VINYL AND ALKYNYL TRIFLATE AND RELATED CHEMISTRY

我们的长远目标是全面阐明和发展 乙烯基三氟甲磺酸盐及其相关化合物的化学和用途 化合物。这包括对自然和环境的系统调查 由三氟化乙烯生成的一些活性中间体的行为。它 涉及探索烯醇磺酸盐的潜在合成用途和 相关物种包括迄今未知的官能化类别 乙炔：炔基磺酸盐(Rc=COSO2Ar)和炔基羧酸盐 (RC=COC(O)R‘)酯。 炔基羧酸酯(可能还有炔基磺酸盐)将是 被认为是潜在的酶介导酯酶抑制剂(新类别 自杀底物)。与上述类型的抗癌药物相关的新的抗肿瘤药物 将开发化合物。“协同”抗肿瘤药物结合 四种主要抗癌药物中的两种作用模式将是 制造。我们将结合DNA络合剂或插层剂(AN 用一种有效的烷基化试剂) (β-官能化-α，β-不饱和羰基或不可逆 Michael Accept)，从而提供了能力的可能协同 烷基化试剂来修饰DNA结构，具有 用于修饰DNA功能的嵌入剂。 我们在这一时期的具体目标有四个：1)准备，描述 探索了β-杂原子取代三氟乙烯酯的化学结构。 将采用改进的彼得森-烯化反应来实现此目的；2) Sigma-乙烯基铁的制备、表征和某些化学研究， 钴、铂、钯、镍和Ir络合物。这将是 通过将各种三氟乙烯基化物与带电的有机金属相互作用而实现的 亲核剂，如CPFE(CO)-2，Co(Dmg)2py-和通过氧化加成 (C6H5)3Pd、(C6H5)3Pd等； 研究最近制备的炔基对甲苯磺酸盐(RC=C-OSO2C6H4CH3)和 尝试制备相关的炔基羧酸酯。这件事会做到的 通过苯基烯基碘对甲苯磺酸盐(C6H5IC=CR)-OSO2C6H4CH3和相关 4)合成并鉴定了一类新的协同抗肿瘤药物。 探员们。我们的特定目标分子是蒽环类类似物 含有贝塔官能化的α，贝塔不饱和羰基部分。 所有新化合物将提交给NCI进行标准的抗肿瘤 筛选和评价。

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.