caulerpa ashmeadii is amongst the foremost resistant Caulerpa
species to herbivorous fishes due to its high content of sesquiter-
penes which act as a chemical defense mechanism against herbivo-
rous fishes (Paul et al. 1987). (1E,3Z)-3-[(acetyloxy)methylidene]-5-
(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-ene-1,4-diyl diacetate
(1), (1E,3E)-3-formyl-5-(2,6,6-trimethylcyclohex-2-en-1-yl)penta-
Fig. 2. Chemical structures of compounds 1-11; (1- 6, 8-11 are sesquiterpenes and 7 is bisindole alkaloid).
227
1,3-dien-1-ylacetate (2), (2E)-2-[2-(2,6,6-trimethylcyclohex-2-en-1-
yl)ethylidene]butanedial (3), (2E)-2-(2-oxoethyl)-4-(2,6,6-trimethyl-
cyclohex-2-en-1-yl)but-2-en-1-yl acetate (4), (2Z)-2-[(E)-2-(acety-
loxy)ethenyl]-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-2-en-1-yl
hexadecanoate (5) and (2Z)-2-[(E)-2-(acetyloxy)ethenyl]-4-(2,6,6-tri-
methylcyclohex-2-en-1-yl)but-2-en-1-yl (2E)-hexadec-2-enoate (6)
(Figure 2) were identified as sesquiterpenes, isolated from C. ashmea-
dii and collected close to Pine Key (Florida) (Paul et al. 1987). Com-
pound (1) in addition to the bisindole alkaloid caulerpin (7) were
detected as major metabolites of C. ashmeadii. These compounds
except (5) and (6), were active towards at least one marine bacte-
rium. Also, compound (2) was active toward the marine fungus Lage-
nidium Callinectes and was the most active compound overall.
Compounds (3) and compound (4) also showed activity towards all
tested bacteria. Compounds (1-7) have often been proposed to func-
tion as chemical defenses in Caulerpa species (Paul et al. 1987). The
major chemical defenses in Caulerpa species contributed to the terpe-
noid metabolites which contain aldehyde, enol acetate or any other
active groups. These compounds are produced in large concentra-
tions but are often not readily isolated because of their unstable and
reactive chemical natures (Paul et al. 1987). Caulerpin (7) was chemi-
cally synthesized in three reaction steps with an overall yield of 11%.
The key reaction concerned a radical oxidative aromatic substitution
which included xanthate and 3-formylindole compounds. It was also
economically synthesized with a new easy-handled procedure to
give a higher overall yield of 25.4 % (Chay et al. 2014). Caulerpin (7)
and all other prepared bis-indole compounds were detected as an
antibacterial against the M. tuberculosis, where caulerpin (7) was
extremely active with half maximal inhibitory concentration value
(IC50) of 0.24 mM (Chay et al. 2014). Cytotoxic activity of caulerpin
(7) was evaluated in six human cancer cell lines, including human
leukemia (K562), human lung cancer (A549), human cervical cancer
(HeLa), human colon cancer (HT29), human breast cancer (SK-BR-3),
and human liver cancer (Huh7) cell lines. Caulerpin (7) exhibited
cytotoxicity with IC50 values of 4.67, 4.20, 1.95, 4.04, 3.71 and
0.72 mM, respectively (Li et al. 2018). The in vivo anti-inflammatory
study of caulerpin (7), (4 mg/kg) using the murine model of peritoni-
tis and ulcerative colitis mice showed promising results in ameliorat-
ing the damage observed in ulcerative colitis. This dose was able to
reduce the pro-inflammatory cytokines in 3% dextran sulfate sodium
(DSS) colitis model, such as nuclear factor kappa-light-chain-
enhancer of activated B cells (NFkB p65), tumor necrosis factor alpha
(TNF-a), interferon gamma (IFN-g ), interleukin 6 (IL-6), and
228 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
interleukin 17 (IL-17) levels, plus increased the levels of interleukin
10 (IL-10) in the colon tissue (Lucena et al. 2018). The mechanism of
wound repair detected in C. ashmeadii collected from the west coast
of Florida (USA), was extremely rapid and efficient. The wound plug
consisted primarily of polysaccharide as well as sulfated forms with
low levels of protein within the wound plug present from cyto-
plasmic leakage at the start of the wounding response. An initial
shrinkage of the vegetative cytoplasm from the wound space
occurred upon wounding, a cytoplasmic band extended across the
wound plug within 1 h after wounding and after 2 h, migrated to an
edge adjacent to the wound plug. Cytological changes were detected
after 30 min to 6 h in a wound cytoplasm which was similar in
appearance to active areas. New wall formation began within 2 h fol-
lowing wounding and was complete by 48 h after wounding (God-
dard and Dawes 1983).
1.2. Caulerpa bikinensis W. R. Taylor 1950
(1E,3E)-4-(acetyloxy)-2-[2-(2,2-dimethyl-6-methylidenecyclo-
hexyl)ethyl]buta-1,3-dien-1-yl acetate (8), (2E)-2-[2-(2,2-dimethyl-
6-methylidenecyclohexyl)ethyl]but-2-enedial (9) and 3-[2-(2,2-
dimethyl-6-methylidenecyclohexyl)ethyl]-5-hydroxyfuran-2(5H)-
one (10) (Fig. 2) were detected as monocyclofarnesol-derived sesqui-
terpenoids with toxic and feeding deterrence properties, from C. biki-
nensis W. R. Taylor, collected from Palau (Western Caroline Islands)
(Paul and Fenical 1982). An unnamed sesquiterpenoid (11) detected
in C. bikinensis was a potent inhibitor of bee venom derived phospho-
lipase A2 (PLA2). These enzymes play a major role in both phospho-
lipid turnover and the regulatory mechanisms controlling
inflammatory responses since the release of arachidonic acid by PLA2
and its subsequent metabolism by the cyclooxygenase or the 5-lipox-
ygenase enzyme systems leads to the synthesis of the bioactive eico-
sanoids (thromboxane, prostaglandins, and leukotrienes) (Mayer
et al. 1993). Sesquiterpenoid (11) was detected as an inhibitor by 63%
for hydrolysis of phosphatidylcholine comparable with manoalide as
control at 0.25 mM (Mayer et al. 1993)..
1.3. Caulerpa brachypus Harvey 1860
Various sulfated polysaccharides (SPs) fractions detected in C. bra-
chypus collected from Kamakura (Japan) were reported for anti-Her-
pes simplex virus type one (HSV-1) activity. All SPs fractions had
potent anti-HSV-1 activities (IC50= 0.38-8.5 mg/mL) with low toxicity.
Among the polysaccharides tested, two polysaccharides (SX4 and SP4
from C. brachypus) showed strong anti-HSV-1 activities (IC50= 6.0 and
7.5 mg/mL, respectively), even upon addition to the medium 8 h
post-infection. These experiments showed that some sulfated poly-
saccharides do not only inhibit the first stages of H. simplex replica-
tion such as virus binding to and penetration into host cells. They can
also conjointly interfered with late steps of virus replication. These
results showed that some sulfated polysaccharides from chlorophyte
might be promising candidates as antiviral agents that could act on
different stages within the virus replication cycle (Lee et al. 2004).
1.4. Caulerpa brownii (C. Agardh) Endlicher 1843
(1E,3E)-2-({(1R,2R,5R)-5-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-4-
oxo-3,6-dioxabicyclo[3.1.0]hex-2-yl}methyl)buta-1,3-diene-1,4-diyl
diacetate (12), (1Z,3E,6E,14E,15E)-2-[(acetyloxy)methyl]-14-[(acetyloxy)
methylidene]-10-(hydroxymethyl)-6-methylhexadeca-1,3,6,15-tet-
raene-1,16-diyl diacetate (13), (1E,5E,9E)-2-[(E)-2-(acetyloxy)ethenyl]-
14-formyl-6,10-dimethyl-12-oxopentadeca-1,5,9,14-tetraen-1-yl acetate
(14) and (5S,6S,13E,14E)-O~15~-acetyl-20-(acetyloxy)-5-hydroxy-15,20-
didehydro-5,6,7,8,11,12-hexahydroretinol (15) (Fig. 3) were character-
ized as diterpenoids detected in C. brownie collected from Southern Aus-
tralia (Paul and Fenical 1985). These metabolites inhibited cellular
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
division within the fertilized sea urchin egg bioassay at concentration of
8 mg/ml. Compound (15), a diterpenoid alcohol was tested at disc con-
centration (100 mg/disk) against several marine bacteria and displayed
inhibitory activity (excess than 4 mm) toward V. harveyi and V. legiogan-
thi, S. aureus, B. subtills, E. coli and V. anguillarum, using the standard Disc
diffusion assay method (Paul and Fenical 1985). (2E)-2-[(3E,7E)-4,8,12-
trimethyltrideca-3,7,11-trien-1-yl]but-2-enedial (16), (1E,6E,10E)-3-for-
myl-7,11,15-trimethylhexadeca-1,6,10,14-tetraene-1,3-diyldiacetate
(17), (14E)-O~15~-acetyl-13-(acetyloxy)-20-oxo-4,15-didehydro-
6,7,8,11,12,13-hexahydroretinol (18), (2Z,5E,9E)-6,10,14-trimethyl-2-(2-
oxoethylidene)pentadeca-5,9,13-trien-1-ylacetate (19), 20-(acetyloxy)-
4,5-didehydro-5,6,7,8,11,12-hexahydroretinal (20), with unnamed diter-
penoid, compound (21) and compound (22) (Fig. 3) were detected in C.
brownii collected from Tasmania (Australia). This species exists in two
morphological forms (branched and unbranched) and each form having
a totally different profile of diterpenoid secondary metabolites (Fig. 3)
(Handley and Blackman 2005). Caulerpol (23) a diterpene alcohol and its
esters (24-29) (Fig. 3) were detected in C. brownii in Tasmania (Australia)
Handley, 2003 .
1.5. Caulerpa chemnitzia (Esper) J. V. Lamouroux 1809
Extracts of hexane, chloroform, ethyl acetate, acetone and metha-
nol were prepared from C. chemnitzia (Esper) J.V. Lamououx, collected
from Mandapam (Biosphere, India), and tested for phytochemical and
bactericidal activity. There were high quantities of terpenoids, tan-
nins and phenolic resin compounds in the ethyl acetate extract. How-
ever, cardiac glycosides were detected only in acetone and methyl
alcohol extracts. Bactericidal activity was highest in the ethyl acetate
extract against B. subtilis, S. pyogenes, E. coli, K. pneumoniae, V. chol-
erae, P. mirabilis, P. vulgaris, P. aeruginosa, S. flexneri, and S. typhimu-
rium. It displayed considerable antibacterial properties with mean
inhibition zones from 7.1 to 13.6 mm, minimum inhibitory concen-
trations (MICs) value between 125 and 500 mg /mL and the minimum
bactericidal concentrations (MBCs) value from 250 to 1000 mg/mL.
The best mean zone of inhibition (13.6 mm) and the lowest MIC (125
mg/mL) and MBC (250 mg/mL) values were determined in the same
extract against B. subtilis (Raj et al. 2015).
1.6. Caulerpa cupressoides (Vahl) C. Agardh 1817
Sulfated polysaccharides (SPs) detected in C. cupressoides var. fla-
bellata, collected from Nísia Floresta (Brazil) had anticoagulant, anti-
oxidant and strong immunostimulatory activities with potential
biomedical and nutraceutical applications (Barbosa et al. 2019). SPs
have potent immunostimulatory activities with wide biomedical
applications (Barbosa et al. 2019). Four SPs detected in C. cupressoides
var. flabellate, collected from nBu! zios beach (Brazil) were evaluated
for their antioxidant activity employing different antioxidant assays.
No activity in the superoxide and hydroxyl radical scavenging assay
Fig. 4. Chemical structures of compounds 30-36; (30-33 are sterols) and (34-36 are sesquiterpenes).
229
was recorded but they exhibited total antioxidant capacity and fer-
rous chelating activity. Moreover, Caulerpa polysaccharides showed
dose-dependent anticoagulant activities in the intrinsic (activated
partial thromboplastin time (aPTT) test) and extrinsic (prothrombin
time (PT) test) pathways (Costa et al. 2012). Lectins are carbohy-
drate-binding proteins that were detected in C. cupressoides var. lyco-
podium, collected from Pacheco (Brazil) (Rivanor et al. 2018). They
are known anti-nociceptive and anti-inflammatory agents (Rivanor
et al. 2018). The protective effects of lectins isolated from C. cupres-
soides var. lycopodium on hyper nociception inflammatory conditions
in temporomandibular joints (TMJ) of rats were tested. Lectins were
able to inhibit the nociceptive response produced by 1.5% capsaicin,
indicating the anti-nociceptive effect that acted directly on the pri-
mary nociceptive neurons and inhibited the nociceptive response
produced by carrageenan (100 mg /TMJ) or serotonin (5-HT) (225
mg/TMJ). The results demonstrated that the administration of lectins
had a potential antinociceptive and anti-inflammatory effect, with a
mechanism that is slightly dependent on interleukin 1 beta (IL-1b),
TNF-a, COX-2, and ICAM-1 inhibition and independently from the
cannabinoid and opioid system and NO/cGMP/PKG/K+ATP channel
pathway (Rivanor et al. 2018). Classical models of nociception using
male Swiss mice were adopted to evaluate the activity of pure glyco-
protein from C. cupressoides collected from Pacheco (Brazil). Doses at
(3, 9 or 27 mg/kg) significantly reduced the number of writhes
induced by acetic acid by 37.2%; 53.5% and 86.0%, severally. Glycopro-
tein was detected at dose 27 mg/kg reduced the second phase of the
formalin test and did not present important antinociceptive effects in
the hot plate test, when compared to morphine, suggesting that its
antinociceptive action is attributed to the peripheral mechanism. The
antinociceptive effects were repealed when glycoprotein was pre-
incubated with mucin (20 mg/kg). Intravenous administered glyco-
protein (9 mg/kg) in Wistar rats 30 min before carrageenan adminis-
tration reduced neutrophil counts by 65.9%. Similarly, glycoprotein
suppressed edematous paw in all time intervals, particularly during
the third hour. Intravenous administration of glycoprotein (9 mg/kg)
did not cause hepatic or renal alterations or body mass or microscopy
of the organs examined (Vanderlei et al. 2010).
1.7. Caulerpa faridii Nizamuddin 1964
The methanol extract of C. faridii, collected from sandy pools of
Manora (Karachi), had a fatty acid profile containing n-pentadeco-
nate, n-hexadeconate, n- heptadeconate, n-tricosanoate, n-tetracosa-
noate, n- pentacosanoate, n- heptacosanoate, 9-tetradecenoate,
pentadecanoate, heptadecanoate, nonadecenoate, 9- eicosenoate and
pentacosenoate. Also, dianoetic and trienoic fatty acid methyl esters
were detected such as 7-ethyl-3-methyl-2,6-undecadienoate, hexa-
decadienoate and heptadecatrienoate. In addition, 24-methyl choles-
terol (30), b- sitosterol (31), 24- methyl-cholesta7,22 dien 3b-ol (32)
230 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
and 4,24- dimethyl-cholesta-5,22-dien-3b-ol (33), (Fig. 4) are sterols
isolated from the same extract (Aliya and Shameel 2004).
1.8. Caulerpa filiformis (Suhr) Hering 1841
The responses of native herbivores to three Caulerpa spp. (C. fili-
formis, C. scalpelliformis, and C. taxifolia) collected near Sydney (Aus-
tralia), were examined. The extracts of C. filiformis deterred the
turbinid mollusc Turbo torquatus and the urchin Heliocidaris tubercu-
lata, while aqueous extract deterred Aplysia sydneyensis (Davis et al.
2005).
1.9. Caulerpa flexilis J. V. Lamouroux ex C. Agardh 1823
Flexilin (34) characterized by the presence of the 1,4-diacetoxy-
buta-1,3-diene moiety, was detected for the first time from a natural
product, in the hexane extract of C. flexilis collected close to Little
Christmas Island (Australia), (Fig. 4) Blackman and Wells, 1978. C.
flexilis collected from Tasmania (Australia) contained an appreciable
quantity of caulerpol (23) (Capon et al. 1983). (1E,3E)-3-[(acetyloxy)
methylidene]-5-(2,6,6-trimethylcyclohex-2-en-1-yl)pent-1-en-1-yl
acetate (35) and (2E)-3-formyl-5-(2,6,6-trimethylcyclohex-2-en-1-
yl)pent-2-en-1-yl acetate (36) (Fig. 4) are sesquiterpenes, detected in
C. flexilis (Lamx) var. muelleri collected from Australia (Capon et al.
1981).
1.10. Caulerpa kempfii A. B. Joly & S. M. B. Pereira 1975
The anti-inflammatory and antinociceptive activities of successive
extracts of C. kempfii collected along the coast of Pitimbu (Brazil)
were evaluated. The models of acetic acid-induced abdominal writh-
ing, hot plate test, and formalin-induced nociception were used to
evaluate the antinociceptive potential of the fractions, while the car-
rageenan-induced peritonitis test was used to investigate the anti-
inflammatory effect of C. kempfii. In the abdominal writhing test, hex-
ane, ethyl acetate, hydroalcoholic, and dipyrone induced inhibition
(76.7, 83.9, 90.8 and 89.3% respectively). In the hot plate test, C. kemp-
fii extracts did not increase the latency time of the animals evaluated.
Fig. 5. Chemical structures of compounds 37-46; (37, 39 are fatty acids, 40 is sterol, 41-42 are sesquiterpenes, and 38, 43-46 are triterpenes).
In the neurogenic phase of the formalin test, the hexane fraction eli-
cited 28.0% inhibition, 37.4% inhibition with the ethyl acetate extract
and 35.9% inhibition with the hydroalcoholic extract. In the inflam-
matory phase, the hexane extract exerted 55.1% inhibition, the ethyl
acetate extract 44.5% inhibition and the hydroalcoholic extract 54.9%
inhibition, while indomethacin inhibited 62.6%. Additionally, in car-
rageenan-induced peritonitis, a reduction in cell migration was
observed after treatment with all fractions (Da Matta et al. 2015).
1.11. Caulerpa lamourouxii (Turner) C. Agardh 1817
Caulerpin (7) was also detected in C. lamourouxii collected from
the Philippines Pai, 2018. b-Sitosterol (31), palmitic acid (37) and tar-
axerol (38) (Fig. 5) were detected in C. lamourouxii, C. racemosa var
clavifera, and C. sertularioides (Azhaguraj et al. 2012; Mehra et al.
2019). b-Sitosterol (31), has been associated with cardiovascular pro-
tection through augmented the antioxidant defense system and
down-regulated the serum cholesterol levels in humans with an anti-
inflammatory effect on endothelium (0.1-200 mM). It also inhibited
vascular adhesion molecule 1 and intracellular adhesion molecule 1
expression in (TNF-alpha)-stimulated human aortic endothelial cells
(HAECs) as well as the binding of monocytes (U937 cells) to (TNF-
alpha)-stimulated human aortic endothelial cells (HAEC) and attenu-
ated the phosphorylation of nuclear factor-kB p65 (Loizou et al.
2010). Additionally, it was evaluated for antibacterial activities
against S. typhimurium and reported as a novel therapy for inflamma-
tory intestinal diseases, down-regulated survival of intracellular S.
typhimurium and augmented expression of antimicrobial peptides.
This compound considerably alleviated microscopic appearances of
colitis induced by dextran sulfate sodium reduced the weight loss
and colon length with down-regulated the levels of (IL-1b, IL-6, and
TNF-a), in intestinal tissue of mice with experimental colitis in a
dose-dependent manner (100 to 200 mg/kg) (Ding et al. 2019). It also
played a considerable role in the regulation of leptin levels in high-
fat diet (HFD), circulating adiponectin and fructose-induced Type-2
diabetic rats (20 mg/kg) for a period of 30 days (Chandran et al.
2019). Palmitic acid methyl ester-induced neuro-protection occurs
independent of cerebral blood flow, alpha-7 nicotinic acetylcholine
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241 231

receptors were responsible for the potential neuro-protection mech- 1.14. Caulerpa mexicana Sonder ex Ku
€ tzing 1849
anism (Neumann et al. 2019). Administration of 0.25 and 0.75 mg/g
of taraxerol acetate suppressed tumor growth in a mouse xenograft The anti-inflammatory impact of the aqueous and methanol
from 1.2 g in the phosphate-buffered saline (PBS)-treated group (con- extracts of C. mexicana, collected from the coastal region of Bessa
trol) to 0.81 and 0.42 g, severally. Similarly, 0.25 and 0.75 mg/g tarax- (Brazil) was evaluated. Each extract was able to suppress cell migra-
erol acetate injection inhibited the tumor volume from 1.3 cm3 tion to the peritoneal cavity in a time-dependent manner. They con-
within the PBS-treated group (control) to 0.67 and 0.25 cm3, severally jointly reduced xylene-induced ear swelling (Bitencourt et al. 2011).
(Hong et al. 2016). Another study designed to analyze the impact of C. mexicana methyl
alcohol extract on the treatment of inflammatory bowel disease eli-
cited by dextran sulfate. The extract considerably ameliorated the
1.12. Caulerpa lentillifera J. Agardh 1837
clinical signs detected in colitis and reduced the amount of protein
from Th1 (IFN-g , IL-12, and TNF-a) and Th17 (IL-6 and IL-17)
The ethyl alcohol extract of C. lentillifera, farmed within the Philip-
response pattern. This reduction might be related to a diminution of
pines, was screened for antidiabetic activity. This extract considerably
tissue injury determined within the colon of the animals that
minimized dipeptidyl peptidase-IV and a-glucosidase enzyme activi-
received dextran sulfate sodium salt (Bitencourt et al. 2015). Sulfated
ties. It effectively repressed necrobiosis and inducible nitric oxide syn-
polysaccharides (SPs) isolated from C. mexicana, collected from Fle-
thase (iNOS) expression in interleukin-1b and interferon-g elicited
cheiras Beach (Brazil), were tested for antinociceptive and anti-
RIN cells. The ethyl alcohol extract considerably increased insulin
inflammatory activities by intravenous doses of 10 or 20 mg/kg. SPs
secretion, glucose transporter expression, glucose uptake in 3T3-L1
considerably reduced nociceptive responses, as measured by the
adipocytes and increased adipogenesis in a dose-dependent manner
number of writhes in response to acetic acid. It conjointly reduced
(Sharma and Rhyu 2014). The cardiovascular protecting effects of C.
the second phase responses within the formalin test. However, it
lentillifera, collected from the Semporna (east coast of North Borneo),
failed to exhibit a major antinociceptive impact in the hot plate test,
were recorded in rats receiving a high cholesterol/high-fat diet (HCF).
suggesting a peripheral mechanism for the antinociception action.
Supplementing 5% seaweeds to the HCF diet fed to rats considerably
SPs (5, 10 or 20 mg/kg), while subcutaneous administered in Wistar
reduced plasma total cholesterol (TC) levels (-11.4% to -18.5%), low-
rats one h before carrageenan, dextran, histamine or 5-hydroxytryp-
density lipoproteins cholesterol (LDL-C) levels (-22% to - 49.3%), and
tamine, were tested in paw swelling models. Concerning the anti-
triglycerides (TG) levels (-33.7% to -36.1%) levels and raised high-den-
inflammatory activity, SPs (10 or 20 mg/kg) reduced carrageenan-
sity lipoproteins cholesterol (HDL-C) levels (16.3% to 55%). The crude
induced paw edema and myeloperoxidase activity within the paw.
extract of C. lentillifera reduced weight gain, blood cell (GSH-Px), and
SPs (20 mg/kg) administered failed to show vital signs of toxicity
plasma lipid peroxidation of HCF diet rats to the values of normal rats
(Carneiro et al. 2014). Screening of extracts of common marine algae
(Matanjun et al. 2010). Additionally, the ethanol extract of C. lentillifera
from the Florida Keys at Chicago State University against an in-depth
collected from Okinawa (Japan) was considered a potential candidate
panel of the environmental bacterium concluded that extracts from
for the prevention of diabetes. It regulated glucose uptake and homeo-
C. mexicana exhibited vital activity against 2 conspecific strains of
stasis via the PI3K/AKT pathway in myocytes and diabetic mice
Vibrio sp. from Florida and one strain of Bacillus sp. from the Red Sea.
(Sharma et al. 2015). The nutrient contents of C. lentillifera, collected
The secondary metabolites content of C. mexicana inhibited the
from the Semporna (east coast of North Borneo) were analyzed and
expansion of one strain of Vibrio sp. or Bacillus sp. and showed broad-
showed the protein content was 10.41% of the dry weight with varia-
spectrum antimicrobial activity against potential pathogens within
tions within protein content of seaweeds because of the season. Fatty
the marine environment (Owens et al. 2015).
acids were detected such as palmitic acid (37), oleic acid (39), capric,
undecanoic, lauric, tridecanoic, myristic, myristoleic, pentadecanoic,
1.15. Caulerpa microphysa (Weber Bosse) Feldmann 1955
palmitoleic, heptadecanoic,cis-10-heptadecanoic, stearic, elaidic, lino-
lelaidic, linoleic, g -linolenic, a-linolenic, arachidic, cis-11-eicosenoic,
C. microphysa samples collected from Chinwan Bay (Taiwan) were
cis-11,14-eicosadienoic, cis-11,14,17-eicosatrienoic, cis-5,8,11,14,17-
digestible with Flavourzyme, Alcalase and pepsin. The angiotensin
eicosapentaenoic, behenic, erucic, cis13,16-docisadienoic, tricosanoic,
converting enzyme (ACE) restrictive activity of enzyme-digested C.
lignoceric and nervonic acid. Palmitic acid (C16:0) (37), and oleic acid
microphysa was minimized within the order of digestion with pepsin
(C18:1v9) (39) were the most abundant fatty acids (Figure 5). The total
> Flavourzyme > Alcalase. Thus the pepsin-extracted samples had
amino acid content detected in C. lentillifera was 48.19%. The highest
considerably higher activity than the other enzyme extractions (Lin
essential amino acid was phenylalanine, while the amino acid profile
et al. 2012). In vitro anti-tumor effects of C. microphysa, pepsin-
consisted of aspartic acid, glutamic acid, serine, glycine, histidine, argi-
digested extracts were applied to BALB/c mice with transplanted
nine, threonine, alanine, proline, tyrosine, valine, methionine, isoleu-
myelomonocytic leukemia (WEHI-3) and Human promyelocytic leu-
cine, leucine, phenylalanine and lysine (Matanjun et al. 2009).
kemia (HL-60) cell lines. The expansion of each cell line was inhibited
and extracts elicited DNA damage (Lin et al. 2012).
1.13. Caulerpa manorensis Nizamuddin 1964
1.16. Caulerpa okamurae Weber Bosse 1897
Cholesterol (40), (Figure 5) was detected in the methanol extract
of C. manorensis, collected from sandy pools of Manora (Karachi). The ethanolic extract of C. okamurae, collected from Jindo (South
Fatty acids were also detected such as n-octanoate, n- nonanoate, n- Korea) inhibited lipid accumulation and reduced the expression of
dodecanoate, n- tetradecanoate, n-pentadeconate, n-hexadeconate, the master regulator of adipogenesis, peroxisome proliferator-acti-
n- heptadeconate,n- docosanoate, n-tricosanoate, n-tetracosanoate, vated receptor-gamma, steroid regulatory component binding pro-
n- pentacosanoate, n- heptacosanoate, n- octadecenoate, n- nonade- tein-1c, and CCAAT/enhancer-binding protein-alpha in 3T3-L1
canoate, tridecenoate, 9-tetradecenoate, pentadecanoate,9-hexade- adipocytes in a high-fat diet (HFD) fed mice. This extract also consid-
cenoate, heptadecanoate, nonadecenoate and heneicosenoate. erably reduced body weight, fat weight and liver weight in the exper-
Dienoic fatty acid methyl esters were detected such as 7-ethyl-3- iment mice. This impact is like that of positive control G. cambogia
methyl-2,6-undecadienoate, hexadecadienoate and trienoic fatty extract, which has been approved by the Korean Food and Drug
acid methyl ester such as 3,7,11-trimethyl-2,6,10-dodecatrienoate Administration as a weight-loss food supplement in South Korea.
(Aliya and Shameel 2004). Similarly, markers of weight gain like free fatty acids, triglyceride,
232 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
total cholesterol, glucose, and insulin within the plasma and free fatty
acid, triglyceride, total cholesterol, and total lipid within the liver
were considerably reduced in ethanolic extract-treated HFD-fed
mice. Also, it considerably reduced peroxisome proliferator-activated
receptor-gamma, CCAAT/enhancer-binding protein-alpha, carboxylic
acid synthase, steroid regulatory element-binding protein-1cand ace-
tyl-CoA synthetase within the fatty tissue. Together, these findings
suggest that C. okamurae could be used as an attainable treatment for
obesity and associated metabolic disorders (Sharma et al. 2017).
1.17. Caulerpa paspaloides (Bory) Greville 1830
Proximate analysis of C. paspaloides, collected from many sites
along the west coast of Florida, was performed for determination of
ash, NaOH-soluble protein, lipid, and trichloroacetic acid (TCA)-solu-
ble carbohydrate. Ash, lipids, soluble carbohydrates, insoluble carbo-
hydrates, and proteins of the entire algae were estimated as 34.7, 3.4,
20.1, 33.5 and 8.3 % of dry weight, respectively (Dawes and Goddard
1978). The auxin indole 3-acetic acid was detected in extract of C.
paspaloides collected off the Florida Keys. The quantity of indole 3-
acetic acid present was estimated to be about 1 mg/kg of fresh weight
(Jacobs et al. 1985).
1.18. Caulerpa peltata J.V. Lamouroux 1809
Samples of C. peltata along with four Caulerpa species, collected
from different sites on the western Australian coast, were analyzed
for the presence of terpenoid metabolites. No important quantities of
terpenes was detected and caulerpin (7) was isolated but in a low
yield. However, the absence of isolatable quantities of terpenoids
from C. brownii and C. flexilis was surprising as samples of those spe-
cies collected from Tasmania (Australia) contained important
amounts of the diterpene caulerpol (23) and the sesquiterpene flexi-
lin (34), respectively (Capon et al. 1983).
1.19. Caulerpa prolifera (Forsskal) J. V. Lamouroux 1809
!
The methanol extract of C. prolifera collected from the Suez Canal
region (Egypt), was screened against some infective bacteria like E.
coli, P. aeruginosa, S. typhimurium, A. hydrophila, B. subtilis, and S.
aureus. The MICs indicated that algal extract inhibits B. subtilis and S.
aureus and MBCs ranged between 1 and 1.4 mg/mL (Selim et al.
2015). SPs detected in C. prolifera (P. Forsskal, Lamouroux), collected
from Natal (Brazil), were tested for osteogenic potential on human
mesenchymal stem cells isolated from human Wharton's jelly mes-
enchymal stem cells (hMSC-WJ) and the potential genotoxicity of SPs
was calculated by cytokinesis-block micronucleus assay. SPs subfrac-
tion (CP0.5) at 5 mg/mL exhibited high osteogenic potential proven
by the increase in alkaline phosphatase activity and the accumulation
of calcium in the extracellular matrix. SPs did not show toxicity
against hMSCs-WJ at a concentration of up to 10 mg/mL and after
72h of exposure (Chaves Filho et al. 2018). Caulerpenyne (41), an
unusual sesquiterpene and its acetylenic analog furocaulerpin (42),
were detected in chloroform extract of C. prolifera collected from Bay
of Salerno (Italy) (Fig. 5). Compounds (41-42) are very rare in nature
and appear to be peculiar to the algae of the family Caulerpaceae and
Codiaceae. The presence of furocaulerpin (42) within algae has bio-
genetic importance because the formation of furan rings in natural
compounds is interesting (De Napoli et al. 1981). Trans-hexamethyl-
tetracosa-hexane-3-ol (43), squalene derivatives such as squalene-
6S,7S-epoxide (44) and squalene-10S,11S- epoxide (45) were
detected in chloroform extract of C. prolifera, collected from Bay of
Salerno (Italy) (Fig. 5) (De Napoli et al. 1982). Additionally, (S)-
(-)-squalene-2,3-epoxide (46), (Fig. 5) was detected in C. prolifera (De
Napoli et al. 1980).
The methanol extracts of C. racemosa and C. prolifera collected
from Mediterranean coast lines were examined for restrained actions
on soybean lipoxygenase. C. prolifera methanol extract exhibited a
restrictive impact during a lipoxygenase enzyme activity assay. A
comparison of the chemical content of each species using HPLC
revealed that C. racemosa extract contained less caulerpenyne (41),
the main secondary metabolite of each alga. Additionally, pure cau-
lerpenyne (41) was found to repress lipoxygenase with an IC50 of
5.1 mM. It was concluded that caulerpenyne (41), the major second-
ary metabolite of Caulerpa species, is a novel lipoxygenase inhibitor
that can be simply obtained in high quantities from the abundant
algae (Cengiz et al. 2011). The two Caulerpa species (C. prolifera, and
C. taxifolia) collected from Balearic Islands (Spain) are also rich in cau-
lerpenyne (41) where its concentration is considerably higher in C.
prolifera than in C. taxifolia. Both species were assessed for the
changes created within the activities of antioxidant enzymes such as
lipid peroxidation levels in the liver of the teleost Coris julis. Glutathi-
one S-transferase, glutathione peroxidase and glutathione reductase
activities were considerably higher in both Caulerpa species com-
pared to the Posidonia oceanica that was employed as a negative con-
trol. No statistical difference existed in catalase activity between the
groups. Glutathione reductase activity is considerably higher in C.
prolifera than in C. taxifolia. Though there are recorded variations in
the antioxidant enzyme activities, there was no considered difference
in malondialdehyde concentration. It could be concluded that the
production of caulerpenyne (41) by Caulerpa species induced an anti-
oxidant adaptation in the liver of C. julis to prevent oxidative damage
(Sureda et al. 2006). Caulerpenyne-like esters e.g. dihydrocaulerpe-
nyne oleic acid methyl ester (47), dihydrocaulerpenyne linoleic acid
methyl ester (48), dihydrocaulerpenyne palmitic acid methyl ester
(49), dihydrocaulerpenyne palmitoleic acid methyl ester (50) and
dihydrocaulerpenyne myristic acid methyl (51) were detected in
chloroform extract of C. prolifera collected in the Bay of Salerno
(Italy). They are dihydro derivatives of caulerpenyne with an acetoxy
group substituted by fatty acid residues (Fig. 6) (De Napoli et al.
1983). (3Z,6E)-4-(acetyloxy)-3-[(acetyloxy)methylidene]-7,11-dime-
thyldodeca-6,10-dien-8-yn-1-yl (9E,12E,15E)-octadeca-9,12,15-tri-
enoate (52), (3Z,6E)-4-(acetyloxy)-3-[(acetyloxy)methylidene]-7,11-
dimethyldodeca-6,10-dien-8-yn-1-yl (5E,8E,11E,14E,17E)-icosa-
5,8,11,14,17-pentaenoate (53), (3Z,6E)-4-(acetyloxy)-3-[(acetyloxy)
methylidene]-7,11-dimethyldodeca-6,10-dien-8-yn-1-yl (11E)-icos-
11-enoate (54), (3Z,6E)-4-(acetyloxy)-3-[(acetyloxy) methylidene]-
7,11-dimethyldodeca-6,10-dien-8-yn-1-yl (5E,8E,11E,14E)-icosa-
5,8,11,14-tetraenoate (55), (3Z,6E)-4-(acetyloxy)-3-[(acetyloxy)
methylidene]-7,11-dimethyldodeca-6,10-dien-8-yn-1-yl
(7E,10E,13E)-hexadeca-7,10,13-trienoate (56), (3Z,6E)-4-(acetyloxy)-
3-[(acetyloxy)methylidene]-7,11-dimethyldodeca-6,10-dien-8-yn-1-
yl (6E,9E,12E,15E)-octadeca-6,9,12,15-tetraenoate (57), (2E,6E)-4-
(acetyloxy)-3-[(acetyloxy)methyl]-7,11-dimethyldodeca-2,6,10-
trien-8-yn-1-yl tetradecanoate (58), (2E,6E)-4-(acetyloxy)-3-[(acety-
loxy) methyl]-7,11-dimethyldodeca-2,6,10-trien-8-yn-1-yl (9E)-hex-
adec-9-enoate (59), (2E,6E)-4-(acetyloxy)-3-[(acetyloxy)methyl]-
7,11-dimethyldodeca-2,6,10-trien-8-yn-1-yl hexadecanoate (60),
(2E,6E)-4-(acetyloxy)-3-[(acetyloxy)methyl]-7,11-dimethyldodeca-
2,6,10-trien-8-yn-1-yl (9E,12E)-octadeca-9,12-dienoate (61), (2E,6E)-
4-(acetyloxy)-3-[(acetyloxy)methyl]-7,11-dimethyldodeca-2,6,10-
trien-8-yn-1-yl (7E,10E,13E)-hexadeca-7,10,13-trienoate (62) and
(2E,6E)-4-(acetyloxy)-3-[(acetyloxy)methyl]-7,11-dimethyldodeca-
2,6,10-trien-8-yn-1-yl (9E)-octadec-9-enoate (63) (Fig. 6) were
detected in C. prolifera collected from Saronicos Gulf (Greece)
(Figure 6). The isolated compounds were classified into two groups of
metabolites;1,2-dihydro-1-caulerpenyne (52-57) and tetrahydro-
2,3-didehydro-1-caulerpenyne (58-63) (Fig. 6). These compounds
characterized by the substitution of the terminal vinyl acetoxy group
of caulerpenyne by various fatty acid residues. The algal extract dis-
played significant antifouling activity against two of the major groups
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 6. Chemical structures of compounds 47-65 (47- 63 are caulerpenyne-like esters and 64-65 are chlorophylls).
of fouling organisms (marine bacteria and marine microalgae; Phae-
dactylum tricornutum) (Smyrniotopoulos et al. 2003). Acetone extract
of C. prolifera, collected from different depths (0"5 m) of the Mar
Menor lagoon (SE Spain), was analyzed for photosynthetic pigments.
Eighteen separate photosynthetic pigments were detected such as
chlorophylls a (64), chlorophylls b (65), chlorophyllide a, siphonein,
neoxanthin, neoxanthin-like, violaxanthin, microxanthin, micronone,
micronone like lutein-5,6-epoxide, siphonoxanthin, lutein, chloro-
phyll b!, chlorophyll a!, a-carotene, b-carotene, and phaeophytin a.
Siphonoxanthin was the most obvious carotene pigment in Caulerpa.
Chlorophyll a (64) and chlorophyll b (65), (Fig. 6) are the most com-
mon pigments and are responsible for the green color of these algae
(Hegazi et al. 1998).
1.20. Caulerpa racemose (Forsskal) J. Agardh 1873
!
SPs detected in C. racemosa collected from Pedra Rachada (Brazil),
did not process any signs of toxicity and reduced nociception and
inflammation activities in a way partly dependent on hemoxigenase-
1 (HO-1) pathway activation (Ribeiro et al. 2014). SPs fractions iso-
lated from the hot water extract of C. racemose collected from the
Gujrat coast (India) were analyzed for sugar content and found to
contain galactose, glucose, arabinose, and xylose as the major compo-
nent sugars. It contained 9-11 sulfate hemiester groups. Sulfation and
methylation occur on O-6 of galactose and O-3 of arabinose. Sugar
linkage analysis indicated that this polysaccharide was branched and
principally contained 1,3- and 1,3,6-linked galactose, 1,3,4-linked
arabinose, 1,4-linked glucose, terminal- and 1,4-linked xylose resi-
dues. The hot water extract was a selective inhibitor of reference
strains and TK(-) acyclovir-resistant strains of Herpes simplex virus
type one (HSV-1) and type two (HSV-2) in Vero cells with antiviral
effective concentration (EC50) values within the range of 2.2-4.2 mg/
mL and lacking to toxic effects and anticoagulant properties at con-
centrations near to the EC50 (Ghosh et al. 2004).
233
The antiproliferative and apoptotic effects on SHSY5Y and Kelly
cell lines, for both extracts and refined caulerpenyne (41) of C .race-
mosa var. cylindracea, collected from Seferihisar coast lines (Turkey)
were investigated. The IC50 values were 0.59 § 0.06; 1.06 § 0.23 g
wet alga and 5.64 § 0.09; 6.02 § 0.09 mM CPN for C. racemosa var.
cylindracea extract and purified caulerpenyne (41) on SHSY5Y and
Kelly cell lines, respectively. Percentages of apoptotic cells of SHSY5Y
and Kelly in 0, 0.1 and 1 mM CPN conditions were 1.00 § 0.71, 3.00 §
0.71 and 49.40 § 3.78, 39.60 § 6.19 and 78.00 § 2.74, 69.40 § 3.78%,
respectively (Cavas et al. 2006). Extracts of C. racemosa and C. taxifolia
were tested against some gram-positive, gram-negative bacteria and
fungal pathogens. Methyl alcohol extract of C. taxifolia showed good
activity against B. subtillis, M. luteus and C. albicans, whereas methyl
alcohol extract of C. racemosa showed high activity against S. aureus,
E. coli and E. aerogenes (Etcherla and Rao 2014).
Methyl alcohol extract of C. racemosa collected from the Gulf of Man-
nar (India) was tested for antibacterial and larvicidal activities. It exhib-
ited antibacterial activity against the tested pathogens with the
maximum zone size of 16 mm observed for P. aeruginosa followed by E.
coli and S. typhi. Larvicidal activity against Culex tritaeniorhynchus larvae
revealed that the lethal concentration of C. tritaeniorhynchus larvae
required for the 50% mortality after 24 h of incubation was 63.324 mg/L.
The bioactive compounds within the crude extract were identified
by GC-MS as 2-(-3-bromo-1-adamantyl) acetic acid methyl ester and
Chola-5, 22- dien-3-ol (Nagaraj and Osborne 2014).
Another report for the larvicidal activity of the ethyl alcohol
extract of C. racemosa collected from the coast of Karachi (Pakistan),
showed significant activity via killing the 4th instar larvae of yellow-
fever mosquito, Aedes aegypti (Linnaeus), at doses LC50 =1000 ppm
(Sultana et al. 2010). Ethanol extract of C. racemosa showed toxicity
against fourth instar larvae of Aedes aegypti, Culex quinquefasciatus
and Anopheles stephensi (LC 50 =0.055 6§0.010 3, 0.067 5§0.136 0 and
0.066 1§0.007 6 mg/mL, respectively) (Ali et al. 2013).
Caulerpicin C14 (66), caulerpicin C16 (67), caulerpicin C18 (68),
caulerpicin C20 (69), caulerpicin C22 (70), caulerpicin C24 (71), and
234 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 7. Chemical structures of compounds 66-76; (66- 72 are ceramides, 73-74 are fatty acids, and 74- 75 are diterpenes).
caulerpicin C26 (72) (Fig. 7) were detected in extracts of C. racemosa
collected from Sri Lanka. Caulerpicin comprised a combination of
ceramides derived from 2S, 3R-sphinganine with C18 (32%), C20(2%),
C22(6%), C24(35%) and C26(25%) saturated fatty acid (Figure 7)
(Mahendran et al. 1979; Nielsen et al. 1982).
The poly acetylenic fatty acid (8E,12Z15Z)-10-hydroxy-8,12,15-
octadecatrien-4-6,-diynoic acid (73) and its methyl ester (74) was
detected in the ethanol extract of C. racemosa collected from the
Zhanjiang coastline (China). Moreover, the known secondary metab-
olites cholesterol (40), trans- phytol (75), trans- phytol acetate (76),
(Fig. 7) and fucosterol (77) and clionasterol (78), (Fig. 8) were also
detected (Mao et al. 2011). Trans-phytol (75) strongly inhibited estro-
gen synthesis (IC50= 0.5 mM), reduced aromatase messenger RNA and
protein expression levels in human granulosa cell line (KGN) and had
no impact on the aromatase catalytic activity in aromatase overex-
pressing of subclone HEK293A cell line, recombinant expressed aro-
matase, and attenuated the expression of aromatase promoter I.3/II.
Although trans-phytol (75) attenuated the phosphorylation or pro-
tein expression of cAMP response, it did not affect intracellular cyclic
AMP (cAMP) levels. Trans-phytol (75) is also a replacement supply of
tissue-selective aromatase modulators and is a new pharmaceutical
tools for the hindrance and treatment of estrogen-dependent cancers
(Guo et al. 2014).
Cholesterol (40), fucosterol (77), clionasterol (78), 22-(E) -dehydro-
cholesterol (79), 24-methylenecholesterol (80), dihydrobrassicasterol
(81), poriferasterol (82), clerosterol (83) and brassicasterol (84),
(Fig. 8) are sterols detected in C. racemosa and collected from Cap-Vert
(Dakar) (Aknin et al. 1992). Sterols such as (23E)-3b-hydroxy-stig-
masta-5,23-dien-28-one (85),(3b,24R)-stigmasta-5,28-diene-3,24-
diol (86), (3b,24S)-stigmasta-5,28-diene-3,24-diol (87), (22E)- 3b-
hydroxy-cholesta-5,22-dien-24-one (88), 24R,28S-epoxyfucosterol
(89), 24S,28R-Epoxyfucosterol (90), (diterpenoids) racemobutenolids
A (91), racemobutenolids B (92), 4a,5a-dehydrodiodictyonema A (93),
(a-tocopheroid) a-tocoxylenoxy (94), (a-tocopheroid) a-tocospiro A
(95), a-tocopherol quinone (96) and a-tocospirone (97), (Fig. 8) were
detected in ethanol extract of C. racemosa collected from the Zhanjiang
coastline (China). Compounds (93- 94) represent the first naturally
occurring hematinic acid ester group and 3,5-dimethylphenoxy func-
tionality, respectively. The enzyme inhibitory activities of the isolated
compounds were estimated in vitro against PTP1B and related PTPs
(TCPTP, CDC25B, LAR, SHP-1, and SHP-2) (Yang et al. 2015). b-sitos-
terol (31), chlorophyll a (64),1-eicosapentaenoyl-2-linolenoyl-3-galac-
tosyl glycerol (98) (Fig. 8) and unsaturated hydrocarbons were
detected in the dichloromethane extract of C. racemosa collected from
Marinduque (Philippines) (Consolacion Y. Ragasa1 et al. 2015).
10-keto-3,7,11-trimethyldodecanoic acid (99), caulerpinic acid
(100), monomethyl caulerpinate (101) were detected in the ethyl
acetate extract of C. racemosa collected from Visakhapatnam coast
(India) (Anjaneyulu et al. 1991). Caulerchlorin (102) is a chlorinated
bisindole alkaloid along with three known related metabolites, cau-
lerpin (7), monomethyl caulerpinate (101), and caulersin (103),
(Figure 9) were detected in the Chinese C. racemosa. Compounds
(101"103) and (7) were examined for their antifungal activity
against C. albicans, C. parapsilosis, C. glabrata, M. gypseum, T. rubrum,
A. fumigatus, and C. neoformans. Only compounds (101) and (102) had
a moderate/weak antifungal activity against C. neoformans (minimum
inhibitory concentration for 80%, MIC80=16 and 64 mg/mL, respec-
tively) (Liu et al. 2012).
Racemosin A (104), racemosin B (105) and caulerpin (7), (Figure 9)
were detected in 95% aqueous ethanol extract of C. racemosa collected
from the Zhanjiang coastline (China). A plausible biosynthetic pathway
of (104) and (105) was proposed as racemosin A (104) derived from
0
the oxidative cleavage of the D3(8) and D2 (9) double bonds of caulerpin
(7), caulerchlorin (102), and monomethyl caulerpinate (100) and then
reduction of the two carbonyls at C-3 and C-20 accompanying cycliza-
tion of C-3"C-20 of racemosin A (104) via a free radical mechanism
might further give racemosin B (105) . In a neuro-protective assay,
compound (104), significantly attenuated the Ab25"35-induced SH-
SY5Y cell damage with a 14.6% increase in cell viability at 10 mM
when compared to epigallocatechin gallate (EGCG, 16.57% increase at
10 mM) as the positive control Liu et al., 2013.
Racemosin C (106), is a unique minor bis-indole alkaloid charac-
terized by a naturally new 8-hydroxy-2,4,6-cyclooctatrienone ring
fused with two indole systems and caulersin (103) were detected in
C. racemose. Compounds (103) and (106) exhibited vital protein tyro-
sine phosphatase-1B (PTP1B) inhibitory activity (IC50= 5.86 § 0.57
and 7.14 § 1.00 mM, respectively) compared with the positive con-
trol oleanolic acid (IC50 = 3.03 § 0.20 mM). Based on the data
obtained, the Caulerpa bisindole alkaloids may be counted as a class
of PTP1B inhibitors, (Fig. 9) (Yang et al. 2014).
Benzene sulfonyl indole-2,3-dicarboxylic anhydride reacted with
methyl 1-benzenesulfonylindole-2-acetate to give the corresponding
2-acylindole-3-carboxylic as the highest yield product that can be
used to regenerate caulersin (103) in four steps. Under the same condi-
tions, three isomers A, B, and C were chemically prepared by the reac-
tion of indole-2,3-dicarboxylic anhydrides with methyl indole acetates
(Miki et al. 2006). Caulerpin (7) and its closely related derivative cau-
lerpinic acid (100) were detected on experimental model rat liver
mitochondrion for the mitochondrial targeting activity. Each com-
pound selectively reduced respiratory complex II activity while
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 8. Chemical structures of compounds 77-98; (77- 90 are sterols, 91-93 are diterpenes, 94-97 are tochopheroids, and 98 is glycerol derivative).
complexes I, III, and IV remained functional. Consequently, it was
hypothesized that each algal metabolite might be used as an antineo-
plastic agent in cell lines with defects in mitochondrial complex I such
as ovarian cancer cisplatin-resistant cell lines with a defective complex
I function. This afforded novel insight towards the potential use of
metabolites from invasive Caulerpa species for the treatment of human
ovarian carcinoma cisplatin-resistant cells (Ferramosca et al. 2016).
Caulerpin (7) was tested for antinociceptive and anti-inflamma-
tory activities using several animal models. It showed a reduction
within the acetic acid-induced nociception at 0.0945 mmol and for
dypirone, it was 0.0426 mmol in the abdominal constriction test.
Within the hot plate test, the inhibition of nociception by caulerpin
(7) (100 mmol/kg) was additionally favorable. Supported by these
results, it was concluded that this compound exhibited a central
activity, without changing the motor activity. Also, caulerpin (7) (100
mmol/kg) decreased the formalin effects in each phase by 35.4% and
45.6%, respectively. The possible observed anti-inflammatory activity
of caulerpin (7) (100 mmol/kg") was confirmed on the capsaicin-
induced ear edema model, where inhibition of 55.8% was presented.
Moreover, within the carrageenan-induced peritonitis, caulerpin (7)
(100 mmol/kg) exhibited anti-inflammatory activity, considerably
reducing the number of recruit cells by 48.3% (De Souza et al. 2009).
235
The first report for the isolation of prenylated para-xylenes from
green algae was recorded for caulerprenylol A (107) and caulerpreny-
lol B (108) (Fig. 9) isolated from the C. racemosa, collected from the
Zhanjiang coastline (China). Caulerprenylol B (108) was additionally
characterized by the associate indane ring system. In vitro bioassays
showed that the two compounds exhibited a broad spectrum of anti-
fungal activity against C. glabrata, T. rubrum and C. neoformans with
MIC80 values between 4 and 64 mg/mL when compared to amphoter-
icin B (MIC80 values of 2.0, 1.0, and 4.0 mg/mL, respectively) as a posi-
tive control. It also showed no growth inhibition activity against the
tumor cells HL60 and A549 Liu et al., 2013.
1,5-Diphenyl-1,4-pentadiene (109), trans-cinnamyl-1-phenyl-2-
propenyl ether (110), dicinnamyl ether (111), cinnamyl-3-phenyl-1-
propenyl ether (112) and cinnamyl dihydro cinnamate (113), (Fig. 9)
are aromatic derivatives detected in C. racemosa collected from Visa-
khapatnam coast (India) (Anjaneyulu et al. 1992). Metabolites identi-
fied in abundantly grown C. racemosa var. cornyphora collected from
Saurashtra coast (India), by GC- MS, were amino acids such as L-
valine, carboxylic acids such as cyclohexaneacetic acid, methoxyace-
tic acid, fatty acids such as palmitic acid (37), butanedioic acid, myo-
inositol, scyllo- inositol, polyol compounds such as glycerol, second-
ary alcohols such as 1, 2, 3- butanetriol, sugars such as D-(-)-
236 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 9. Chemical structures of compounds 99-114; (99 is fatty acid, 100-106 are bisindol alkaloids, 107-113 are aromatic derivatives, 114 is sesquiterpene).
tagatose, D-(+)-xylose, D-2- deoxyribose,d-galactose,d-mannose and
sugar alcohol such as 1-heptanol, D-mannitol and D- sorbitol.
On the other hand, metabolites identified by GS-MS in abundantly
grown C. racemosa var. macrophysa collected from Saurashtra coast
(India), were amino acids such as glycine, amino fatty acid such as 4-
aminobutanoic acid, carboxylic acids such as methoxyacetic acid,
fatty acids such as butanedioic acid, malic acid, myo-inositol, scyllo-
inositol, miscellaneous such as monocarpin, polyol compounds such
as glycerol, L-(-)- arabitol, secondary alcohols such as 1, 2, 3- butane-
triol, sugars such as D-(-)- tagatose, D-(+)-xylose, D- arabinose, d-
galactose, d-mannose, D-ribose, D-xylopyranose, methyl galactoside,
sugar acids such as glyceric acid and sugar alcohol such as 1-heptanol
and D-mannitol.
Similarly, GC- MS analysis of the abundantly grown C. racemosa var.
occidentalis, collected from Saurashtra coast (India), revealed the pres-
ence of amino acids such as L- valine, carboxylic acid such as methoxy-
acetic acid, fatty acids such as palmitic acid (37), butanedioic acid,
docosanoic, myo-inositol, scyllo- inositol, miscellaneous such as mono-
carpin, organic acids such as lactic acid, polyol compounds such as glyc-
erol, sugar such as 2-a-mannobiose, b-L-(-)-fucopyranose, D-(-)-
tagatose, D-(+)-xylose, D-2- deoxyribose, D- arabinose, d-galactose, d-
mannose, sugar acids such as glyceric acid and sugar alcohols such as D-
mannitol and D-sorbitol. Caulerpa spp. (CRM: C. racemosa var. macro-
physa, CRC: C. racemosa var. cornyphora, and CS:C. scalpelliformis) have
potential total antioxidant activity (>50%), and the highest scavenging
activity potential (>60%) was found in CRM followed by CS and CRC
extracts. CRM and CS extracts also showed maximal reducing activity
(>78%). A low half-maximal effective concentration (EC50) for different
biochemical activities was determined for Caulerpa spp., especially CRM
(total antioxidant: 150.8 § 5.7, scavenging: 560 § 2, and reducing:
86.4 § 3.1 mg/mL) compared to other alga (CRC: C. racemosa var. corny-
phora, and CS: C. scalpelliformis) . CRC, CRM, and CS showed consider-
ably high total phenolic contents, 29.2 § 2.4 and 25.0 § 3.2 mg gallic
acid equivalents (GAE)/g extract, respectively. High total flavonoid con-
tent was detected in CRC (562 § 44), and CRM (523 § 60 mg quercetin
equivalents (QE)/g extract). The principal component analysis confirmed
that CRC may be a rich supply of phenolics and flavonoids (Tanna et al.
2018). Solvent extracts of ethanol, chloroform, petroleum ether and
water were prepared from C. racemosa var. occidentalis, collected from
the Red Sea coast of Jeddah (KSA) and were tested for antibacterial
activity against a range of infective bacteria like S. aureus, E. faecalis, E.
coli and P. aeruginosa. The water extract was inactive against the
selected infective bacteria, petroleum ether extract was active against E.
faecalis with a mean inhibition zone value of 9.5 mm and the chloroform
extract was active against all tested infective bacteria with mean inhibi-
tion zone values ranged from 9.6 to 30 mm. The total protein (1.77%),
total fat (0.12%), flavonoids specifically rutin (0.55§0.01 mg/kg), querce-
tin (0.15§0.014 mg/kg), and kaempferol (0.07§0.02 mg/kg) were also
quantified in each extract (Al-Saif et al. 2014).
1.21. Caulerpa scalpelliformis (R. Brown ex Turner) C. Agardh 1817
The metabolic pattern of the abundantly grown C. scalpelliformis,
collected from the Saurashtra coast (India) was investigated using
GC-MS analysis. The identified metabolites were amine such as tyra-
mine, amino acids such as alanine, glycine, L- asparagine, L-cysteine,
L-tyrosine, carbonic acid such as arabinonic acid, dicarboxylic acid
such as succinic anhydride, fatty acid such as palmitic acid (37), 3, 4,
5- trihydroxypentanoic acid, butanedioic acid, methylsuccinic acid,
myo-inositol, myristic acid, scyllo- inositol, organic acid such as lactic
acid, nonanoic acid, oxalic acid, polyol compound such as glycerol,
sugars such as 4- ketoglucose, D-(-)- tagatose, D-(+)-ribono-1,4-lac-
tone, D-(+)-xylose, D-2-deoxyribose, D-arabinose, d-galactose, D-glu-
cose, DL-glyceraldehyde, d-mannose, D-psicose, D-ribose,
gluconolactone, glyceryl-glycoside, L-(-)-sorbose, L(+)-erythrulose,
levoglucosan, sedoheptulose, sugar acids such as glyceric acid, L-
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
threonic acid and sugar alcohol such as 1-heptanol, arabinitol, d-
galactitol, d-mannitol and xylitol. C. scalpelliformis showed a high
total phenolic content (23.8 § 3.3 mg(GAE)/g extract) and a high total
flavonoid content (769 § 33 mg (QE)/g extract) (Tanna et al. 2018).
1.22. Caulerpa sertularioides (S.G. Gmelin) M. Howe 1905
The methanol extract from C. sertularioides collected from the
north-west coast of Mexico, was examined for the hindrance of shrimp
vibriosis, caused by Vibrio parahaemolyticus and Vibrio alginolyticus.
Additionally, the methyl alcohol extract was investigated for antibacte-
rial activity. Extracts effects on the mortality of juvenile Litopenaeus
vannamei were tested at doses of 150 and 300 mg/L. The methanolic
extract of C. sertularioides exhibited activity against V. parahaemolyti-
cus and V. alginolyticus (MIC<1000 and < 1500 mg/mL, respectively).
L. vannamei mortality within the presence of each V. parahaemolyticus
and V. alginolyticus bacteria was considerably reduced upon treatment
with 300 mg/L of C. sertularioides methanolic extract (Esquer-Miranda
et al. 2016). Extract of C. sertularioides, collected from the Persian Gulf,
prepared by 20 minutes boiling of the alga in 20% glycerin solution fol-
lowed by sterilization was tested for antibacterial activity. The extract
showed antibacterial activity against S. epidermidis and E. coli in the
concentrations of 34 mg/mL and 27.2 mg/mL, respectively (Tajbakhsh
et al. 2008). The anti-dermatophyte activities of hexane, chloroform,
ethyl acetate, ethanol, methanol and water extracts obtained from six
medicinal plants and two algae including, C. sertularioides, collected
from Port Dickson (Malaysia) was measured. The medicinal plant
extracts exhibited more potent anti-dermatophyte activities compared
to the algae extracts. The minimum fungicidal concentration ranges for
the tested algae extracts against T. rubrum and T. interdigitale were
0.08"2.50 mg/mL, respectively (Sit et al. 2018).
1.23. Caulerpa serrulata (Forsskal) J. Agardh 1837
!
Caulersin (103) is a bisindole alkaloid (Fig. 9) that was detected in
C. serrulata collected from the Xisha Islands (China) (Su et al. 1997).
Silver nanoparticles prepared from the extract of C. serrulata collected
from the Red Sea coast (Egypt) had antibacterial activities against E.
coli, S. aureus, Shigella sp., S. typhi, and P. aeruginosa. The maximum
inhibition zone was found in E. coli (21 mm) while the inhibition
zone of S. typhi was minimum (10 mm) (Aboelfetoh et al. 2017).
1.24. Caulerpa taxifolia (M. Vahl) C. Agardh 1817
C. taxifolia is widely spread in the Mediterranean Sea due to its
rapid plug formation after wounding, to prevent the loss of cell con-
tents. This process involves the rapid transformation of the secondary
metabolite caulerpenyne (41) to the reactive 1,4-dialdehyde oxytoxin
2 (114) (Fig. 9) which acts as a protein cross-linker in plug formation.
The main metabolites of the algae wound plug were identified as pro-
teins, caulerpenyne derivatives, and SPs (Weissflog et al. 2013). C. taxi-
folia may be considered as a potent source of anti-cancer drugs. The
methanol extract of C. taxifolia collected from coasts of Tenneti (India)
was evaluated as selective anti-proliferative against breast cancer MB-
231, T-47D, and lung carcinoma H1299 cells (IC50=0.19 + 0.1,
0.27 + 0.1, and 0.43 + 0.1 mg/mL, respectively). In addition, a dose-
dependent increase in mitochondrial membrane potential up to 40%
and G1/S phase mitotic arrest was documented by methanol extract
treatment in MDA-MB-231 cells Mehra et al., 2019.
The cytotoxic effects of caulerpenyne (41), the major secondary
metabolite detected in C. taxifolia, collected from the Mediterranean
Sea was detected in different in vitro models: skin cells, primary cul-
tures of melanocytes and keratinocytes, immortalized keratinocytes
(HaCaT and HESV), and bone marrow cells (hematopoietic progeni-
tors CFU-GM) at IC50 starting from 6 to 24 mM. Hematopoietic pro-
genitors were more sensitive to caulerpenyne (41) than melanocyte
237
and keratinocyte cell lines due to it is higher proliferative rate (Par-
ent-Massin 1996). The effect of caulerpenyne (41), on the central ner-
vous system of the leech Hirudo medicinalis was investigated using
three different approaches; neuroethological, electrophysiological
and organic compound techniques. Caulerpenyne application mimics
the impact of a nociceptive stimulation (brushing), eliciting a clear-
cut synergism of the animal swim response to the check stimulation
(non-associative learning method like sensitization). This impact is
like the one elicited by the endogenous neurotransmitter 5-hydroxy-
tryptamine (5HT). It powerfully reduced the after-hyperpolarization
(AHP) recorded from T sensory neurons. This impact overlaps that
one created by 5HT, however, it is not affected by the serotonergic
antagonist methysergide. The reduction of AHP amplitude due to the
caulerpenyne (41) application was determined in the presence of
apamin, an agent of Ca++-dependent K+channels, suggesting that it is
acting through the depression of the Na+K+ electrogenic pump. Cau-
lerpenyne (41) exerted unique effects on leech neurons by acting
onto specific molecular targets as the Na+K+ATPase. This effect
explained the sensitizing action produced by the toxin on swim
induction. Finally, Caulerpenyne (41) does not act through the path-
ways concerned within the 5HT action, and the result is not mediated
by the second messenger cyclic AMP (Brunelli et al. 2000). The bio-
synthesis of caulerpenyne (41) was studied in the invasive C. taxifolia.
Results concluded that upon the incorporation of 1-13C-acetate and
13
CO2 respectively, the biogenesis of the sesquiterpene backbone
occurs within the plastid and follows the methylerythritol-4-phos-
phate (MEP) pathway. Also, the acyl group residues of caulerpenyne
are derived from a cytosolic resource (Pohnert and Jung 2003). Cau-
lerpenyne (41), the most important secondary metabolite synthe-
sized by C. taxifolia, is cytotoxic against many cell lines, e.g.
neuroblastoma SK-N-SH cell line. It induced inhibition of SK-N-SH
cell proliferation with an IC50 of 10 § 2 mM after 120 min incubation..
Caulerpenyne (41) influenced the microtubule network in the SK-N-
SH cell line and loss of neurites and compaction of the microtubule
network at the cell periphery by inhibition of microtubule polymeri-
zation and bundling of residual microtubules (Barbier et al. 2001).
Another study reported the chemical synthesis of associate analog of
caulerpenyne (41) having a trimethoxyaryl moiety was achieved in
11% overall yield over eleven steps. Its biological activity was evalu-
ated as an inhibitor of in vitro tubulin polymerization or angiogenesis
(Bourdron et al. 2006).
Chloroform-methanol (9:1) extract of C. taxifolia collected near
Imperia (Italy) was tested for its antiviral activity. It showed a high
inhibitory activity in vitro towards the feline immunodeficiency virus
(FIV), a legitimate model for studying the noninheritable immune defi-
ciency syndrome. The extract reduced the virus-induced syncytia within
the cultured cells, the viral reverse transcriptase activity and therefore
the viral capsid protein P24 expression (Nicoletti et al. 1999). C-Didehy-
dro-hydroxy-dihydrocaulerpenyne (115) and taxifolione (116) are trace
amounts of terpenes and the most active of the toxins isolated from C.
taxifolia collected from Mediterranean Sea. Both act as an in vitro inhibi-
tor of the expansion of marine bacterium and as a cytotoxic agent
toward marine ciliate protists (Guerriero and Marchetti 1993).
Taxifolial A (117), taxifolial B (118), taxifolial C (119), taxifolial D
(120) and 10,11-epoxycaulerpenyne (121) are sesquiterpenes toxins
were detected in C. taxifolia (VAHL) growing in the region of Cap Mar-
tin (France) (Guerriero and Meinesz 1992). Caulerpal A (122) and
caulerpal B (123), (Fig. 10) are sesquiterpenes possessing an uncom-
mon aromatic valerenane-type carbon skeleton detected in acetone
extract of C. taxifolia (Vahl) C. Agardh collected from Nanji Island
(China). They failed to produce any repressive activity against human
protein tyrosine phosphate 1B (hPTP1B) (Mao et al. 2006). Addition-
ally, 2-[(7Z,10Z,13Z)-hexadeca-7,10,13-trienoyloxy]-3-(hexopyrano-
syloxy)propyl(9Z,12Z,15Z)-octadeca-9,12,15-trienoate (124), 1-
[(7Z,10Z,13Z)-hexadeca-7,10,13-trienoyloxy]-3-(hexopyranosyloxy)
propan-2-yl(9Z,12Z,15Z)-octadeca-9,12,15-trienoate (125) and 3-
238 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 10. Chemical structures of compounds 115-131; (116 is miscellaneous compound, 115, 117-123 are sesquiterpenes, 124- 126 are fatty acid derivatives, and 127 - 131 are diter-
penes
(hexopyranosyloxy)propane-1,2-diyl(9Z,12Z,15Z,90 Z,120 Z,150 Z)bis-
octadeca-9,12,15-trienoate (126) (Fig. 10), are bioactive glycoglycero-
lipids detected in C. taxifolia collected from northeastern Mediterra-
nean Sea (Mancini et al. 1998).
1.25. Caulerpa trifaria Harvey 1863
(6S,13E,14E)-O~15~-acetyl-20-(acetyloxy)-4,5,15,20-tetradehy-
dro-5,6,7,8,11,12-hexahydroretinol (127), (6S,13cis)-20-oxo-4,5-
didehydro-5,6,7,8,11,12-hexahydroretinal (128), (6S,13cis)-O~15~-
acetyl-20-(acetyloxy)-4,5-didehydro-5,6,7,8,11,12-hexahydroretinol
(129) and (6S,13cis)-O~15~-acetyl-20-oxo-4,5-didehydro-
5,6,7,8,11,12-hexahydroretinol (130) are monocyclic diterpenes
detected in C. trifaria collected from Tasmania (Australia) (Handley
and Blackman 2000). Trifarin (131) was detected in hexane extract of
C. trifaria collected from Tasmania (Australia) which contained a 1,4-
diacetoxybuta-1,3-diene moiety (Fig. 10) (Blackman et al. 1978).
1.26. Caulerpa verticillata J. Agardh 1847
Chloroform/methanol (2:1) extract of C. verticillata J. Ag, collected
from coastal waters of Puerto Rico, exhibited antibacterial activity
against S. aureus (Ballantine et al. 1987).
2. Conclusion
There had been a large increase in the publication rate in papers
dealing with the metabolites in the genus Caulerpa over the past ten
years (Fig. 11) where 27 species which represent about 16.6% of the
genus Caulerpa were investigated for chemically and pharmacologi-
cally activities. The genus Caulerpa is one of the foremost invasive
genera in many coastal zones due to its ability for rapid plug forma-
tion after wounding, to prevent the loss of cell content. Chemical
defenses of genus Caulerpa against environmental herbivores are due
to its terpenoid metabolites which contain an aldehyde or enol ace-
tate. These compounds are produced in large concentrations but are
often not readily isolated because of their unstable and reactive
chemical natures. Some species are considered as a good source of
food in several marine cultures around the world (C. racemosa and C.
lentillifera), with local names such as Sea grapes, Bulung boni, green
Caviare, Limu-fuafua, Lelato, and Kumejima. Some species are consid-
ered deadly such as a killer algae (C. taxifolia). Poisons that were
detected in Caulerpa are sesquiterpenes which are toxic, creating
their use as a food resource unsafe. Chemical diversity confirmed that
Caulerpa is a rich source of phytochemicals that possessed many
pharmacological activities (Fig. 12). Unique phytochemicals were
detected within Caulerpa such as Compounds (93-94) represent the
 M.I. Rushdi et al. / South African Journal of Botany 132 (2020) 226"241
Fig. 11. Annual publication rate on the genus Caulerpa. X axis; Publication year, Y axis;
number of published articles.
Fig. 12. Chemical and pharmacological diversity of the genus Caulerpa.
first naturally occurring natural products with a hematinic acid ester
group and prenylated para-xylenes (107-108) while compound (131)
contained a 1,4-diacetoxybuta-1,3-diene moiety represented the first
report of this functionality in a natural product. Various sulfated poly-
saccharides (SP) fractions were detected in Caulerpa for osteogenic
potential antinociceptive, anti-inflammatory, anticoagulant,
immune-stimulatory, antioxidant and anti-Herpes simplex activities.
The mechanism of interaction is unique for each Caulerpa polysaccha-
ride with potential biomedical and nutraceutical applications. More
investigations of Caulerpa are required in order to get the full picture
of it is nutritional, industrial, agriculture as a plant growth enhancer,
and clinical applications. Additionally, structure-activity relationship
studies of the bioactive metabolites obtained from this genus should
be performed. Furthermore, the preparation of synthetic analogs of
239
the bioactive metabolites isolated from Caulerpa should be devel-
oped, focusing on improving the efficacy and economic production of
Caulerpa phytochemicals.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgement
We thank Minia University for supporting this work
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