VINYL AND ALKYNYL TRIFLATE AND RELATED CHEMISTRY

我们的长期目标是充分阐明和发展 乙烯基三氟甲烷磺酸酯及相关化合物的化学和用途 化合物. 这包括系统调查的性质， 由乙烯基三氟甲磺酸酯产生的一些反应性中间体的行为。 它 涉及探索烯醇磺酸盐的潜在合成用途， 包括迄今为止未知的官能化的种类的相关物质 炔类：炔基磺酸酯（RC= COSO 2Ar）和炔基羧酸酯 (RC=COC（O）R ′）酯。 炔基羧酸酯（和可能的炔基磺酸酯）将是 作为潜在的酶介导的酯酶抑制剂（新一类的 硅化物衬底）。 与上述类型的肿瘤相关的新的抗肿瘤剂 将开发化合物。 “协同”抗肿瘤剂组合了 四种主要抗癌药物类型中的两种的作用模式将是 进行了 我们将结合联合收割机DNA络合剂或嵌入剂（一种 蒽环类类似物）与有效的烷基化剂 （β-官能化的-α，β-不饱和羰基或不可逆的 迈克尔受体），从而提供了可能的协同作用的能力 的烷化剂修饰DNA结构，与能力的烷化剂， 嵌入剂以修饰DNA功能。 我们在这一时期的具体目标有四个方面：1）准备， 并探索β-杂原子取代的乙烯基三氟甲磺酸酯的化学。 将采用改进的Peterson烯烃化来实现这一点; 2） 制备、表征和研究Sigma-乙烯基铁的一些化学性质， 钴、铂、钯、镍和铱络合物。 这将是 通过使各种乙烯基三氟甲磺酸酯与带电的有机金属相互作用来实现 亲核试剂如CpFe（CO）_2，Co（dmg）_2py-和通过氧化加成 乙烯基三氟甲磺酸酯转化为（C6 H5）3 Pt、（C6 H5）3 Pd等; 3）充分表征和 研究了最近制备的炔基甲苯磺酸酯（RC= C-OSO 2C 6 H4 CH 3）和 尝试制备相关的炔基羧酸酯。 为此将 通过苯基炔基碘鎓甲苯磺酸盐（C6 H5 IC =CR）+-OSO 2C 6 H4 CH 3和相关的 4）合成并评价了一类新的协同抗肿瘤药物 剂. 我们的特异性靶分子是蒽环类药物 掺入β-官能化的α，β-不饱和羰基部分。 所有新化合物将提交给NCI进行标准抗肿瘤 筛选和评估。

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.