76100 Rehovot, Israel
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I. Target Oriented Organic Synthesis, Including Total Synthesis of Physiologically Active CompoundsA total syntheses of (-)-alpha-kainic acid, a neuroactive amino acid and of yingzhaosu A, an antimalarial endoperoxides were completed. Beside the synthesis of yingzhaosu A itself we designed and synthesized scores of structurally related endoperoxides. Antimalarial in vitro and in vivo screening and preliminary toxicity tests indicated that some of these peroxides exhibit potent antimalarial activity and, being non-toxic, are considered as potential antimalarial drug candidates.
II. Development of New Synthetic Methods and Strategies Based on Free Radical ProcessesMethodologies based on sulfur-mediated sequential free radical reactions and on temporary sulfur connection were developed. In sequential reactions several new bonds are formed and cleaved in a single operation without isolating intermediates, thus increasing the overall efficacy of a process. In temporary connection reaction-selectivity and stereoselectivity are controlled through intramolecularization of the process. The particular properties of sulfides and of thiyl radicals allow the integration of the strategy of temporary connection, and the strategy of sequencing reactions in single processes. This strategy has been applied to the stereospecific synthesis of 2,4-cis-disubstituted pyrrolidines.
III. Iron(II) Induced Degradation of PeroxidesInvestigating some controversial aspects regarding the origin of the antiparasitic properties of peroxides the mechanism of the iron(II)-induced degradation of some endoperoxide-sulfones was studied. We found that beside free radicals and electrophilic products also carbocations are generated. It is conceivable that the antimalarial activity of endoperoxides may derive from alkylation of vital intra-parasitic biomolecules by free-radicals and/or carbocations, generated within the malaria parasite through a similar iron(II)-induced degradation process.
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Paul M. O'Neill, Edite Verissimo, Stephen A. Ward, Jill Davies, Edward E. Korshin, Nuna Araujo, Matthew Pugh, M. Lurdes S. Cristiano, Paul A. Stocks, Mario D. Bachi, "Diels –Alder/Thiol-Olefin Co-Oxygenation Approach to Antimalarials Incorporating the 2,3-dioxabicyclo[3.3.1]nonane Pharmacophore.", Bioorg. Med. Chem. Lett. 16, 2991-2995 (2006).[Read online]
Junwon Kim, Hong Bin Li, Andrew S. Rosenthal, Dongpei Sang, Theresa A. Shapiro, Mario D. Bachi, and Gary H. Posner, "Ground State Oxygen in Synthesis of Cyclic Peroxides. Part 1: Benzo Fused Ketals.", Tetrahedron 62, 4120-4127 (2006).[Read online]
Edward E. Korshin and Mario D. Bachi, "Synthesis of Cyclic Peroxides", In The Chemistry of Peroxides (ed. Z. Rappoport); John Wiley & Sons, Chichester, England, 2006; Volume 2, Part 1, pp 189-305.
A. M. Szpilman, E. E. Korshin, H. Rozenberg, and M. D. Bachi, Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer Including the First Evaluation of Their Antimalarial and Cytotoxic Actvities J. Org. Chem. 70, 3618-3632 (2005). [Read online]
Paul M. O'Neill, Paul A. Stocks, Matthew D. Pugh, Nuna, C. Araujo, Edward, E. Korshin, Jamie, F. Bickley, Stephen A. Ward, Patrick, G. Bray, Erica Pasini, Jill Davies, Edite Verissimo, and Mario D. Bachi. Design and Synthesis of Endoperoxide Antimalarial Prodrug Models, Angew. Chem. Int. Ed. 43, 4193-4197 (2004). [Read online]
Paul M. O'Neill, Amira Mukhtar, Stephen A. Ward, Jamie, F. Bickley, Jill Davies, Mario D. Bachi, and Paul A. Stocks. Application of Thiol-Olefin Co-oxygenation Methodology to a New Synthesis of the 1,2,4-Trioxane Pharmacophore, Org. Lett. 6, 3035-3038 (2004).[Read online]
Edward E. Korshin, Yaroslav V. Bilokin, Hailin Zheng, and Mario D. Bachi. "Efficient Stereoselective Alkenylation through a Homolytic Domino Reaction Involving a 1,5 Sulfur-to-Carbon Translocation", J. Am. Chem. Soc. 126, 2708-2709 (2004). [read online]
M. D. Bachi, E. E. Korshin, R. Hoos, A.M. Szpilman, P. Ploypradith, S. Xie, T. A. Shapiro, and G. H. Posner, A Short Synthesis and Biological Evaluation of Potent and Nontoxic Antimalarial Bridged Bicyclic beta-Sulfonyl Endoperoxides. J. Med. Chem. 46, 2516-2533 (2003). [read online]
E. E. Korshin, R. Hoos, A. M. Szpilman, L. Konstantinovski, G. H. Posner and M. D. Bachi, An Efficient Synthesis of Bridged-Bicyclic Peroxides Structurally Related to Antimalarial Yingzhaosu A Based on Radical Co-Oxygenation of Thiols and Monoterpenes. Tetrahedron 58, 2449-2469 (2002). [read online]
A. M. Szpilman, E. E. Korshin, R. Hoos, G. H. Posner and M. D. Bachi, Iron(II)-Induced Degradation of Antimalarial beta-Sulfonyl Endoperoxides. Evidence for the Generation of Potentially Cytotoxic Carbocations. J. Org. Chem. 66, 6531-6540 (2001). [read online]Y.V. Bilokin, A. Melman, V. Niddam, B. Benhamú and M.D. Bachi, Synthesis of thiabicyclic heterocycles through free radical cyclization of beta-thioacrylates. Tetrahedron, 56, 3425 (2000)[read online]
M.D. Bachi, E.E. Korshin, R. Hoos and A.M. Szpilman, Synthesis and reactions of antimalarial bicyclic peroxides. J. Heterocycl. Chem. 37, 639 (2000)[reference].
M.D. Bachi and A. Melman, Enantioselective total synthesis of (-)-alpha-kainic acid. Pure & Appl. Chem. 70, 259 (1998).[reference]
M.D. Bachi, Y.V. Bilokin and A. Melman, Stereospecific intramolecular Michael addition to (-)-carvone based on temporary sulfur connection. Tetrahedron Lett. 39, 3035 (1998).[read online]
M.D. Bachi, E.E. Korshin, P. Ploypradith, J.N. Cumming, S. Xie, T.A. Shapiro and G.H. Posner, Synthesis and in vitro antimalarial activity of sulfone endoperoxides. Bioorg. Med. Chem. Lett. 8, 903 (1998).[read online]
M.D. Bachi and E.E. Korshin, Thiol-oxygen cooxidation of monoterpenes. Synthesis of endoperoxides structurally related to antimalarial yingzhaosu A. Synlett. 112 (1998).[read online]
M.D. Bachi and A. Melman, Enantioselective total synthesis of (-)-alpha-kainic acid through free-radical cyclization of an alkenyl monothioformimide. J. Org. Chem. 62, 1896 (1997).[read online]
M.D. Bachi, N. Bar-Ner and A. Melman. Stereoselective synthesis of +/-alpha-kainic acid using free-radical key reactions. J. Org. Chem. 61, 7116 (1996).[read online]
M.D. Bachi and A. Melman,Temporary sulfur connection in an intramolecular SN2 reaction. A stereocontrolled synthesis of (+/-)-kainic acid. Synlett. 60 (1996).[read online]
G.H. Posner, S.B. Park, L. Gonzacutelez, D. Wang, J.N. Cumming, D. Klinedinst, T.A. Shapiro and M.D. Bachi, Evidence for the importance of high-valent Fe=O and of diketone in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin. J. Am. Chem. Soc. 118, 3537 (1996).[read online]
M.D. Bachi and A. Melman, Stereocontrolled 5-exo-trig cyclization of imidoyl radicals in the synthesis of substituted alkylthiopyrrolines, pyroglutamates, and thiopyroglutamates. J. Org. Chem. 60, 6242 (1995).
M.D. Bachi, A. Balanov, and N. Bar-Ner, Thiol-mediated free radical cyclization of alkenyl and alkynyl isocyanides. J. Org. Chem. 59, 7752 (1994).