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CHEM-705 Biosynthesis and Isolation of Natural Products and Bioassay Screenings Set A February - 2014 Prof. Dr. Shaheen Faizi 1.

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1 CHEM-705 Biosynthesis and Isolation of Natural Products and Bioassay Screenings Set A February - 2014 Prof. Dr. Shaheen Faizi 1

2 2 CHEM-705 Biosynthesis of Natural Product Set A First – Third Lectures Prof. Dr. Shaheen Faizi

3 The people of understanding remember Allah standing, sitting and reclining, and ponder over the creation of the heavens and the earth, which impels them to supplicate: “O Lord! Thou hast not created all this without purpose. Glory be to thee.” (3:191) 3

4 CHEM-705 Biosynthesis and Isolation of Natural Products and Bioassay Screenings a) Bioassay screening  Prof. Dr. Iqbal Choudhary (7) Dr. Talat Makhmoor (6) Dr. Shabana Simjee (7) b)Isolation techinques –Dr. Mussharaf (20) c) Biosynthesis  Prof. Dr. Shaheen Faizi (30) Prof. Dr. Sabira Begum (30) Total Number = 100 4

5 Biosynthesis of Natural Products a) Natural Products b) Biosynthesis Natural Products From Plants, animals, microorganisms, marine organisms as medicines as templates Compounds which have biological activities and are derived from natural sources, e.g., plants, animals and microorganisms, are defined as natural products. Natural products have been used by human societies for millennia. (a)Dwight D. Baker, Min Chu, Uma Oza and Vineet Rajgarhia, The value of natural products to future pharmaceutical discovery, Nat. Prod. Rep., 2007, 24, 1225–1244, b) G. M. Cragg, P. G. Grothaus, D. J. Newman, Natural products in drug discovery: Recent advances, In plant bioactive and drug discovery: Principles, practice, and perspectives, V. Cechinel- Filo, ed. 2012, vol. 17 of Wiley series. John Wiley & Sons. pp. 1-42, http://www.nlm.nih.gov/hmd/collections/archives/index.html, c) http://www.botanical-online.com/theimportanceofplants.htm d) M. S. Butler, Natural products to drugs: natural product derived compounds in clinical trials, Nat. Prod. Rep., 2008, 25(3), 475-516. 5

6 Aloe barbadensis (Liliaceae) PLANTS 6

7 Coleus forskohlii (Labiatae / Lamiaceae) Artemisia annua (Composetae / Asteraceae) 7

8 Catharanthus roseus (Apocynaceae) 8

9 Digitalis purpurea (Scrophulaciaceae) Agave sisalana (Agavaceae) 9

10 Citrus paradisi (Rutaceae) J. Agric. Food Chem., 2010, 58, 180-186 Phytother. Res., 2009, 23, 948-954 Citrus aurantium (Sour orange)  -Sitosterolglucoside Limonexic acid Chem. Rev., 2011, 111, 7437-7522 10

11 Allium sativum - garlic (Alliaceae) Allium sepa - Onion (Alliaceae) J. Agric. Food Chem., 2007, 55, 10067-10080 11

12 Animal Bufo spp. (Toad) Stenus similis beetles J. Nat. Prod, 2011, 74, 2231-2234 Insect 12 J. Nat. Prod. 2013, 76, 865-872 J. Nat. Prod, 2013, 76, 1078-1084

13 Penicillium griseofulvumPenicillium patulm Microorganisms Fungus 13

14 Streptomyces orchidaceusStreptomyces venezuelaeClavicep spp. 14

15 Cribrochalina sp. (Sponge) Tet. Lett., 2006, 47, 997-998. Marine Natural Product Dysidera avara (Sponge) Nat. Prod. Rep., 2011, 28, 400-410. 15

16 Asparagopsis of taxiforms Red Alga Nat. Prod. Rep., 2011, 28, 186-195 Marine Bacillus sp. J. Nat. Prod., 2011, 74, 1606-1612 Streptomyces sp. J. Nat. Prod., 2007, 24, 777-797 (Deep-sea actinomycete) 16

17 Natural products from plant-associated microorganisms According to a recent review, the classification and documenting of terrestrial flora have been intensively investigated, with estimates of the number of higher plant species ranging from 300 000 to as high as 500 000. In terms of pharmacological and phytochemical investigation, however, estimates are as low as 6% and 15%, respectively. Furthermore, the marine environment remains virtually unexplored as a potential source of novel drugs, and until recently, the investigation had largely been restricted to tropical and subtropical regions. The power of Nature as applied to plant secondary metabolite production can be augmented through the use of chemical elicitors and selected derivatives of biosynthetic precursors. Thus, exposure of the roots of hydroponically grown plants to chemical elicitors induces the selective and reproducible production of bioactive compounds, while the feeding of seedlings of Catharanthus roseus with various tryptamine analogues has resulted in the production of non-natural terpene indole alkaloids related to the vinca alkaloids. With the current ability to cultivate only a vanishingly small number of naturally accurring microorganisms, the study of either terrestrial or marine natural microbial ecosystems has been severely limited. As a result, it has been estimated that less than 1% of microorganisms seen microscopically have been cultivated. Nevertheless, despite this limitation, a most impressive number of highly effective microbially derived chemotherapeutic agents has been discovered and developed. Given the observation that “a handful of soil contains billions of microbial organisms”, and the assertion that “the workings of the biosphere depend absolutely on the activities of the the microbial world”, the microbial universe clearly presents a vast untapped resource for drug discovery. There is mounting evidence that many bioactive compounds isolated from various macro-organisms, which can include plants, marine, terrestrial invertebrates, and even fungi, are actually metabolites synthesized by symbiotic bacteria. The discovery of a bacterium – fungus – plant interaction occurring in the case of rice seedling blight provides an interesting example of an even more complex symbiotic-pathogenic relationship. 17

18 It is a fact that plants have been relatively extensively studied as sources of bioactive metabolites, but the role of endophytic microbes that reside in the tissues between living plant cells has only recently started receiving attention. The relationships between endophytes and their host plants may vary from symbiotic to pathogenic, and studies are revealing an interesting realm of novel chemistry. Among the wide range of new bioactive molecules reported, are peptide antibiotics, the coronamycins (structure not determined), isolated from a Streptomyces species associated with an epiphytic vine (Monastera species) found in the Peruvian Amazon. Histrocally, the major impediments to the development of a natural product lead have been limited availability and structural complexity. Natural products are often produced in trace quantities, and biomass is limited or, in the case of microbial sources, unculturable. The discovery of novel natural products has been revolutionized by advances in genomic mining and the engineering biosynthetic pathways. These methods can also be utilized to enable large-scale production of natural products in the native or engineered organisms. Nature has been a source of medicinal products for millennia, and during the past century, many useful drugs have been developed from natural sources, particularly plants. It is clear that Nature will continue to be a major source of new drug leads. The drug potential of the marine environment remains relatively unexplored, but it is becoming increasingly evident that the realm of microorganisms offers a vast untapped potential. With the advent of genetic techniques that permit the isolation and expression of biosynthetic cassettes, microbes and their marine invertebrate hosts may well be the new frontier for natural products lead discovery. Plant endophytes also offer an exciting new resource, and research continues to reveal that many of the important drugs originally thought to be produced by plants are probably products of an interaction with endophytic microbes residing in the tissues between living plant cells. This has been further accentuated by the recent report of the isolation of hypericin form an endophytic fungus from Hypericum perforatum. Effective drug development will depend on multidisciplinary collaboration embracing natural product lead discovery and optimization through the application of total and diversity-oriented synthesis and combinatorial chemistry and biochemistry, combined with good biology. 18

19 1S. Kusari and M. Spiteller, Are we ready for industrial production of bioactive plant secondary metabolites utilizing endophytes? Nat. Prod. Rep., 2011, 28, 1203-1207. 2R. N. Kharwar, A. Mishra, S. K. Gond, A. Stierle and D. Stierle, Anticancer compounds derived from fungal endophytes: their importance and future challenges, Nat. Prod. Rep., 2011, 28, 1208-1228. 3C.-L. Shao, C.-Y. Wang, Y.-C. Gu, M.-Y. Wei, J.-H. Pan, D.-S. Deng, Z.-G. She, Y.-C. Lin, Penicinoline, a new pyrrolyl 4-quinolinone alkaloid with an unprecedented ring system from an endophytic fungus Penicillium sp. Bio. Med. Chem. Lett., 2010, 20, 3284-3286. 4Y. Zhang, T. Han, Q. Ming, L. Wu, K. Rahman, L. Qin, Alkaloids produced by endophytic fungi: a review, Nat. Prod. Commun., 2012, 7, 963-8. 5J. M. Crawford and J. Clardy, Bacterial symbionts and natural products, Chem. Commun. 2011, 47, 7559-7566. 6S. Kusari, S. P. Pandey, M. Spiteller, Untapped mutualistic paradigms linking host plant and endophytic fungal production of similar bioactive secondary metabolities, Phytochem., 2012, http://dx.doi.org/10.1016/j.phytochem.2012.07.021. http://dx.doi.org/10.1016/j.phytochem.2012.07.021 7S. Kusari, C. Hertweck, M. Spiteller, Chemical ecology of endophytic fungi: origins of secondary metabolites, Chem. & Biol., 2012, 19, 792-798. 8E. Adelin, C. Servy, S. Cortial, H. Lévaique, M.-T. Martin, P. Retailleau, G. L. Goff, B. Bussaban, S. Lumyong, J. Quazzani, Isolation structure elucidation and biological activity of metabolites from Sch-642305-producing endophytic fungus Phomopsis sp. CMU-LMA, Phytochem., 2011, 72, 2406-2412. 9Q. Ming, T. Han, W. Li, Q. Zhang, H. Zhang, C. Zheng, F. Huagn, K. Rahman, L. Qin, Tanshinone IIA and tanshinone I production by Trichoderma atroviride D16, an endophytic fungus in Salvia miltiorrhiza, Phytomed., 2012, 19, 330- 333. 10M. Tadych, J. F. White, Endophytic Microbes, In Encyclo. Microbiol., 2009, 431-442. 19

20 11Gordon M. Gragg, Paul G. Grothaus, and David J. Newman, Impact of natural products on developing new anti- cancer agents, Chem. Rev. 2009, 109, 30120-3043. 12A. A. Leslie Guantilaka, Natural products from plant-associated microorganisms: Distribution, structural diversity, bioactivity, and implication of their occurrence, J. Nat. Prod. 2006, 69, 509-526. 13G. Strobel, B. Daisy, U. Castillo and J. Harper, Natural products from endophytic microorganisms, J. Nat. Prod. 2004, 67, 257-268. 14Li-Li Xua, Ting Han, Jin-ZhongWu, Qiao-Yan Zhang, Hong Zhang, Bao-Kang Huang, Khalid Rahman, Lu-Ping Qin, Comparative research of chemical constituents, antifungal and antitumor properties of ether extracts of Panax ginseng and its endophytic fungus, Phytomedicine, 2009, 16, 609–616. 15Hua Wei Zhang, Yong Chun Song and Ren Xiang Tan, Biology and chemistry of endophytes, Nat. Prod. Rep., 2006, 23, 753-771. 16Ravindra N. Kharwar, Ashish Mishra, Surendra K. Gond, Andrea Stierle and Donald Stierle, Anticancer compounds derived from fungal endophytes: their importance and future challenges, Nat. Prod. Rep., 2011, 28, 1208-1228. 17Stefan Schulz and Jeroen S. Dickschat, Bacterial volatiles: the smell of small organisms, Nat. Prod. Rep., 2007, 24, 814-842. 18Jörn Piel; Metabolites from symbiotic bacteria, Nat. Prod. Rep., 2009, 26, 338-362. 19J. Piel, Metabolites from symbiotic bacteria, Nat. Prod. Rep., 2009, 26, 338-62. 20G. Strobel and B. Daisy, Bioprospecting for microbial endophytes and their natural products, Microbio. & Molecul. Biol. Rev., 2003, 491-502. 20

21 Plant associated microorganisms Penicillium sp. Mangrove endophytic fungus Bio. & Med. Chem. Lett., 2010, 20, 3284-3286 Salvia miltiorrhiza Trichoderma atroviride Endophytic fungus Phytomed., 2012, 19, 330-333 Mangrove plant 21

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23 Naturally occurring organohalogen compounds It is sometimes assumed by the lay press, environmental activists, politicians, and others, that organohalogen compounds – organic chemicals containing one or more carbon – chlorine, carbon – bromine, carbon – iodine, or carbon – fluorine bond – are generally not found in nature. One purpose of this account is to document that not only are naturally occurring organohalogen compounds ubiquitous in our environment, but concentrations of some of these chemicals exceed their anthropogenic levels. In addition, previously unknown naturally occurring organohalogen compounds are continually being isolated and characterized from a variety of marine and terrestrial plant and animal sources. The explosion of activity in the area of organohalogen natural product chemistry is certain to continue. The continued improvements in isolation, analytical, and spectroscopic techniques over the past few years ensure the fact that even the most structurally complex organohalogen natural products can and will be identified. As our understanding of natural enzymatic halogenation reaction continues to increase, it will be possible to separate more accurately natural from anthropogenic sources of halogenated chemicals. 23

24 Now it is well known that naturally occurring organohalogen compounds are abundant in plants, fungi, microorganisms, and especially marine invertebrates. Surprisingly, although fluorine is the most abundant halogen in Earth’s crust, fluorinated natural products are very rare. Since the first organo-fluorine compound, fluoroacetate (1), was identified in 1943 from the South African plant Dichapetalum cyosum, only eighteen (18) fluorine-containing secondary metabolites have been isolated from plants and microorganisms. These include fatty acid homolgues (e.g 2), fluorothreonine (3), nucleocidin (4) and 5- fluorouracils (e.g 5). 24 Enhanced production of the fluorinated nucleoside antibiotic nucleocidin by a rif R -resistant mutant of Streptomyces calvus IFO13200, Actinomycetologica (2009) 23:51-55.

25 Because of fluorine’s unusual properties (high electronegativity, small Van der Waals radius, high dissociation energy of C-F), fluorinated compounds have found myriad applications such as foaming agents, blood substitutes, refrigerants, anaesthetics, lubricants and catalysts. In the pharmaceutical and agricultural sectors, the number of fluorinated compounds is ever increasing; 20-25% of currently available drugs and approximately 28% of agrochemicals contain at least one fluorine atom. 25

26 1G. W. Gribble, Naturally occurring organohalogen compounds – a survey, J. Nat. Prod., 1992, 55, 1353-1395. 2 D. B. Harper and D. O. Hagan, The fluorinated natural products, Nat. Prod. Rep., 1994, 123-133. 3G. W. Gribble, Naturally occurring organofluorines, The Handbook of Environmental Chemsistry, vol. 3, part N, organofluorins, 2002, 3, 121-136. 4C. J. Thomas, Fluorinated natural products with clinical significance Current Topics in Medicinal Chemistry, 2006, 6, 1529-1543. 5J. P. Bégué, and D. B. Delpon, Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products, J. Fluorine Chemistry, 2006, 127, 992-1012. 6C. S. Neumann, D. G. Fujimori1 and C. T. Walsh, Halogenation strategies in natural product biosynthesis, Chemistry & Biology, 2008, 22, 99-109. 7A. S. Eustáquio, D. O’Hagan and B. S. Moore, Engineering fluorometabolite production: Fluorinase expression in Salinispora tropica yields fluorosalinosporamide, J. Nat. Prod., 2010, 73, 378–382. 8K. Müller, C. Faeh, F. Diederich, Fluorine in pharmaceuticals: looking beyond intuition, Science, 2007, 317, 1881-1886. 9L. C. Blasiak, C. L. Drennan, Structural perspective on enzymatic halogenation, Acc Chem Res. 2009, 42, 147-55. 10C. Dong, F. Huang, H. Deng, C. Schaffrath, J. B. Spencer, D. O'Hagan1 & J. H. Naismith, Crystal structure and mechanism of a bacterial fluorinating enzyme, Nature, 2004, 427, 561-565. 11J. P. Bégué and D. B. Delpon, Bioorganic and medicianl chemistry of fluorine, John Wiley & Sons, 2008. 12Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, Kong CH., 5-Fluorouracil derivatives from the sponge Phakellia fusca, J Nat Prod. 2003, 66(2), 285-288. 13J. Amadio, C. D. Murphy, Biotransformation of fluorobiphenyl by Cunninghamella elegans, Appl Microbiol Biotechnol. 2010, 86(1), 345-351. 14L. L. Xua, T. H. Jin-ZhongWu, Qiao-Yan Zhang, Hong Zhang, Bao-Kang Huang, K. Rahman, Lu-Ping Qin; Comparative research of chemical constituents, antifungal and antitumor properties of ether extracts of Panax ginseng and its endophytic fungus, Phytomedicine, 2009, 16, 609–616. 15D. B. Harper, D. O. Hagan and C. D. Murphy; Fluorinated natural products: Occurrence and biosynthesis; The Handbook of Environmental Chemistry; 2003, 3, 141-169. 16K. Fukuda, T. Tamura, Y. Segawa, Y. Mutaguchi and K. Inagaki, Enhanced production of the fluorinated nucleoside antibiotic nucleocidin by a rif R - resistant mutant of Streptomyces calvus IFO13200, Actinomycetol., 2009, 23, 51-55. 26

27 Untapped plant power abounds everywhere. Almost, two_ third of the Earth’s 6.1 billion people rely on the healing power of plants. One important source of new drugs of the pharmaceutical industry is from Nature. We need a new way to listen to Nature, while maintaining all the advantages of science. By definition science welcomes new evidence, new ways of thinking. It has no final truths. It is a continuous quest and exploration. Chemistry, a discipline of science plays a vital role in the discovery and development of pharmaceuticals. In Romeo and Juliet, William Shakspeare describes “the powerful grace that lies in herbs.” It is obvious that plant’s powerful arsenal of bioactive substances ________ compounds that affect living cells _________ can be of significant value in waging against human ailments. In fact the plant kingdom represents a largely unexplored reservoir of valuable compounds to be discovered. Of the estimated 400,000_500,000 plant species around the globe, only a small percentage has been investigated phytochemically and the fraction submitted to biological or pharmalogical screening is even lower. About 25% of the pharmaceuticals prescribed by doctors in the developed world have, as their origins, the chemicals produced by flowering plants. If compounds produced by fungi and some animals are included, the figure is above 40%. The ability of plants and some other living organisms to produce stereospecific molecules with very complex skeleton is one aspect that makes them attractive as sources of novel molecules, since some structures are beyond the imagination of even the most fanciful synthetic chemist. 27

28 J. Chem. Educ., 2007, 84, 2012-2018 Complexation between a biologically-active molecule (ligand), arriving from outside a cell, and receptor, embedded in the membrane of this cell (schematic drawing): left) components before binding; (center) the ligand-receptor complex showing a change of the receptor conformation, generating a biological message to the organism; and (right) components after binding. 28

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30 30 Investigation of biosynthetic pathways Eighty years ago, investigations of biosynthetic pathways progressed from purely hypothetical speculation to studies of the regiospecificity of incorporation of isotopically labelled precursors by whole cells or partially purified enzymes. Towards the end of the twentieth century, interdisciplinary approaches to establish many general precursor – product relationship were made which were based on: a)Enzymology b)Genomics c)Proteomics d)X-ray crystallography of enzyme substrate complexes e)Advanced NMR spectroscopy f)Advanced Mass spectroscopy Reference: 1E. Haslam, Editor D. Barton, Comprehensive organic chemistry, Biological Compounds, 5, 1979. 2R. Thomas, Biogenetic speculation and biosynthetic advances, Nat. Prod. Rep., 2004, 21, 224-248. 3R. Bentley, From miso, saké and shoyu to cosmetics: a century of science for kojic acid, Nat. Prod. Rep., 2006, 23, 1046-1062. 4D. Shemin and R. Bentley, David Rittenberg 1906-1970, Biographical Memories, The National Academy Press, Washington D.C. 2001, 80, 1-20. 5S. J. Weininger, Deuterium as a probe of the boundaries between physics, chemistry and biochemistry, 6 th International Conference on the History of Chemistry, 2009, 187-194. 6S. F. Previs, S. T. Ciralo, C. A. Fernandez, M. Beylot, K. C. Agarwal, M. V. Soloviev and H. Brunengraber, Use of [6,6- 2 H 2 ] glucose and of low-enrichment [U- 13 C 6 ]-glucose for sequential or simultaneous measurements of glucose turnover by gas chromatography – mass spectrometry, Analytical Biochem., 1994, 218, 192-196. 7H. Schierbeek, T. C. W. Moerdijk-poortviet, C. H. P. V. D. Akeer, F. W. J. T. Braake, T. S. Boschker and J. B. V. Goudoever, Analysis of [U- 13 C 6 ] glucose in human plasma using liquid chromatpgraphy/isotope ratio mass spectrometry compared with two other mass spectrometry techniques, Rapid Comm. Mass Spectrom., 2009, 23, 3824-3830. 8P. Adam, M. Gutlich, H. Oschkinat, A. Bacher and W. Eisenreich, Studies of the intermediary metabolism in cultured cells of the insect Spodoptera frugiperda using 13 C- or 15 N-labelled tracers, BMC Biochem., 2005, 6, 1-11. 9S. C. Morrison, D. A. Wood, P. M. Wood, Characterization of a glucose 3-dehydrogenase from the cultivated mushroom (Agaricus bisporus), Appl. Microbiol. Biotechnol., 1999, 51, 58-64. 10A. Lai, M. Casu and G. Saba, NMR investigation of the intramolecular distributin of deuterium in natural triacylglycerols, Mag. Res. Chem., 1995, 33, 163-166. 11N. Matsui, F. Chem, S. Yasuda, K. Fukushima, Conversion of guaiacyl to syringly moieties on the cinnamyl alcohol pathway during the biosynthesis of lignin in angiosperms, Planta, 2000, 210, 831-835. 12N. P. Botting, Isotope effects in the elucidation of enzyme mechanisms, Nat. Prod. Rep., 1994, 11, 337-353.

31 Using the Natural Molecule as a Template__________ Willow to Aspirin In some cases it is not very suitable to use the isolated compounds from a medicinal plant as a pharmaceutical. The plant may not have a sufficiently strong effect, or most seriously, it might have undesirable side effects. In such cases, a common approach, is to determine which parts of the molecule are responsible for the desired activity (this portion of the molecule is sometimes termed the pharmacophore) and which parts are not necessary or contribute to the undesired effects. The natural compound is thus used as a template in attempts to synthesize the pharmacophore, eliminate the undesired portions of the molecule, and synthesize related compounds so that structure activity (SA) studies can be carried out. This approach has led to the introduction of several major groups of drugs, including probably the best-known drug in all the world, aspirin. Aspirin is made completely synthetically but its development is based on the traditional use in Europe of plants such as Willow and meadowsweet to treat rheumatism and general aches and pains. 31

32 32 Some important drugs synthesized using natural molecules as templates

33 33

34 34 Anti HIV Nat. Product

35 NP-derived drugs launched in USA, Europe or Japan since 1998 by year with reference to their lead compound, classification and therapeutic area. (Nat. Prod. Report, 22, 162-195, 2005) S. No.YearGeneric name (trade name) Lead compound ClassificationDisease area 1.1998Orlistat (Xenical ® ) LipstatinSemisynthetic NP Antiobesity 2.1998Cefoselis (Wincef ® ) CephalosporinNP-derivedAntibacterial 3.1999Valrubicin (Valstar ® ) DoxorubicinNP-derivedOncology 4.1999Colforsin daropate (Adele, Adehl ® ) ForskolinSemisynthetic NP Cardiotonic 5.2000Arteether (Artemotil ® ) ArtemisininSemisynthetic NP Antimalarial 6.2002Galantamine (Reminyl ® ) GalantamineNPAlzheimer’s disease 7.2003Mycophenolate sodium (Myfortic ® ) Mycophenolic acid NPImmunosup- pression 8.2003Rosuvastatin (Crestor ® ) MevastatinNP derivedDyslipidemia NP = Natural Product 35

36 36

37 Natural Products in Crop Protection Clove Eugenia caryophyllus Mentha piperita (Peppermint) Cymbopogon citratus (Lemon grass) Leaves Bioorg. & Med. Chem. 2009, 17, 4022-4034 37

38 Azadirachta indica (Meliaceae) Capsicum frutesceus Nicotiana tabacum 38

39 There are more than 3,00,000 compounds described in literature as Natural Products. In the following pages structures of some aliphatic and aromatic compounds are given, which provide a glimpse of structural diversity of Natural Products. 39

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49 The information provided above highlights the continuing role that natural products and structures derived from or related to natural products from all sources have played and continue to play in the development of the current therapeutic armamentarium of the physician. Inspection of the data shows this continued important role for natural products, in spite of the current low level of natural products- based drug discovery programs in major pharmaceutical houses. It is already clear that there is considerable potential in compounds obtained through plowing in the landscape of natural products. Particularly impressive are those compounds that are obtained through diverted total synthesis, i.e., through methodology, which was redirected from the original (and realized) goal of total synthesis, to encompass otherwise unavailable congeners. There is strong expectation that enterprising and hearty organic chemists will not pass up the unique head start that natural products provide in the quest for new agents and new directions in medicinal discovery. Organic chemists in concert with biologists and even clinicians will be enjoying as well as exploiting the rich troves provided by nature’s small molecules. There is no doubt that a host of novel, bioactive chemotypes await discovery from both terrestrial and marine sources. Finally, a multidisciplinary approach to drug discovery, involving the generation of truly novel molecular diversity from natural product sources, combined with total and combinatorial synthetic methodologies, and including the manipulation of biosynthetic pathways (so-called combinatorial biosynthesis), provides the best solution to the current productivity crisis facing the scientific community engaged in drug discovery and development. 49

50 The facts stated above further serve to illustrate the inspiration provided by Nature to receptive organic chemists in devising ingenious syntheses of structural mimics to compete with Mother Nature’s longstanding substrates. Even discounting these categories, the continuing and overwhelming contribution of natural products to the expansion of the chemotherapeutic armamentarium is clearly evident, and much of Nature’s “treasure trove of small molecules” remains to be explored, particularly from the marine and microbial environments. 50

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