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Natural Products: Essential Resources for Drug Discovery

Natural Products: Essential Resources for Drug Discovery. Professor SC Jain Department of Chemistry University of Delhi Delhi, India. A Short History of Medicine. 2000 B.C. ---- Here, eat this root. 1000 A.D. ---- That root is heathen. Here, say this prayer.

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Natural Products: Essential Resources for Drug Discovery

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  1. Natural Products: Essential Resources for Drug Discovery Professor SC Jain Department of Chemistry University of Delhi Delhi, India

  2. A Short History of Medicine 2000 B.C. ---- Here, eat this root. 1000 A.D. ---- That root is heathen. Here, say this prayer. 1850 A.D. ----That prayer is superstition. Here, drink this potion. 1940 A.D. ---- That potion is snake oil. Here, swallow this pill. 1985 A.D. ----That pill is ineffective. Here, take this antibiotic. 2005 A.D. ---- That antibiotic doesn’t work anymore. Here, eat this root….

  3. Ancient Medicines

  4. Aspirin • Extract of myrtle bark used for rheumatism and back pain. • Salicin was isolated by Johann A Buchner in 1828. • 3,500 years ago, Egyptian physicians advocated salicin in the form of herbal preparation. • Felix Hoffmann synthesized in 1897

  5. Quinine • Extract of cinchona tree was used to treat malaria. • Referred in Indian Vedic writing (3600 yrs ago) and in the prose of Hippocrates (2,500 yrs ago). • Robert B. Woodward synthesized in 1944.

  6. Penicillin • Penicillin was discovered by Alexander Flemming in 1928. • Penicillin antibiotics are the first drugs that were effective against syphilis and Staphylococcus infections. • It is a group of antibiotics derived from Penicilliumnotatum fungi

  7. Taxol • Extracted from the bark and needles of the yew tree, Taxus brevifolia. • Monroe E. Wall and Mansukh C. Wani identified Taxol in 1971. • Taxol is one of the newer chemotherapy drugs, and in use. • K C Nicolaou synthesized in 1994

  8. Ecteinascidin • New anticancer agent isolated from "the mangrove tunicate" (Ecteinascidia turbinata) found in the Florida. • This drug is in human trials for breast and ovarian cancers and is one of the most promising new treatment under development for solid tumors.

  9. Bryostatin • Product produced by a spiral bryozoan, Bugula californica, It is an exciting new form of chemotherapy as it selectively kills cancer cells without harming normal and healthy ones. • Expected to be shortly available as a new weapon against cancer.

  10. Pseudopterosins • Present in carribean sea whip, Pseudopterogorgia elisabethae in Florida. • Possess anti-inflammatory and analgesic properties (better than indomethacin).

  11. 200 150 100 50 0 Non-active Active sponges molluscs tunicates red algae bryozoans green algae coelenterates echinoderms brown algae miscellaneous microorganisms Phylum Distribution of biologically active and non-active marine natural products by phylum, 2003

  12. 120 100 80 60 AC 40 20 AM 0 IV sponges AO molluscs tunicates red algae bryozoans green algae brown algae echinoderms coelenterates miscellaneous microorganisms Other Phylum Distribution of biological activity by phylum. (AC- cancer related assays including cytotoxicity, antimiotic, histone deacetylase, proteasome, DNA binding and matrix metalloproteinase; AM- antimicrobial, antiinfective; AO- antimalarial assays; IV-in vivo assays such as brine shrimp and sea urchin eggs; Other- includes antiviral assays, assays based on central nervous system, feeding deterrent assays, ion channel assays, antifouling assays and assays for Fe siderophores and sperm attractant).

  13. Naturally Occurring 3-alkyl/ alkenyl pyridine alkaloids • Source :Marine Sponges • 37 Alkaloids known from various species • Varied in chain length, number & position of unsaturation and substitution in the side chain • Possess various biological activities: • Cytotoxic • Antileukaemic • Antineoplastic • Antimicrobialand  • Antifungal • Strong calcium ion inducers (20 times more potent thanCaffeine)

  14. Cytotoxic alkaloids (P-388 Murine Leukemia cells) Name Structure Species IC50 Value (g/ml) Xestospongia 2.2 Hachijodine A Xestospongia 2.2 Hachijodine B Hachijodine C Xestospongia 2.2 Hachijodine D Xestospongia 2.2 Hachijodine E Amphimedon 2.3 Hachijodine F Amphimedon 1.0 Hachijodine G Amphimedon 1.0 N. Fusetani et al, J. Nat. Product, 2000, 63, 682-684

  15. Cytotoxic alkaloids ( KB cells)

  16. -D-Glucosylated cytotoxic alkaloids ( P-388 murine leukemia cells) Nobuhiro Fusetani et al., American Chemical Society and American Society of Pharmacognosy, Published on Web 10/11/2006

  17. Anti-microfouling alkaloids

  18. Literature Method (a) n-BuLi, THP, -400C (b) 3N HCl, MeOH (c) Swern oxidation (d) NH3 or MeNH2, MeOH, NaBH4 (e) Pd-C/H2, EtOH Rao, A.V.R., Reddy, G.R. and Rao, B.V., J. Org. Chem., 1991, 56, 545-47.

  19. Target Molecules

  20. Retro Analysis

  21. Synthesis of Synthon A Synthesis of Synthon B

  22. Some New Analogues by Molecular Modification

  23. Some New Analogues by Molecular Modification

  24. Comparison of DNA, RNA and protein content in E. coli bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  25. Comparison of DNA, RNA and protein content in Bacillus cerus bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  26. Comparison of DNA, RNA and protein content in Lactobacillus bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  27. Compounds tested

  28. Antimicrobial Evaluation of Some More Synthetic Compounds * Ciprofloxacin for bacteria and Miconazole for fungi; Cup-Plate method used

  29. SYNTHESIS OF BIOLOGICALLY IMPORTANT PHENOLIC LIPIDS

  30. Some Naturally Occurring Non-isoprenoid Phenolic Acids

  31. Non-isoprenoid phenolic acids possess: • Antiviral Activity * Coxsackie B2 * Herpes simplex • Antibacterial Activity (at 3-25 g/ml concentration) * Bacillus cereus * Streptococcus pyogenes * Mycobacterium fortuitum • Molluscicidal Activity (Lc90 down to 1-3 ppm) * Biomphalaria glabrata

  32. Molluscicidal activity LC50 and LC90 values in ppm of some Non-isoprenoid phenolic acids (PA) isolated from Spondias mombin L.

  33. OUR TARGET MOLECULE Problems encountered in direct synthesis • -OH group is ortho-para directing while –COOH group is meta directing, so difficult to carry a. direct alkylation or alkenylation at C-6 b. direct hydroxylation at C-2 • Difficult to carry direct carboxylation because of steric hindrance due to the presence of long alkyl or alkenyl chain and hydroxyl group at adjacent carbons.

  34. Synthesis of Target Molecule

  35. List of Compounds Synthesized

  36. Molluscicidal activity: Methodology: Sullivan et al., Planta Medica, 1982,44, 175-177. Corthout et al., Planta Medica, 1994, 60, 460-463. From these preliminary experiments it can be concluded that molluscicidal activity is associated with an unsaturated side chain and that a double bond in position 12 of the side chain is better than in position 10. Both OCH3/COOH and OH/COOH substitution pattern show good activity.

  37. Inhibition of Cyclooxygenase-1, Cyclooxygenase-2 Methodology: Redl K. et al., Planta Medica, 1994,60, 58-62. Reginer E. and Bauer R., 46th Annual Congress of the Society for Medicinal Plant Research, 31.09.98-04.09.98, Vienna (abstract) Inhibition of Lipoxygenase Apparently compounds with a side chain unsaturated in position 12 are the most potent inhibitors of lipoxygenase. Further experiments to establish more detailed structure-activity relationships are in progress.

  38. Comparison of DNA, RNA and protein content in E. coli bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  39. Comparison of DNA, RNA and protein content in Bacillus cerus bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  40. Comparison of DNA, RNA and protein content in Lactobacillus bacterial growth after the treatment with synthetic samples 100* mean there is no inhibition in control samples. Values out of the bracket in green shows the amount in g. Values in blue shows the total growth in percent Values in red shows the %growth inhibition - means no significant inhibition was observed.

  41. Compounds tested

  42. SYNTHESIS OF 6-ALKYL/ALKENYL AMINO ACIDS

  43. Used as herbicides to weeds including Digitaria sanguinalis, Rumex obtusifolius, Sorghum halepense, Imperata cylindrica, Parricum spp. and Paspalurn spp. • N-Acyl derivatives inhibited the growth of blue grass algae. • Increases frost resistance in wheat, tobacco, corn and grape plants. • Used for increasing sugar contents in sugar cane. • Possesses both pre-emergent and post-emergent plant growth regulant activity. The post-emergent activity is most significant that control weeds by reducing their vigor and competitiveness and, thus prevent their spread and stop normal seeding

  44. OUR TARGET MOLECULE

  45. List of Amino Acids Synthesized

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