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Synthesis of Phenol and Benzoquinone derivatives from New Zealand Brown Alga Perithalia capillaris A proposal submitte

Synthesis of Phenol and Benzoquinone derivatives from New Zealand Brown Alga Perithalia capillaris A proposal submitted to the Faculty Of Drexel University By Khalid Baig Mirza In partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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Synthesis of Phenol and Benzoquinone derivatives from New Zealand Brown Alga Perithalia capillaris A proposal submitte

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  1. Synthesis of Phenol and Benzoquinone derivatives from New Zealand Brown Alga Perithalia capillaris A proposal submitted to the Faculty Of Drexel University By Khalid Baig Mirza In partial fulfillment of the requirements for the degree of Doctor of Philosophy

  2. Natural products of medicinal importance • Natural products have long been used for medicinal purposes. They include compounds like morphine, strychnine, Atropine, Colchicine, etc. • Few other compounds include • Warfarin (a coumarin analog) ---- A blood thinner • Taxol, Irinotecan ---- Anti cancer agents • Salicylates ---- Anti inflammatory, Anti pyretics Atropine Morphine Warfarin Taxol

  3. Phenols, Benzoquinone and benzopyranscontaining drugs Metaraminol Phenylephrine Treatment of hypotension Decongestant Fenoterol Warfarin Doxorubicin Treatment of asthma Blood thinner Anti-cancer

  4. Compounds isolated from New Zealand brown alga Perithalia capillaris • Eight compounds were isolated from a brown alga through a bioactivity-directed isolation process. • Compound 4 inhibits superoxide production by human neutrophils (IC50 2.1uM) • It also is highly potent at inhibiting the proliferation of HL60 cells (IC50 0.3uM)

  5. Need for a new way to target an inflammation • Superoxide production by neutrophils are the main cause of an inflammation in certain conditions like gouty arthritis and non-atopic asthma, etc. • Body produces Superoxide Dismutase (SOD) to mop-up the superoxide. • Following an inflammation in the above conditions, there is a downregulation of SOD and also there is an increased superoxide production. • Commonly used NSAIDS target Cyclooxygenase and Phospholipase enzymes in the cascade of reactions leading to an inflammation.. • Therefore there is a specific need for compounds that inhibit superoxide production in conditions associated with acute inflammation, rheumatoid arthritis, inflammatory bowel disease, some heart diseases, neuropathic and cancer pain and also opiate intolerance.

  6. Potential Anti Cancer agent • The bis-prenylated quinone 4 also showed high potency at inhibiting leukemia cells from HL60 cell line. • HL60 cell line once isolated from a patient with acute myeloid leukemia resembles promyelocytes. These cells can differentiate terminally in vitro to granulocyte-like and monocyte / macrophage-like cells • Since the compounds isolated from the brown alga, inhibit the proliferation of the HL60 cell, they could be used in treating leukemia and related cancers

  7. The Proposal • Describes possible routes directed towards syntheses of these eight compounds isolated from Perithalia capillaris. • Compounds 1, 2, 3, 4, 5 and 6 contain a five carbon chain (an isoprene unit) attached to them. A regioselective synthesis involving modest number of steps has been proposed to synthesize each compound. • Most reactions presented in the proposal are well established achieving quantitative yields. However a few reactions may result in some undesired side products, although in small percentages.

  8. Compound 1

  9. Compound 2

  10. Compound 3

  11. Compound 4

  12. Compound 5

  13. Compound 6 Proposed mechanism for the formation of 27

  14. Compound 7

  15. Compound 8 Retrosynthesis

  16. a. Methylene Chloride, reflux; b. AlCl3 / Chlorobenzene, 120oC; c. NaOH/(CH3)2SO4; d. nBuLi, NCCO2CH3,THF -78 oC; e. NaBH4, EtOH, 0oC; f. EtOH/ HCl, pH 3-4; g. Me3SiCN, ZnCl2, CH2Cl2, -78oC r.t.; h. NaHCO3, H2O; i. HCl / H2O; j. SOCl2/EtOH ; k. CAN, MeCN/ H2O.

  17. Conclusions • The synthetic scheme for compounds 1-8 provides a simple and effective way for their preparation. Compound 1 may be synthesized from 2-acetamidophenol and prenyl bromide. • Different conditions used during alkylation provides different alkylation pattern. • Similarly compound 2 maybe synthesized from 2-acetamidophenol and prenyl bromide, however here a Friedel crafts alkylation is used to obtain a branched chain –para alkylation. • Further in-vitro and in-vivo studies have to be performed on animal models in order to confirm there safety and effectiveness.

  18. REFERENCES (1) Sansom,C.E; Larsen, L; Perry, N.B; Berridge, M.V; Chia, E.W; Harper, J.L; and Webb, V.L; J. Nat.Prod.2007; 70 2042–2044. (2) Vane. J; and Botting. R;The FASEB Journal, 1987, 1, 89-96. (3) Winyard, P.G; Blake, D.R; Evans, C.H; Free Radicals and Inflammation; 2000 135-136. (4)McCarthy, A.A; Chem. & Biol; 2003, 10, 1139–1140. (5) Fleck, R.A; Romero-Steiner, S; and Nahm, M.H; Clin. Diagn. Lab. Immunol. 2005 12; 19-27. (6) Pearce, A.N; Chia, E.W; Berridge, M.V; Clark, G.R; Harper, J. L; Larsen, L; Maas, E.W; Page, M.J; Perry, N.B; Webb, V.L; and Copp, B.R; J. Nat. Prod. 2007, 70, 936-940. (7) Hoarau, C; Pettus, T.R.R; Synlett 2003,1, 127-137. (8) Mehta, G. and Pan, S.C; Org. Lett. 2004, 6, 811-813. (9) Mundy, B.P; Ellerd, M.G; Favaloro, Jr..F.G; Name reactions and Reagents in Organic Synthesis; 2005, 156-157 (10) Solomons, T.W.G; Fryhle, C.B; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc. (11) Morrison, R.T; and Boyd, R. N; Organic Chemistry; 6/e 1992; Prentice Hall. (12) Inoue, S; Ikeda, H; Sato, S; Horie, K; Miyamoto,T.O.O; Sato, K; J. Org. Chem.; 1987; 52, 5495-5497. (13) Gassman, P.G; and Amick, D.R; J. Am. Chem. Soc.; 1978; 100, 7611 – 7619. (14) Mikhailova, T .V; Misharina, T.A; Aérov, A.F; Lyapin, V.A; Gren, A.I; Vysotskaya, L.E and Golovnya, R.V; Russ. Chem. Bull; 1987; 36; 1407-1410. (15) Grob, C.A; Waldner, A; Helv. Chim. Acta; 1979; 62; 1854-1865. (16) Kalena, G.P; Jain, A; and Banerji, A; Molecules 1997; 2; 100–105. (17) Wang, T; Chen,Y; Lee, K and Tzeng, C; Tet.Lett.; 1996; 37; 6369-6370. (18) Talamás, X.F;Smith, D.B; Cervantes, A; Franco, F; Cutler, S.T; Loughhead, D.G; Morgans, Jr. D.J; and Weikert, R.J; Tett. Lett; 1997; 38; 4725-4728.

  19. Thank You • Dr. Robert Hutchins -- Chair • Dr. Jean-Claude Bradley – Research Advisor • Dr. Aleister Saunders • Dr. Kevin Owens • Dr. Louis Scerbo • Dr. Daniel King • Dr. Jun Xi • Dr. Anthony Addison • All the Graduate Students • Special Thanks to Dr. Anthony Wambsgans.

  20. Questions ??

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