河北医科大学：《天然药物化学》课程参考文献（海洋天然产物）Marine Pharmaceuticals

THE OCEANS AND HUMAN HEALTH Marine BY WILLIAM FENICA Pharmaceuticals Past,Present, and Future

110 Oceanography Vol. 19, No. 2, June 2006 Marine Pharmaceuticals Past, Present, and Future THE OCEANS AND HUMAN HEALTH BY WILLIAM FENICAL 110 Oceanography Vol. 19, No. 2, June 2006 Th is article has been published in Oceanography, Volume 19, Number 2, a quarterly journal of Th e Oceanography Society. Copyright 2006 by Th e Oceanography Society. All rights reserved. Permission is granted to copy this article for use in teaching and research. Republication, systemmatic reproduction, or collective redistirbution of any portion of this article by photocopy machine, reposting, or other means is permitted only with the approval of Th e Oceanography Society. Send all correspondence to: info@tos.org or Th e Oceanography Society, PO Box 1931, Rockville, MD 20849-1931, USA

BENEFICIAL ROLE OF THE OCEANS? the salicylates [aspirin])were utilized in single-ingredient for- In this issue of Oceanography,the majority of the papers pre mulations(i.e"drugs").As time passed,these molecules be- sented focus on the harmful health effects of the oceans cre- came the foundation of the new discipline of organic chemis- ated by oceanic events,anthropogenic influences,and harmful try.The developing pharmaceutical industries evolved to focus marine life.These are important issues that dramatically affect their efforts on purifying new drugs from these traditional eth human health,but at the same time this view does not reflect nomedicines(Therapeutic Research Faculty,2006). the fact that we are just now realizing some of the health-re The discovery of penicillin in the late 190s by Alexander lated benefits from the oceans.Comprising 34 of the 36 Phyla Fleming was perhaps the single most important medical dis- of life,marine ecosystems are indeed our last genetic diversity covery in modern times.This,and subsequent discoveries by and biotechnological frontier terrestrial systems possessony Selman Waksman(ie.,actinomycin and other antibiotics)and 17 Phyla.We have much to learn. other researchers,changed how drugs were discovered and Humankind has explored and explo oited the terrestrial envi- how Nature was explored (Berdy,005).The pharmaceuti ronment for more than 3000 years,leading to the examination cal industry,worldwide,quickly evolved by embracing these of almost every possible resource on land.In the future,similar findings,and subsequently discovered hundreds of"wonder explorations of the world's oceans,using modern chemical and drugs"that had the capability to cure pneumonia and almost molecular genetic technologies,will uncover a rich treasure all bacterial infectious diseases.These natural"wonder drugs chest of new medicinal products,cosmetics,foods,industrial saved millions of lives during and after World War II.and gav chemicals,and new,environment-friendly industrial processes. us the false sense that the great plagues of the past(c.g..chol- As we have benefited from life on land,it is reasonable to pre- era)would never again be seen (see Laws case study,this issue). dict that the next few decades will be filled with new discoveries More than 120 antibiotics,anticancer agents,and other thera- from our greatest untapped resource,the world's oceans.In this peutics originally derived from microorganisms that are found short synopsis,I will attempt,admittedly in a non-comprehen- nsoil are still prescribed today sive way,to summarize the past and current status of marine medicine,and to emphasize the important role the oceans will DISCOVERY OF THE OCEANS IN THE 1960s- play in human medicine in the decades to come THE PAST It is interesting to note that,historically,the oceans were rarely NATURAL PRODUCTS AND THE TREATMENT considered as a likely soure for natural medicines.In souther OF HUMAN DISEASE China,a poorly described marine ethnomedicine evolved,but More than 3000 years ago,early societies recognized that the this approach was not generally seen elsewhere.Despite biolo- diversity of plant lifearound them could be used for the treat- gists exploring life in the oceans in the ment of human illness.Natural "preparations,"in the form the linkage of medicine and marine biodiversity was never of teas or salves derived from plants,were commonly used to made.Even in more modern times,the pharmaceutical indus treat pain,infections,gastrointestinal maladies,inflammation, tries made little effort to examine life in the sea.This is under cancer,and many other common illnesses.Traditional healers standable because the ocean was virtually unknown,and diffi evolved who were consulted to treat illness,and the knowledge cult and dangerous to explore,while new drugs from terrestria of these individuals was passed down to understudies or ap- plants,and later soil microorganisms,were plentiful. prentices who continue to practice todayToday,for economic Asa consequence,the enormous resources of the oceans lay as well as traditional reasons,much of the developing world dormant until the mid to late 1960s when small groups of or. still relies on natural medicines(e.g.,ethnomedicines or tradi- ganic chemists in the United States,Europe,and Japan begar tional medicines)for the treatment of human disease to collect,extract,and chemically explore the diversity of ma Over time,the"active ingredients"from traditional medi- rine life.Pioneers like Paul Scheuer and Richard Moore in the cines were chemically purified,and during theand United States,Luigi Minale and Ernesto Fattorusso in Italy,and 2cnturies some of these drugs (morphie,unne, a small group of Japanese researchers(who were already the Oceanography I Vol 19.No.June 2006 111

Oceanography Vol. 19, No. 2, June 2006 111 BENEFICIAL ROLE OF THE OCEANS? In this issue of Oceanography, the majority of the papers pre￾sented focus on the harmful health effects of the oceans cre￾ated by oceanic events, anthropogenic infl uences, and harmful marine life. These are important issues that dramatically affect human health, but at the same time this view does not refl ect the fact that we are just now realizing some of the health-re￾lated benefi ts from the oceans. Comprising 34 of the 36 Phyla of life, marine ecosystems are indeed our last genetic diversity and biotechnological frontier; terrestrial systems possess only 17 Phyla. We have much to learn. Humankind has explored and exploited the terrestrial envi￾ronment for more than 3000 years, leading to the examination of almost every possible resource on land. In the future, similar explorations of the world’s oceans, using modern chemical and molecular genetic technologies, will uncover a rich treasure chest of new medicinal products, cosmetics, foods, industrial chemicals, and new, environment-friendly industrial processes. As we have benefi ted from life on land, it is reasonable to pre￾dict that the next few decades will be fi lled with new discoveries from our greatest untapped resource, the world’s oceans. In this short synopsis, I will attempt, admittedly in a non-comprehen￾sive way, to summarize the past and current status of marine medicine, and to emphasize the important role the oceans will play in human medicine in the decades to come. NATUR AL PRODUCTS AND THE TREATMENT OF HUMAN DISEASE More than 3000 years ago, early societies recognized that the diversity of plant life around them could be used for the treat￾ment of human illness. Natural “preparations,” in the form of teas or salves derived from plants, were commonly used to treat pain, infections, gastrointestinal maladies, infl ammation, cancer, and many other common illnesses. Traditional healers evolved who were consulted to treat illness, and the knowledge of these individuals was passed down to understudies or ap￾prentices who continue to practice today. Today, for economic as well as traditional reasons, much of the developing world still relies on natural medicines (e.g., ethnomedicines or tradi￾tional medicines) for the treatment of human disease. Over time, the “active ingredients” from traditional medi￾cines were chemically purifi ed, and during the 19th and 20th centuries some of these drugs (e.g., morphine, quinine, the salicylates [aspirin]) were utilized in single-ingredient for￾mulations (i.e., “drugs”). As time passed, these molecules be￾came the foundation of the new discipline of organic chemis￾try. The developing pharmaceutical industries evolved to focus their efforts on purifying new drugs from these traditional eth￾nomedicines (Therapeutic Research Faculty, 2006). The discovery of penicillin in the late 1920s by Alexander Fleming was perhaps the single most important medical dis￾covery in modern times. This, and subsequent discoveries by Selman Waksman (i.e., actinomycin and other antibiotics) and other researchers, changed how drugs were discovered and how Nature was explored (Bérdy, 2005). The pharmaceuti￾cal industry, worldwide, quickly evolved by embracing these fi ndings, and subsequently discovered hundreds of “wonder drugs” that had the capability to cure pneumonia and almost all bacterial infectious diseases. These natural “wonder drugs” saved millions of lives during and after World War II, and gave us the false sense that the great plagues of the past (e.g., chol￾era) would never again be seen (see Laws case study, this issue). More than 120 antibiotics, anticancer agents, and other thera￾peutics originally derived from microorganisms that are found in soil are still prescribed today. DISCOVERY OF THE OCEANS IN THE 1960s THE PAST It is interesting to note that, historically, the oceans were rarely considered as a likely source for natural medicines. In southern China, a poorly described marine ethnomedicine evolved, but this approach was not generally seen elsewhere. Despite biolo￾gists exploring life in the oceans in the 18th and 19th centuries, the linkage of medicine and marine biodiversity was never made. Even in more modern times, the pharmaceutical indus￾tries made little effort to examine life in the sea. This is under￾standable because the ocean was virtually unknown, and diffi - cult and dangerous to explore, while new drugs from terrestrial plants, and later soil microorganisms, were plentiful. As a consequence, the enormous resources of the oceans lay dormant until the mid to late 1960s when small groups of or￾ganic chemists in the United States, Europe, and Japan began to collect, extract, and chemically explore the diversity of ma￾rine life. Pioneers like Paul Scheuer and Richard Moore in the United States, Luigi Minale and Ernesto Fattorusso in Italy, and a small group of Japanese researchers (who were already the Oceanography Vol. 19, No. 2, June 2006 111

leaders in marine toxin research),began marine organisms.Their goal was to carbonimidic dichlorides(Wratten and to examine sponges,marine algac,and fully comprehend the sources of these Faulkner,1977)and molecules of un- other unfamiliar forms of marine life molecules and the extent to which these precedented size and complexity,such as To their great surprise.new molecules new compounds were different from the polvether toxin brevetoxin-B (Lin et of unprecedented types were found those produced by terrestrial plants and al,1981),were isolated and identified (Faulkner.2000a.2000b).The struc- microorganisms.Chemical structures The new field of marine natural prod- tures of entirely new chemical entities were found that pletely changed the ucts chemistry had been initiated with a which challenged accepted biosynthetic foundations of natural-product biosyn- resounding success understanding,were published at an im- thesis.Perhaps to be kDected.the halo- In the beginning,financial support pressive rate.These pioneering chemical gens(i.e.,iodi and chlorine, to expand this entirely new and explor researchers.who were amateur biolo- but not fluorine)were found to play atory science was yery difficult to obtain gists at best,found that marine animals prominent roles, ly a ent Ocean scientists asked why this was be- possessed a rich new chemistry that had in complex molecule but also by act- ing done?But the chemists,who were never been seen before.It then became ng as reactants(in halocyclization reac- largely not trained as marine scientists clear that the oceans were indeed a new tions,for example)to create entirely new and exciting resource (Figure 1). classes of terpenoids and other structure William Fenical (wfenical@ucsdedu)is classes of bioactive molecules(Figure 2). Director Center for Marine Biotechnolog THE "EXPLORATORY DECADE' In a mere ten-year span,the complex- and Biomedicine and Professor of Ocean During the 1970s,small groups of chem- ity of terpenoid biosynthesis was more ography.Scripps Institution of Oceanogra- ists continued to explore the amazing than doubled!Molecules possessing un phy,University of California San Diego,La diversity of novel molecules present in precedented functional groups such as Jolla,CA,USA. nderwater photo e and plan Figure 2.The widely distributed red seaweed Laurencia was the first to b ognized as a robust sourc per square meter. ing enzymes.Laurinterol (shown)was the first brominated terpene to be olated(1968】 112 Occanography I Vol 19,No.2.June 2006

112 Oceanography Vol. 19, No. 2, June 2006 Figure 2. Th e widely distributed red seaweed Laurencia was the fi rst to be recognized as a robust source for halogenated natural products. Th is and related seaweeds produce a diversity of halogenated compounds (some with 5–6 bromine and chlorine atoms) by processes involving halogenat￾ing enzymes. Laurinterol (shown) was the fi rst brominated terpene to be isolated (1968). leaders in marine toxin research), began to examine sponges, marine algae, and other unfamiliar forms of marine life. To their great surprise, new molecules of unprecedented types were found (Faulkner, 2000a, 2000b). The struc￾tures of entirely new chemical entities, which challenged accepted biosynthetic understanding, were published at an im￾pressive rate. These pioneering chemical researchers, who were amateur biolo￾gists at best, found that marine animals possessed a rich new chemistry that had never been seen before. It then became clear that the oceans were indeed a new and exciting resource (Figure 1). THE “EXPLOR ATORY DECADE” During the 1970s, small groups of chem￾ists continued to explore the amazing diversity of novel molecules present in marine organisms. Their goal was to fully comprehend the sources of these molecules and the extent to which these new compounds were different from those produced by terrestrial plants and microorganisms. Chemical structures were found that completely changed the foundations of natural-product biosyn￾thesis. Perhaps to be expected, the halo￾gens (i.e., iodine, bromine, and chlorine, but not fl uorine) were found to play prominent roles, not only as substituents in complex molecules, but also by act￾ing as reactants (in halocyclization reac￾tions, for example) to create entirely new classes of terpenoids and other structure classes of bioactive molecules (Figure 2). In a mere ten-year span, the complex￾ity of terpenoid biosynthesis was more than doubled! Molecules possessing un￾precedented functional groups such as carbonimidic dichlorides (Wratten and Faulkner, 1977) and molecules of un￾precedented size and complexity, such as the polyether toxin brevetoxin-B (Lin et al., 1981), were isolated and identifi ed. The new fi eld of marine natural prod￾ucts chemistry had been initiated with a resounding success. In the beginning, fi nancial support to expand this entirely new and explor￾atory science was very diffi cult to obtain. Ocean scientists asked why this was be￾ing done? But the chemists, who were largely not trained as marine scientists, William Fenical (wfenical@ucsd.edu) is Director, Center for Marine Biotechnology and Biomedicine and Professor of Ocean￾ography, Scripps Institution of Oceanogra￾phy, University of California, San Diego, La Jolla, CA, USA. Figure 1. Close-up underwater photograph of the invertebrate and plant diversity typically observed on coral reefs. Diversity can reach 1000 species per square meter

knew that they had uncovered an amaz- ingly complex new science,one that would ultimately explain much of the ecology of marine life.In the funding arena,the National Sea Grant Program (United States)was a clear exception. The founders of this program,who had the wisdom to envision the discovery of marine drugs,were rewarded by the huge successes that were subsequently achieved.Later,the Divisions of Chem- istry and Ocean Sciences at the U.S National Science Foundation became involyed,showing an interest in this new and developing field of study.No one knew where this was going,but ev- eryone saw the potential for the future. Beginning in the early 1980s,a new component of marine ecology."marine chemical ecology,"was established by small group of scientists who used this chemical knowledge base to demon- strate that bioactive molecules produced e 3.The C sea whip.Pseudo by(mainly)soft-bodied marine plants ins (shov wn)which po and animals are the foundation of ar Lauder,in collaboration with California Sea Grant researchers,developed these agents as skin care ad- elaborate strategy of chemical defense and communication in the ocean(Hay 1996,2002). COULD THESE MOLECULES BE DRUGS?CONNECTIONS continued to be seen. a marine source.During this same pe- WITH INDUSTRY AND With the help of Estee Lauder scien riod,both the National Cancer Institute PHARMACOLOGY tists,Sea Grant researchers in Califor (NCI)and many researchers began to see On the basis of the recognized "prom- nia developed a new skin-care additive the promise of the marine environment ise of the sea,"many researchers in the “pseudopterosins”from the Caribbean in the treatment of cancer.The NCI had mid to late 1980s began to see how the sea whip Pseudopterogorgia elisabethae undertaken a screening program ten complex chemistry from the marine en- (Figure 3)(Look et al,986).This prod- vears earlier,and they were finding that vironment could be applied to improv- uct,still in use today,dramatically reduc marine samples provided the highest ing human health.Academic researchers es the allergenic responses of skin lotions botential for anticancer drug discovery probed industry,seeking collaborations to some individuals and provides strong Evidence that this would utimately bea and approached the national Institutes anti-inflammatory properties.This successful endeavor came from the sub of Health (NIH)to support these devel product was perhaps the first cinically equent isolation of a broad structural oping studies.Although slow,successes validated"cosmeceutical"derived from diversity of more than 500 molecules Occanography I Vol 19.No.2.June 2006 113

Oceanography Vol. 19, No. 2, June 2006 113 knew that they had uncovered an amaz￾ingly complex new science, one that would ultimately explain much of the ecology of marine life. In the funding arena, the National Sea Grant Program (United States) was a clear exception. The founders of this program, who had the wisdom to envision the discovery of marine drugs, were rewarded by the huge successes that were subsequently achieved. Later, the Divisions of Chem￾istry and Ocean Sciences at the U.S. National Science Foundation became involved, showing an interest in this new and developing fi eld of study. No one knew where this was going, but ev￾eryone saw the potential for the future. Beginning in the early 1980s, a new component of marine ecology, “marine chemical ecology,” was established by a small group of scientists who used this chemical knowledge base to demon￾strate that bioactive molecules produced by (mainly) soft-bodied marine plants and animals are the foundation of an elaborate strategy of chemical defense and communication in the ocean (Hay, 1996, 2002). COULD THESE MOLECULES BE DRUGS? CONNECTIONS WITH INDUSTRY AND PHARMACOLOGY On the basis of the recognized “prom￾ise of the sea,” many researchers in the mid to late 1980s began to see how the complex chemistry from the marine en￾vironment could be applied to improv￾ing human health. Academic researchers probed industry, seeking collaborations, and approached the National Institutes of Health (NIH) to support these devel￾oping studies. Although slow, successes continued to be seen. With the help of Estee Lauder scien￾tists, Sea Grant researchers in Califor￾nia developed a new skin-care additive “pseudopterosins” from the Caribbean sea whip Pseudopterogorgia elisabethae (Figure 3) (Look et al., 1986). This prod￾uct, still in use today, dramatically reduc￾es the allergenic responses of skin lotions to some individuals and provides strong anti-infl ammatory properties. This product was perhaps the fi rst clinically validated “cosmeceutical” derived from a marine source. During this same pe￾riod, both the National Cancer Institute (NCI) and many researchers began to see the promise of the marine environment in the treatment of cancer. The NCI had undertaken a screening program ten years earlier, and they were fi nding that marine samples provided the highest potential for anticancer drug discovery. Evidence that this would ultimately be a successful endeavor came from the sub￾sequent isolation of a broad structural diversity of more than 500 molecules Figure 3. Th e Caribbean sea whip, Pseudopterogorgia elisabethae (Gorgonaceae), contains the pseudop￾terosins (shown) which possess potent topical anti-allergenic and anti-infl ammatory properties. Estee Lauder, in collaboration with California Sea Grant researchers, developed these agents as skin care ad￾ditives. Th e fi rst application was in their “Resilience” cosmetic line. Photo courtesy V.J. Paul, Smithson￾ian Institution Marine Laboratory, Fort Pierce, Florida

that had the ability to inhibit the growth mind,society now places exceptionally oceans best serve human medicine? of cancer cells at sub-micromolar con strong demands on drug safety and ef- Over the past ten years,the oceans centrations.These highly bioactive mol- ficacy.As a consequence,many of the have provided exciting medical dis- ecules came mainly from sponges,ascid- drugs developed in past years would not coveries that are now yielding drugs ians,and bryozoans,classes of marine survive today's high-level expectations. The first marine drug wasZiconotid invertebrates that are now recognized Drug resistance in the treatment of can- (Pralt),a potent pain medication as the most chemically prolific of all the cer and infectious diseases isemerging that was developed based upon knowl- marine animal groups(Figure 4). at a frightening rate,just when the phar- edge of the highly toxic small peptide maccutical industries are turning away 0-conotoxin mVIlA extracted from the DISCOVERIES AND from some of these areas,only to focus venomous gastropod mollusk Conus successes-cuRrent their attention on the development of magus (Figure 5)(Olivera et al,1987). Many natural products were developed "block-buster drugs"(sales in excess of Ziconotide,a potent calcium channel into medicines in the mid 20 century. $2 billion)in therapeutic areas requiring blocker,is the only drug in this class of but the challenges and difficulties to do chronic treatment over a lifetime.Ex- agents that provides relief from severe so now have dramatically changed.In plorations for new anti-infective agents, neurogenic pain.Although this is the the 214 century,we live in a more com- especially antibacterial drugs,have all first marine drug generally recognized, plex world in which diseases are comple but ceased.Given these new realities, in the 1950s,Werner Bergman and resistant to cures.With the past in how can the biomedical potential of the in marine sterol chemistry,isolated two Figure4.An underwater photo of theascidian Ecteinasdi turbinata grow (shown)a powerful anticancer agent currently in advanced rials. is currenty marketed for intense pain under the trade are in ake City.Utah. 114 Oceaography I Vol 19,No..June 2006

114 Oceanography Vol. 19, No. 2, June 2006 that had the ability to inhibit the growth of cancer cells at sub-micromolar con￾centrations. These highly bioactive mol￾ecules came mainly from sponges, ascid￾ians, and bryozoans, classes of marine invertebrates that are now recognized as the most chemically prolifi c of all the marine animal groups (Figure 4). DISCOVERIES AND SUCCESSESCURRENT Many natural products were developed into medicines in the mid 20th century, but the challenges and diffi culties to do so now have dramatically changed. In the 21st century, we live in a more com￾plex world in which diseases are complex and resistant to cures. With the past in mind, society now places exceptionally strong demands on drug safety and ef- fi cacy. As a consequence, many of the drugs developed in past years would not survive today’s high-level expectations. Drug resistance in the treatment of can￾cer and infectious diseases is emerging at a frightening rate, just when the phar￾maceutical industries are turning away from some of these areas, only to focus their attention on the development of “block-buster drugs” (sales in excess of $2 billion) in therapeutic areas requiring chronic treatment over a lifetime. Ex￾plorations for new anti-infective agents, especially antibacterial drugs, have all but ceased. Given these new realities, how can the biomedical potential of the oceans best serve human medicine? Over the past ten years, the oceans have provided exciting medical dis￾coveries that are now yielding drugs. The fi rst marine drug was Ziconotide (Pralt™), a potent pain medication that was developed based upon knowl￾edge of the highly toxic small peptide ω-conotoxin MVIIA extracted from the venomous gastropod mollusk Conus magus (Figure 5) (Olivera et al., 1987). Ziconotide, a potent calcium channel blocker, is the only drug in this class of agents that provides relief from severe neurogenic pain. Although this is the fi rst marine drug generally recognized, in the 1950s, Werner Bergman, a pioneer in marine sterol chemistry, isolated two Figure 4. An underwater photo of the ascidian, Ecteinascidia turbinata, grow￾ing on hanging mangrove prop roots. Th is animal contains ecteinascidin 743 (shown), a powerful anticancer agent currently in advanced clinical trials. Figure 5. Th e cone snail, Conus magus, produces the potent analgesic peptide ω-conotoxin MVIIA (or ziconotide, shown). A synthetic version of this peptide is currently marketed for intense neurogenic pain under the trade name Prialt™. Mollusks of the genus Conus produce numerous highly bioactive peptides that are in clinical trials for pain relief and treatment of asthma and Alzheimer’s Dis￾ease. Photo courtesy B. Olivera, University of Utah, Salt Lake City, Utah

modified nucleosides,spongothymidine to pharmaceutical partners for clinical tional sense.These molecules are now and spongouridine,from the sponge development,manufacture,and sales. being shown by academic researcher Cryptotethia crypta(Bergman and Fee- Of particular importance over the to possess diverse and highly complex ney,1951).These compounds possessed past 15 years is the NCI's"National Co. pharmacological properties with appli activities,and over the operative Drug Discovery Groups"or cations to many diseases.Many unique decades were the inspiration for the de- NCDDGs,and productive researchers molecular probes with activities relevan velopment to two related antiviral drugs such as G.R.Pettit at Arizona State Uni- to fundamental processes have been Ara-A (Vidabarine)and Ara-C. versity's Cancer Research Institute,who isolated and defined.The problem of As might be expected,the large phar- have dedicated their work to cancer-drug developing a greater diversity of marine maceutical industries have had only discovery(Figure 6).The NCDDG col drugs lies in the lack of funding for th modest interest in embracing marine laborative grants were cleverly crafted discovery of drug leads in other thera- drug discovery.This area continues to the close ration of peutic areas.As of 06,the NCI is the day to be one of uncertainty and high academic researchers and industrial only NIH institute that had a dedicated predicted risk,and one that industry has scientists,whose respective abilities to drug-discovery program(Cragg et al, not learned to reliably control.Asa con- focus on new source for possible drugs 2005).Furthermore,there is an unde sequence,more and more discoveries are were coupled with the pharmacological veloped relationship between those who being made by academic researchers and strengths ind develo ntal expe ertise of discover new marine molecules and by the flourishing small biotechnology industry.The result has been productive those who have the biological expertise industries(see Toledo et al.case study. collaborative programs that link these and screening capacity to develop new this issue).Increasingly,the large phar avors(Figure 7). drugs in diverse therapeutic areas.Im maceutical industries rely on the "in- Table 1 lists the cancer drugs discovered pressively,three new marine drugs are in licensing"of drugs discovered in these and related prog ams,their clinical trials for acute pain,three more (Table 1).Thus,in the decades to come,it sources,and discoverers.Seventeen novel are in clinical evaluation for the treat can be predicted that marine biotechnol- molecules,produced by marine bacteria. ment of asthma,and one drug is in clini- ogy companies will evolve as opportuni sponges,as idians,mollusks,bryozoans cal assessment for Alzheimer's Disease ties arise to exploit marine biodiversity. and sharks.are currently in clinical trials. (Table 1).Other molecules are being Cancer continues to be a major disease This impressive list can leav no doubt shown to be effective against malaria and worldwide;in the United States,Europe, that the oceans have the ability to offer other infectious diseases.Indeed,today, and lapan it is a major cause of human new pharmaceuticals,particularly for the the study of bioactive marine molecules mortality.It is thus no surprise that the treatment of cance continues at a spectacular pace(Blunte NCI has invested heavily over the past It is often asked why marine sources al,2003.2004.2005). three decades in the discovery and de- should yield new antica agents?Is it While the ocean is clearly a new fron velopment of anticancer drugs from ma simply that the oceans contain many po- tier in drug discovery,it remains isolated rine sources(Cragg et al,2005).What is tent toxins,and these are useful in killing from the mainstream discovery and de. not widely known is the degree of their cancer cells but have no other utility? velopmental processes,which require success.In 2006,more than 30 marine This is an inaccurate view of the medical hundreds of millions of dollars of in- derived molecules are in preclinical de potential of the orld's oceans created by vestment.How can we change this?One velopment or clinical trials against a wide the significant funding available world can predict that the next decade will see diversity of cancers.A significant number wide to discover new anticancer drugs. major changes in the pharmaceutical of these new drug candidates was devel- Marine life produces a m industry and in how NIH will respond to oped with direct or indirect NCI assis- of complex,bioactive molecules only a medical discoveries and human medical tance,and once brought to the point of small percentage of which is"toxi"to needs.More academia-industry linkages perceived utility,they were then humans and other species in the tradi- will be observed,and the responsibility Occanography I Vol 19.No.2.June 2006 115

Oceanography Vol. 19, No. 2, June 2006 115 modifi ed nucleosides, spongothymidine and spongouridine, from the sponge Cryptotethia crypta (Bergman and Fee￾ney, 1951). These compounds possessed unique antiviral activities, and over the decades were the inspiration for the de￾velopment to two related antiviral drugs, Ara-A (Vidabarine) and Ara-C. As might be expected, the large phar￾maceutical industries have had only modest interest in embracing marine￾drug discovery. This area continues to￾day to be one of uncertainty and high predicted risk, and one that industry has not learned to reliably control. As a con￾sequence, more and more discoveries are being made by academic researchers and by the fl ourishing small biotechnology industries (see Toledo et al. case study, this issue). Increasingly, the large phar￾maceutical industries rely on the “in￾licensing” of drugs discovered elsewhere (Table 1). Thus, in the decades to come, it can be predicted that marine biotechnol￾ogy companies will evolve as opportuni￾ties arise to exploit marine biodiversity. Cancer continues to be a major disease worldwide; in the United States, Europe, and Japan it is a major cause of human mortality. It is thus no surprise that the NCI has invested heavily over the past three decades in the discovery and de￾velopment of anticancer drugs from ma￾rine sources (Cragg et al., 2005). What is not widely known is the degree of their success. In 2006, more than 30 marine￾derived molecules are in preclinical de￾velopment or clinical trials against a wide diversity of cancers. A signifi cant number of these new drug candidates was devel￾oped with direct or indirect NCI assis￾tance, and once brought to the point of perceived utility, they were then licensed to pharmaceutical partners for clinical development, manufacture, and sales. Of particular importance over the past 15 years is the NCI’s “National Co￾operative Drug Discovery Groups” or NCDDGs, and productive researchers such as G.R. Pettit at Arizona State Uni￾versity’s Cancer Research Institute, who have dedicated their work to cancer-drug discovery (Figure 6). The NCDDG col￾laborative grants were cleverly crafted to require the close collaboration of academic researchers and industrial scientists, whose respective abilities to focus on new sources for possible drugs were coupled with the pharmacological strengths and developmental expertise of industry. The result has been productive collaborative programs that link these diverse scientifi c endeavors (Figure 7). Table 1 lists the cancer drugs discovered in these and related programs, their sources, and discoverers. Seventeen novel molecules, produced by marine bacteria, sponges, ascidians, mollusks, bryozoans, and sharks, are currently in clinical trials. This impressive list can leave no doubt that the oceans have the ability to offer new pharmaceuticals, particularly for the treatment of cancer. It is often asked why marine sources should yield new anticancer agents? Is it simply that the oceans contain many po￾tent toxins, and these are useful in killing cancer cells but have no other utility? This is an inaccurate view of the medical potential of the world’s oceans created by the signifi cant funding available world￾wide to discover new anticancer drugs. Marine life produces a massive diversity of complex, bioactive molecules only a small percentage of which is “toxic” to humans and other species in the tradi￾tional sense. These molecules are now being shown by academic researchers to possess diverse and highly complex pharmacological properties with appli￾cations to many diseases. Many unique molecular probes with activities relevant to fundamental processes have been isolated and defi ned. The problem of developing a greater diversity of marine drugs lies in the lack of funding for the discovery of drug leads in other thera￾peutic areas. As of 2006, the NCI is the only NIH institute that had a dedicated drug-discovery program (Cragg et al., 2005). Furthermore, there is an unde￾veloped relationship between those who discover new marine molecules and those who have the biological expertise and screening capacity to develop new drugs in diverse therapeutic areas. Im￾pressively, three new marine drugs are in clinical trials for acute pain, three more are in clinical evaluation for the treat￾ment of asthma, and one drug is in clini￾cal assessment for Alzheimer’s Disease (Table 1). Other molecules are being shown to be effective against malaria and other infectious diseases. Indeed, today, the study of bioactive marine molecules continues at a spectacular pace (Blunt et al., 2003, 2004, 2005). While the ocean is clearly a new fron￾tier in drug discovery, it remains isolated from the mainstream discovery and de￾velopmental processes, which require hundreds of millions of dollars of in￾vestment. How can we change this? One can predict that the next decade will see major changes in the pharmaceutical industry and in how NIH will respond to medical discoveries and human medical needs. More academia-industry linkages will be observed, and the responsibility

Table 1.Status of Marine-Derived Natural Products in Clinical and Preclinical Trials Compound Name Source Status(Disease) Comment Bryostatin 1 Phase ll(Cancer) licensed to Bugula neritina TZT-1027 Synthetic Dolastatin Phase ll(Cancer) Also known as Auristatin PE and Soblidotin Cematodin Synthetic derivative Phase I/Il(Cancer) Some positive effects in melanoma of Dolastatin 15 ILX651,Synthatodin g hase I/ll (Cancer) Ecteinascidin 743 Ascidian Phase ll/ll(Cancer】 Licensed to Ortho Biotech(1&l/lanssen Ecteinascidia turhinata in2003.2005 Pharmaceuticals) Aplidine Phase ll(Cancer) Dehydrodidemnin B:made by total synthesis E7389 Sponge Phase ll (Cancer) Eisai's synthetic halichondrin B derivative Lissodendoryx sp. breast and lung Discodermolide Phase I(Cancer) Licensed to Novartis by Harbor Branch ermia dissoluta Kahalalide F Mollusk Evlsia rufescens Phase ll(Cancer) Licensed to PharmaMar by University of Hawaii and Alga Bryopsis sp. Zalypsis PhaseI(Cancer) PharmaMar(based on saframycin molecule) E5-285 Spisula polynyma Phase I(Cancer) Rho-GTP inhibitor KRN-7000 Phase I(Cancer) An agelasphin derivative Squalamine Sharl hase ll (Cancer) Anti-angiogenic activity as wel Squalus acanthias -941(Neovastat) Shark Phase ll/Ill(Cancer Defined mixture of<500 kDa from cartilage anti-angiogenic NVP-LAQ824 Synthetic PhaseI(Cancer) Derived from Psammaplin,Trichostatin and Irapoxin structures E-7974(isa0 Synthetic Phase l(Cancer) Carboxylate-end modified hemisasterlin hasel(Cancer Prot asome inhibitor Nereus Pharma GTS-21(aka DMBX) Marine worm PhaseI(Alzheimer's) Licensed to Taiho by the University of Florida 1) hase ll(anti-asthmatic Derivative of contignasterol,Inflazyme Pharma Petrosia contignata 1PL-512.602 Derivative of 576092 Phase ll(anti-asthmatic) With Aventis.no further data as of 08/2005 IPL-550,260 Derivative of 576092 Phase I(anti-asthmatic) With Aventis.No further data as08/2005 Ziconotide Mollusk Approved EDA 28DEC04 Licensed by Elan to Warner Lambert:launched (aka Prialt) Conus magus (Neuropathic pain) in U.S.and Europe in 2005 CGX-1160 Conus geographus Phase I(Pain) Corporation(lreland) ACV1 Conus victorae Phase I (Pain) Metabolic Pharma(Australia)(06/2006). conotoxin Vc1.1 This table was adapted from information kindly provided by David I.Ne National Cancer Institute.Bethesda.MD.USA 116 Occanography I Vol 19,No.2.June 2006

116 Oceanography Vol. 19, No. 2, June 2006 Table 1. Status of Marine-Derived Natural Products in Clinical and Preclinical Trials Compound Name Source Status (Disease) Comment Bryostatin 1 Bryozoan Bugula neritina Phase II (Cancer) Now in combination therapy trials; licensed to GPC Biotech by Arizona State University TZT –1027 Synthetic Dolastatin Phase II (Cancer) Also known as Auristatin PE and Soblidotin Cematodin Synthetic derivative of Dolastatin 15 Phase I /II (Cancer) Some positive eff ects in melanoma ILX 651, Synthatodin Synthetic derivative of Dolastatin 15 Phase I/II (Cancer) For melanoma, breast, and non-small cell lung cancer (NSCLC) Ecteinascidin 743 Ascidian Ecteinascidia turbinata Phase II/III (Cancer) in 2003-2005 Licensed to Ortho Biotech (J&J/Janssen Pharmaceuticals) Aplidine Ascidian Aplidium albicans Phase II (Cancer) Dehydrodidemnin B; made by total synthesis E7389 Sponge Lissodendoryx sp. Phase II (Cancer) Eisai’s synthetic halichondrin B derivative; breast and lung Discodermolide Sponge Discodermia dissoluta Phase I (Cancer) Licensed to Novartis by Harbor Branch Oceanographic Institution Kahalalide F Mollusk Eylsia rufescens and Alga Bryopsis sp. Phase II (Cancer) Licensed to PharmaMar by University of Hawaii Zalypsis Synthetic Safracin B de￾rivative Phase I (Cancer) PharmaMar (based on saframycin molecule) ES-285 Spisula polynyma Phase I (Cancer) Rho-GTP inhibitor KRN-7000 Sponge Agelas mauritianus Phase I (Cancer) An agelasphin derivative Squalamine Shark Squalus acanthias Phase II (Cancer) Anti-angiogenic activity as well Æ-941 (Neovastat) Shark Phase II/III (Cancer) Defi ned mixture of < 500 kDa from cartilage; anti-angiogenic NVP-LAQ824 Synthetic Phase I (Cancer) Derived from Psammaplin, Trichostatin and Trapoxin structures E-7974 (Eisai) Synthetic Phase I (Cancer) Carboxylate-end modifi ed hemisasterlin Salinosporamide A (NPI-0052) Bacterium Salinispora tropica Phase I (Cancer) Proteasome inhibitor Nereus Pharma GTS-21 (aka DMBX) Marine worm Phase I (Alzheimer’s) Licensed to Taiho by the University of Florida IPL-576,092 (aka HMR-4011A) Sponge Petrosia contignata Phase II (anti-asthmatic) Derivative of contignasterol; Infl azyme Pharma IPL-512,602 Derivative of 576092 Phase II (anti-asthmatic) With Aventis. No further data as of 08/2005 IPL-550,260 Derivative of 576092 Phase I (anti-asthmatic) With Aventis. No further data as 08/2005 Ziconotide (aka Prialt) Mollusk Conus magus Approved FDA 28DEC04 (Neuropathic pain) Licensed by Elan to Warner Lambert; launched in U.S. and Europe in 2005 CGX-1160 Conus geographus Phase I (Pain) Cognetix and Elan Corporation (Ireland); Phase II late 2005 ACV1 Conus victoriae Phase I (Pain) Metabolic Pharma (Australia)(06/2006), conotoxin Vc1.1 Th is table was adapted from information kindly provided by David J. Newman, National Cancer Institute, Bethesda, MD, USA

for drug discovery,particularly in the to generate a huge diversity of new mo- than 40 years,those adapted for life in less-profitable areas such as antibiotics lecular architectures.New resources the sea are only superficially known. discovery,will be more greatly embraced which had been difficult to examine in Advances in genomics-based tax- by the NIH.These changes are beginning the past,will now be the focus of signifi- onomy,and in the acquisition and cul- now with industry reconsidering natural cant study.A prime example is the taxo tivation of marine bacteria,are already product-based drug discovery and the nomically complex microbial life that leading to the recognition of new classes NIH planning their own drug-discover resides in the world's oceans.In contrast of bacteria that produce unprecedented efforts as part of the"NIH Roadmap for to terrestrial microbes,which formed the antibiotics and potential anticancer Medical Research"(for more informa- foundation for drug discovery for more drugs.Shotgun cloning of DNA directly tion go to http://nihroadmap.nih.gov) NEW MARINE BIOMEDICAL SCIENCES-THE FUTURE We are about to enter an exciting new era in medicine,one that is already em bracing a new paradigm involving ge nomics-based drug discovery.Not only will knowledge of the human genome provide new drug targets and assist in discase diagnoses,but sequencing the full genomes of marine life will illustrate entirely new biosynthetic pathways that code for the production of a diversity of compounds as yet undiscovered.Genes from new and diverse marine sources will be cloned,combined,and expressed Figure6The bryozoan Bugula neritina ontains complex ma rolides,exem n)whic ment of human cancers Bryostatin lis anography. nge Cym shown),was de ed and now in develo Andersen,University of British Columbia,Vanco British Columbia.Canada. Oceanography I Vol 19,No..June 2006 117

Oceanography Vol. 19, No. 2, June 2006 117 Figure 6. Th e bryozoan Bugula neritina contains complex macrolides, exem￾plifi ed by bryostatin I (shown), which show unique properties in the treat￾ment of human cancers. Bryostatin I is currently in clinical trials. Photo cour￾tesy K. Sharp, Scripps Institution of Oceanography, La Jolla, California. Figure 7. Th e Pacifi c sponge Cymbastella sp. contains highly cytotoxic peptides of the hemiasterlin class. As part of the NCI’s National Cooperative Drug Dis￾covery Grant program, a synthetic derivative, HTI- 286 (shown), was developed and is now in develop￾ment for the treatment of cancer. Photo courtesy R. Andersen, University of British Columbia, Vancouver, British Columbia, Canada. for drug discovery, particularly in the less-profi table areas such as antibiotics discovery, will be more greatly embraced by the NIH. These changes are beginning now with industry reconsidering natural product-based drug discovery and the NIH planning their own drug-discovery efforts as part of the “NIH Roadmap for Medical Research” (for more informa￾tion go to http://nihroadmap.nih.gov). NEW MARINE BIOMEDICAL SCIENCESTHE FUTURE We are about to enter an exciting new era in medicine, one that is already em￾bracing a new paradigm involving ge￾nomics-based drug discovery. Not only will knowledge of the human genome provide new drug targets and assist in disease diagnoses, but sequencing the full genomes of marine life will illustrate entirely new biosynthetic pathways that code for the production of a diversity of compounds as yet undiscovered. Genes from new and diverse marine sources will be cloned, combined, and expressed to generate a huge diversity of new mo￾lecular architectures. New resources, which had been diffi cult to examine in the past, will now be the focus of signifi - cant study. A prime example is the taxo￾nomically complex microbial life that resides in the world’s oceans. In contrast to terrestrial microbes, which formed the foundation for drug discovery for more than 40 years, those adapted for life in the sea are only superfi cially known. Advances in genomics-based tax￾onomy, and in the acquisition and cul￾tivation of marine bacteria, are already leading to the recognition of new classes of bacteria that produce unprecedented antibiotics and potential anticancer drugs. Shotgun cloning of DNA directly

derived from seawater has shown that a teria(>80 percent of all our microbial drug discovery.When the sheer immen. truly amazing compleity of microbial antibiotics are produced by this ass sity of the ocean bottom is considered life exists in the sea (Venter et al.,2004). of bacteria)were found there.The best (70 percent of Earth's surface),it is not These studies have further shown that example is the recently discovered and difficult to conceive of the importance microbial diversity varies by 8 percent widely distributed marine actinomy- of these resources in contributing to the between samples collected only 100 miles cete genus,Salinispora,which produces badly needed antibiotics for the next (161km)apart. a diversity of no molecules such as millennium (Figure9). Clearly,new genomics tools are great- salinosporamide A,a potent cancer cell As time passes,marine scientists are ly expanding our understanding of mi- growth inhibitor scheduled for clinical continually illustrating the important crobial diversity of the open ocean.One evaluation in 2006 (Figure8).At least roles symbiotic bacteria play in the bio of our greatest resources now appears to 13 new groups (likely to be new genera) synthesis of invertebrate-derived drug be deep ocean sediments.Althe ugh sedi- of actino ia have een dis. candidates.That microbes are found ments have been known for decades to covered in the last three years (Jensen in symbiotic relationships with inver harbor over 10 microbial cells per cubic et al.,2005;Stach and Bull,2005),sug- tebrates is almost the rule in marine centimeter,it was just recently that the gesting that these chemically rich micro- systems,but it has taken more thar medically significant actinomycete bac organisms will be a major resource for 30 years to begin to define their roles.A recent example is the discovery that the manzamine alkaloids,originally isolated from diverse sponges,are produced by an actinomycete bacterium of the genus Micromonospora,isolated directly from the invertebrate host (Figure 10).This is ete,Salinispora tropica,the of great importance,as the manzamines source of the potent protea are potent anti-malarial agents currently A(shown).Salinosporamide A in preclinical trials(Rao et) vill enter clinical trials in mid It is also easy to predict that the role of combinatorial gene biosynthesiswill increase as new sources for novel mol ecules are"manufactured"by cleverly combining and eliminating genes from whole biosynthetic gene clusters.It has also been shown that complex DNA can be extracted from environmental samples and expressed in host bacteria to gener- ate molecules not seen before(Brady and Clardy,2000;Brady et al.,2001;Clardy. 2005).Although this is reality in 2006. these studies are pioneering,and few complex pathways have been cloned. ent antibacterial activity agains Although not yet routine,these new bio technologies applied to the biosyntheti- rusand vancomycin-re cally complex life in the sea are likely to Enterococcus faecium. create immense chemical diversity. 118 Occanography I Vol 19,No.2.June 2006

118 Oceanography Vol. 19, No. 2, June 2006 drug discovery. When the sheer immen￾sity of the ocean bottom is considered (70 percent of Earth’s surface), it is not diffi cult to conceive of the importance of these resources in contributing to the badly needed antibiotics for the next millennium (Figure 9). As time passes, marine scientists are continually illustrating the important roles symbiotic bacteria play in the bio￾synthesis of invertebrate-derived drug candidates. That microbes are found in symbiotic relationships with inver￾tebrates is almost the rule in marine systems, but it has taken more than 30 years to begin to defi ne their roles. A recent example is the discovery that the manzamine alkaloids, originally isolated from diverse sponges, are produced by an actinomycete bacterium of the genus Micromonospora, isolated directly from the invertebrate host (Figure 10). This is of great importance, as the manzamines are potent anti-malarial agents currently in preclinical trials (Rao et al., 2004). It is also easy to predict that the role of combinatorial gene biosynthesis will increase as new sources for novel mol￾ecules are “manufactured” by cleverly combining and eliminating genes from whole biosynthetic gene clusters. It has also been shown that complex DNA can be extracted from environmental samples and expressed in host bacteria to gener￾ate molecules not seen before (Brady and Clardy, 2000; Brady et al., 2001; Clardy, 2005). Although this is reality in 2006, these studies are pioneering, and few complex pathways have been cloned. Although not yet routine, these new bio￾technologies applied to the biosyntheti￾cally complex life in the sea are likely to create immense chemical diversity. derived from seawater has shown that a truly amazing complexity of microbial life exists in the sea (Venter et al., 2004). These studies have further shown that microbial diversity varies by 80 percent between samples collected only 100 miles (161 km) apart. Clearly, new genomics tools are great￾ly expanding our understanding of mi￾crobial diversity of the open ocean. One of our greatest resources now appears to be deep ocean sediments. Although sedi￾ments have been known for decades to harbor over 109 microbial cells per cubic centimeter, it was just recently that the medically signifi cant actinomycete bac￾teria (> 80 percent of all our microbial antibiotics are produced by this class of bacteria) were found there. The best example is the recently discovered and widely distributed marine actinomy￾cete genus, Salinispora, which produces a diversity of novel molecules such as salinosporamide A, a potent cancer cell growth inhibitor scheduled for clinical evaluation in 2006 (Figure 8). At least 13 new groups (likely to be new genera) of actinomycete bacteria have been dis￾covered in the last three years (Jensen et al., 2005; Stach and Bull, 2005), sug￾gesting that these chemically rich micro￾organisms will be a major resource for Figure 8. Close-up photograph of the new marine actinomy￾cete, Salinispora tropica, the source of the potent protea￾some inhibitor salinosporamide A (shown). Salinosporamide A will enter clinical trials in mid 2006 with the primary target being multiple melanoma. Figure 9. Th e new actinomycete genus “Marinispora,” produces novel polyene-polyols with po￾tent antibacterial activity against drug resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium

The field of marine medicine has clearly advanced from its early stages of chemical exploration to a new era in which marine-derived drugs are here. Over the next decade,we will see sig nificant numbers of marine drugs being used in the treatment of cancer,other for intense pain and infectious diseases. There will be an expansion of these stud- ies to focus on many therapeutic areas of growing human need.After all,if we are to return to natural products as a source Figure 10.A clo for new drugs,where else might we go? up underwat r photo of the Indonesian sponge Acanthostrongylophora sp.This sponge tains complex molecules of the manzamine cass (manzamine A shown)The manzamines.which ACKNOWLEDGEMENTS I apologize to the many contributors to this field whose workI simply did not have space to describe.I am particularly grateful for the photos provided by sev- 122:12903-12.90 of the national eral colleagues (sce the figures for phote I.Handels .BMy of se c ce 83: .W.LeChemi- credit),which allowed me to adequately Zeiku illustrate their excellent work. Lc31.981-1.984 sts Discri r natu REFERENCES Andersen,RL,and M.Roberge.2005.HTI-286,A Rao.K.V.N. nah s Wah ,DG.L Kingsto nd D.I.N n,eds. R.F.Schinazi,and M.T.Hamann.2004.Three ney CRC Pr nd Fr Boca Raton,FL sponge and their activity against inf ph9 PA 31 5.Einaig stry (I Hay, oy:Whats e Dat 006. pare Copp,M.H.G.Munr North y200(1-2:103-134 kton.C 。 gy.Journal of Che mical Ecology 28(10):1.897 mth 06nmcd php llast accessed Blunt,LW.B.R.Copp.M.H.G.Munro,PT.Northc PR TI Minc and W Eenical cete di 7 Kna P,M.V Risk 5 M Ra Golik.I.C.Ia nd K 1981.1 CPfannkoch,YH.Rogers,and H.O.Smit 1.200 n sequencing of th 415080E 30466-74 1036773-6.776 Look 5.A.,W.Fenical,R.S.Ja and I.Clardy 1986 ONA.bmalgytheAm rican Chemical Society Occanography I Vol 19.No.2.June 2006 119

Oceanography Vol. 19, No. 2, June 2006 119 The fi eld of marine medicine has clearly advanced from its early stages of chemical exploration to a new era in which marine-derived drugs are here. Over the next decade, we will see sig￾nifi cant numbers of marine drugs being used in the treatment of cancer, others for intense pain and infectious diseases. There will be an expansion of these stud￾ies to focus on many therapeutic areas of growing human need. After all, if we are to return to natural products as a source for new drugs, where else might we go? ACKNOWLEDGEMENTS I apologize to the many contributors to this fi eld whose work I simply did not have space to describe. I am particularly grateful for the photos provided by sev￾eral colleagues (see the fi gures for photo credit), which allowed me to adequately illustrate their excellent work. REFERENCES Andersen, R.J., and M. Roberge. 2005. HTI-286, A synthetic analog of the antimitotic natural prod￾uct hemiasterlin. 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Hamann, University of Mississippi, Oxford, Mississippi