Our long term objectives are the full elucidation and development of the chemistry and uses of vinyl trifluoromethanesulfonates and related compounds. This includes a systematic investigation of the nature and behavior of some reactive intermediates generated from vinyl triflates. It involves exploration of the potential synthetic uses of enol sulfonates and related species including the hitherto unknown class of functionalized acetylenes: alkynyl sulfonate (RC=COSO2Ar) and alkynyl carboxylate (RC=COC(O)R') esters. Alkynyl carboxylate esters (and perhaps alkynyl sulfonates) will be examined as potential enzyme mediated esterase inhibitors (new class of suicide substrates). New antitumor agents related to the above type of compounds will be developed. """"""""Synergistic"""""""" antitumor agents combining the modes of action of two of the four major anti-cancer drug types will be made. We will combine a DNA complexing or intercalating agent (an anthracycline analog) with a potent alkylating agent (Beta-functionalized-Alpha,Beta-unsaturated carbonyl or irreversible Michael acceptor) thereby providing the possible synergism of the ability of the alkylating agents to modify DNA structure, with the ability of the intercalating agents to modify DNA function.
Our specific aims for this period are four-fold: 1) Prepare, characterize and explore the chemistry of Beta-heteroatom substituted vinyl triflates. A modified Peterson-olefination will be employed to achieve this; 2) Prepare, characterize and investigate some chemistry of Sigma-vinyl iron, cobalt, platinum, palladium, nickel and irridium complexes. This will be achieved by interacting various vinyl triflates with charged organometallic nucleophiles such as CpFe(CO)-2, Co(dmg)2py- and by oxidative addition of vinyl triflates to (C6H5)3Pt, (C6H5)3Pd, etc,; 3) Fully characterize and investigate recently prepared alkynyl tosylates (RC=C-OSO2C6H4CH3) and attempt to prepare related alkynyl carboxylate esters. This will be done via phenyl alkynyl iodonium tosylates (C6H5IC=CR)+-OSO2C6H4CH3 and related species; 4) Synthesize and evaluate a new class of synergistic antitumor agents. Our specific target molecules are anthracycline analogs incorporating a Beta-functionalized Alpha, Beta-unsaturated carbonyl moiety. All new compounds will be submitted to the NCI for standard antitumor screening and evaluation.
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| Banzon, J A; Kuo, J M; Miles, B W et al. (1995) Mechanism-based inactivation of phosphotriesterase by reaction of a critical histidine with a ketene intermediate. Biochemistry 34:743-9 |
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