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Changing Strategies NPChem Phytochemistry 1995-40-1585

Changing Strategies NPChem Phytochemistry 1995-40-1585

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Pergamon0031-9422(%)00444-O
Phytochemistry, Vol. 40, No. 6, pp. 1585-1612. 1995Copyright 0 1995 Ekvier Science LtdPnnted in Great Britain. All nghts reserved0031-9422/95 $29.50 + 0.00
REVIEW ARTICLE NUMBER 109
CHANGING STRATEGIES IN NATURAL PRODUCTS CHEMISTRY
GEOFFREYA. CORDELLProgram for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry andPharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612,
U.S.A.
(Received
1
May
1995)
IN HONOUR OF PROFESSOR ANTONIO G. GONZALEZKey Word Index-Natural products chemistry; drug discovery; ethnomedicine; plant selection andcollection; structure elucidation; biosynthesis, biological evaluation; strategy changes.Abstract-Scientific strategies for the study of natural products from plants have changed substantially in the past fewyears for a number of reasons, including advances in technology, new molecules of substantial interest, changingethical principles for organism collection and heightened awareness of the chemical and biological potential of thetropical rain forests. This review reflects on these changes and discusses, with recent examples, how they haveimpacted the conduct of natural products chemistry.INTRODUCTIONduct of natural product chemistry which have occurredfor political, scientific and technological reasons.In the past 10 years, approaches to the study of biolo-Some of the areas in which strategies for the conduct ofgically active natural products have changed so dramati-natural product chemistry have changed include plantcally that one is almost tempted to say that a new science selection and collection, isolation techniques, structurehas been born. Of course that it is not really the case, butelucidation, biological evaluation, semisynthesis, derepli-certainly the quiet, almost silent, revolution that has cation, and biosynthesis. Aspects of the tremendousoccurred has for ever altered the way that natural prod-changes occurring in each one of these areas will beucts research will be conducted. In other presentationsmentioned, recognizing that each of these topics could bemy colleagues and I have commented on some aspects of the subject of individual review articles or even books.these changes, and in particular, how this has affectedPerhaps one of the significant aspects of the past 10 yearspharmacognosy [l-16]. Here, I would like to takehas been the number of new journals devoted in whole, ora somewhat broader approach and examine how thein part, to aspects of the chemistry of natural products.combined impacts of changing biologies, technological These include
Phytochemical Analysis, Natural Product
advancements and the impact of new philosophies and
Letters, Phytotherapy Research,
the
Thai Journal of
a new awareness of biological diversity and its import-
Phytochemistry
and the revived
International Journal of
ance to the human race has modified the strategies by
Pharmacognosy.
Established journals such as the
Journal
which natural product chemistry and biology are being
of Natural Products
and
Phytochemistry
have steadilypursued. In a previous article [17], Hamburger and Hos- expanded. For example, in 1984 the
Journal of Natural
tettmann reviewed the development of medicinal plant
Products
published 1088 pages in six issues. For 1994 theresearch in the period 1960-1990, as a celebration of the corresponding data were 1787 pages in 12 issues. Also30th anniversary of the founding of Phytochemistry. Sev-noteworthy are the plethora of books at the scientificeral other articles have reviewed progress in natural level, as well as many popular books on herbal remediesproduct chemistry and the importance of natural prod- and the value of plants as medicinal and biological agentsucts to the discovery of new biological and medicinalwhich are published each year. Some of the books re-agents [lo, 13,15, 18 - 251. In addition,
Natural Product
viewed in
Phytochemistry
and the
Journal of NaturalReports
published by the Royal Society of Chemistry
Products
in 1994 are cited [26-461, including booksprovides regular coverage of many individual groups ofwhich are devoted to broad-based studies on single com-compounds. This review complements and expands on pounds [45-473, the publication of papers from sympo-certain aspects of those reviews and reflects, with the sia on the chemistry of natural products [27, 30, 31,441assistance of selected examples, on changes in the con-and detailed compilations of natural products and their1585
 
1586G.
A.
CORDELL
sources [32-34, 36;.38, 421, something that would havebeen unheard of 10 years ago.The burgeoning natural product literature has alsospawned several current awareness services, includingthose of
Chemical Abstracts,
the Royal Society of Chem-istry and
Phytochemical Analysis.
For natural productchemists, a significant development is having a sourcesuch as the
Dictionary of Natural Products
available inCD-ROM format, with a commitment to provide regularupdates. Other database systems will surely follow.Coupled with desktop, essentially instantaneous, accessto the Science and Technology Network (STN) of theChemical Abstracts Service and the Grateful Med serviceof the National Library of Medicine, strategies for theacquisition of prior information have also changed sub-stantially in the past few years. With more and more ofthe primary literature being available directly on-line,one can imagine that while strategies for publishing andaccessing the chemical literature on natural productshave changed substantially in the recent past, they willchange even more dramatically in the very near future.The era of the printed scientific paper may be nearly at anend, replaced by a submission, review and publishing pro-cess which is totally electronic and instantaneously global.This paper could almost be titled the ‘Yin and Yang ofPharmacognosy’, for what has happened in natural prod-ucts chemistry in the past few years has been the estab-lishment of a new balance, or rather several newbalances. The very yang, masculine, pharmaceutical com-panies are still ever present, producing allopathic medi-cines at a steadily increasing cost, but now balanced, ina yin, feminine, way in many parts of Europe and theUSA by a return to nature, to phytopharmaceuticals, andto natural remedies and cosmetics. The yang activities ofcollecting plants and other organisms without per-mission and consent are now mollified by a yin view inwhich indigenous rights are respected. Thus while theyang, high-tech, approach has certainly advanced boththe pace and the sophistication of natural product chem-istry, in the long run it will be the yin approach ofsustainable conservation which will ultimately yield thegreatest benefit for the Earth [48].Besides a number of broad and quite general literaturesources, including the popular press, articles in the 1994issues of
Phytoehemistry,
the
Journal of Natural Products,Phytochemical Analysis and Natural Product Letters
werespecifically scanned for glimpses of these new strategies.Let us begin then at the beginning, for one of the mostimportant issues that natural products chemistry mayface in the years to come in access to biodiversity. Althoughthis article is focussed primarily on plants and their derivedproducts, many of the same comments also apply to thestudy of lower plants and microorganisms, as well as tomarine organisms in all their vast diversity. One disclaimer:this brief review is not intended to be an up-to-date surveyof the status of natural product drug discovery.
PLANTSELECTION
the selection plant materials fored elsewhere [6,7,10,15]. Here itis sufficient to indicate that of these approaches, thelocally random, the taxonomic, the ethnomedical, thephytochemical, the information based and serendipity,two in particular, the phytochemical and the informationbased, essentially for the same reason, have been modi-fied in recent years. That reason, of course, is the intro-duction of the personal computer and the resultantdesk-top access to large databases which can be pro-cessed in a myriad of ways.One example of such usage was described in connec-tion with our discovery program on plant anticanceragents [7, 8, 11, 12, 141. But theoretically, the samestrategy could be applied for programs aimed at drugdiscovery in any one of a number of therapeutic areas,including antifungal, antiviral, analgesic, antimalarial,antibacterial, antidiabetic, and cardioactive agents. Sucha strategy relies on the ability to have availablea database which has three sets of information: (i) a list ofthose plants for which there exist ethnomedical reports ofbiological activity, (ii) a list of those plants for whichthere is either
in vitro, in uioo
or in human biological dataregarding activity, and (iii) a list of the sources of thenatural products which show activity in this thera-peutic category or in any one of the bioassays mentionedin (ii).In a discovery program, there is rarely a desire toreisolate known active metabolites which do not have thepotential to be developed further. Thus, the goal is estab-lished of matching these data bases in order to &$ablisha group of plants, or other organisms, for which there areboth ethnomedical and biological data available, but fromwhich no active principle has been isolated. If this list ofplants is long, and potentially beyond the fiscal resourcesneeded to collect the whole list, secondary criteria can beapplied, including, the incidence of multiple usagesaround the world, clinical versus biological data and theendemicity, uniqueness or phytochemical knowledge re-lated to a particular genus. From such a study, a list ofpotential plants to be collected may be whittled downfrom several hundred to a more manageable 50 or 100high-priority, targeted plants for collection. Recognizingthat such collection programs are very expensive andmore time consuming that locally random collection, it iscommon that all available plant parts, other than solelythe part indicated from the ethnomedical usage, are col-lected.Farnsworth appreciated that the compilation of litera-ture data was important for the future of natural productchemistry, and began in 1969 to publish a current aware-ness journal
Pharmacognosy Titles
on a monthly basis. In1975, it was recognized that these data should be com-puterized in a more accessible and malleable form, andNAPRALERT was born. This system has the ability todo analyses of the type described above, and indeed hasbeen used for that purpose in the development of severaldrug discovery programmes both by our group at theUniversity of Illinois at Chicago, as well several pharma-ceutical companies and the World Health Organization.NAPRALERT contains ethnomedical, chemical and bio-logical information from more than 115000 scientificresearch articles representing 129 000 chemical com-
 
Changing strategies in natural products chemistry1587pounds, and over 48000 plant, marine, microbial andanimal species. The database is available through a num-ber of global information networks, including the Scient-ific and Technical Information Network of the ChemicalAbstracts Service. It is extensively used by the pharma-ceutical and herbal industries, as well as by governmentagencies and individuals in academic settings all over theworld.Since more than 80% of the world’s population useplants as their primary source of medicinal agents [49], itis not surprising to find that in many countries of theworld there is a well-established system of traditionalmedicine, whose remedies are still being compiled. Insome instances, such as the Chinese, the Ayurvedic or theKampo systems these remedies are well documented, andmany are commercially available, being produced aslyophilized extracts in facilities comparable to those be-ing used for the production of allopathic medicines. Inother cases, traditional remedies are closely guarded se-crets held only by the shaman or curandero and passedon solely to tribal apprentices [SO]. While alarm at therate of disappearance of traditional healers and theirapprentices has been expressed [Sl]. it is also true thatuntil the late 1980s there was relatively limited interest inthe developed world in such indigenous knowledgeproviding only minimal assistance to developing coun-tries to preserve, collect and systematize such knowledge.The recent substantial interest in natural products hasresulted in an increasing respect for this knowledge, par-ticularly as products based’on some of this knowledgehave been introduced in the developed countries. Thenumerous issues surrounding biodiversity prospectinghave been described in several books [52-551; aspectswill be discussed subsequently.The area of science which has recently come to the fore,as at least an alternative way to discover biologicallyactive natural products from plants, is ethnobotany,whose leading journal is the
Journal of Ethnopharmacol-ogy.
Ethnobotany has evolved rapidly in the past fewyears, and several authors have reviewed aspects of thesedevelopments [S&59]. The CIBA Foundation recentlyorganized a follow-up symposium [60] entitled ‘Eth-
nobotany and the Search for New Drugs’
demonstratingthe substantial rise in activity and acceptance of using anethnobotanical approach for drug discovery. In this sym-posium, the approach of Shaman Pharmaceuticals hasbeen described by King and Tempesta [61] and else-where by King [62]. Before an expedition, regionalstudies are conducted on the epidemiology, traditionalmedicine, culture and ecology of the people and theirenvironment. In the field, ethnobotanists and medicaldoctors work together in presenting specific disease casedescriptions having visible symptoms to shamans. Work-ing initially with local translators, once the shaman hasrecognized the disease, the plant material(s) and theirmethod of preparation
used
for treatment are recordedand the plant collected. Further observations are madewhen the physician assists the shaman in providinghealth care to the local people. Shaman has focused onthe establishment of long-term relationships with variousindigenous communities and has established policieswhich provide for short-, medium- and long-term bene-fits to these communities through a conservation organ-ization: The Healing Forest Conservancy. One of thegoals of returning resources to the community is toestablish sustainable supply and extraction industries,which is considered a vital aspect of economic develop-ment. Besides returning results of biological experimentsto the communities, such partnerships also involveassistance in the conservation of biological and culturaldiversity, thereby forging a strong linkage between thediscovery and sustainability.In 1989, Phillipson and Anderson [63] reviewed thecontribution that plants had made to Western medicine,using as an example the application of various alkaloidsin current medical practice and also citing the proceed-ings of several meetings which focussed on drug dis-covery from traditional medicines. Their conclusion wasthat this area deserved ‘to be pursued rigorously’. How-ever, the fact remains that many scientists in pharmaceut-ical industry offer scant respect for the possibleeffectiveness of an antimalarial remedy of a hill-tribe inThailand.Cox and Balick, both former students of RichardSchultes, who is regarded as ‘the father of ethnobotany’,have also described their approach to ethnobotanicallybased drug discovery [64]. They discuss the validity ofsearches based on ecological niches, such as absence ofpredation, or use as fish poisons or in blow darts, and theapproach of working in regions with tribes which havepowerful healers. It has long been established that suchinformation sources provide a much higher ‘hit rate’ forplant extracts than random screening, and Cox andBalick have independently confirmed this. They go on todescribe how to select a tribal society with which to work,biological diversity, stability of the society, tradition ofhealers who pass their knowledge on through appren-tices. Cox has worked in Samoa with the herbalists ortaluasea and describes how it may take weeks, months oreven years to establish relationships, learn local customsand language and the uses of the plants in healing.Permission is sought to collect plants which are thendried and shipped. Cox has described how from theSamoan plant
Homalanthus nutans,
the phorbol deriva-tive prostratin was discovered as possessing good anti-HIV activity, following on the lead of a plant used locallyfor yellow fever. Compensation to the Samoan peoplehas been assured through royalty commitments, anda foundation has raised funds to establish rain forestpreserves in Samoa for the sustainable use of medicinalplants by future generations. Balick has described hiswork in Belize which has led to the founding of anethnomedical forest preserve, managed by a local associ-ation of traditional healers. Such steps are very empower-ing to local peoples who typically feel powerless in theface of logging companies and ranching combines.Holland [65] has suggested that an alternative ap-proach to drug discovery would be to scan ancient textsfor clues to new biological agents, as part of a collabora-tion between classicists (Greek and Latin) and scientists.Additionally, as Bruhns has related [66], even ancientmonasteries, such as one in Soutra, Scotland, the site of

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