Tools to Fight Cancer: Exploiting Heck-type Olefinations to Forge Medium Rings

描述（由申请人提供）：背景和相关性：开发含有中等大小环的潜在抗癌剂的主要障碍是不能有效地产生这些七至十元碳环。这项建议针对的是建立中型环的战略中的一个缺陷。这一建议开发了一种收敛的方法，一类分子具有广泛的但选择性的抗癌和抗阿尔茨海默氏症的活动：愈创木倍半萜。愈创木倍半萜包括脱氢木香内酯和硫胡萝卜素。脱氢木香内酯在几种关键癌细胞系中显示出与顺铂相当的细胞毒性。毒胡萝卜素促进增殖和静止细胞的细胞死亡，包括雄激素非依赖性前列腺癌细胞，这些细胞对常规化疗没有反应。硫代胡萝卜素类似物已经通过29步合成获得，并且比硫代胡萝卜素更有效。更好的合成方法是必要的，以产生这些分子结构，以开发具有成本效益的癌症治疗。我们在此开发的工具将与构建一系列不相关的细胞毒性化合物相关，这些化合物包含中等大小的环。具体目标：这些研究将开发一种Heck型碳-碳交叉偶联，涉及碳-活化剂键的金属催化断裂，这是一种迄今未见报道的技术。具体目标是：（1）活化酰基化合物的分子内Heck型烯化反应，形成中等大小的碳环;（2）活化杂环化合物的分子内Heck烯化反应，组装中等大小的环;（3）烯烃与活化底物的分子间碳-碳偶联反应;（4）通过与活化的杂芳酯型化合物的串联顺序Heck型烯化反应高度收敛地合成七元环。研究设计：该方法的设计要求由Heck-t5 T）e环化的机制决定。为了启动研究，将采用简单的底物来优化碳-碳交叉偶联。最佳条件将被应用于更复杂的底物，以构建潜在癌症治疗的结构支架，包括脱氢木香内酯，毒胡萝卜素和sargassinone。公共卫生相关性：碳基小分子是预防、理解、诊断和治疗疾病的重要工具。这些努力的一个主要障碍是我们无法以具有成本效益的方式迅速制造这些化学品。我们计划开发一种连接碳的新工艺，这将使我们能够组装目前无法获得的药物和化学探针。

DESCRIPTION (provided by applicant): Background and Relevance: A major obstacle to development of potential anti-cancer agents that contain medium-sized rings is the inability to produce these seven- to ten-member carbocycles efficiently. This proposal addresses a deficiency in strategies to form medium-sized rings. This proposal develops a convergent approach to a class of molecules with broad yet selective anti-cancer and anti-alzheimers activities: the guaianolide sesquiterpenes. The guaianolide sesquiterpenes include dehydrocostuslactone, and thiapsigargin. Dehydrocostuslactone shows cytotoxicities comparable to those of cisplatin in several key cancer cell lines. Thapsigargin promotes cell death in proliferative and quiescent cells including androgen-independent prostate cancer cells, which do not respond to conventional chemotherapy. Thiapsigargin analogues have been accessed through 29-step syntheses, and are more potent than thiapsigargin. Better synthetic methods are necessary to produce these molecular architectures so as to develop cost-effective cancer treatments. The tools we develop herein will be relevant to construction of a range of unrelated cytotoxic compounds that incorporate medium-sized rings. Specific aims: These investigations will develop a Heck-type carbon-carbon cross-coupling involving metal-catalyzed scission of a carbon-activator bond, a hitherto unreported technology. The specific aims of this proposal are to develop (1) the intramolecular Heck-type olefination of activated acyl compounds to forge medium-sized carbocycles; (2) the intramolecular Heck olefination with activated heteroaromatics to assemble medium-sized rings; (3) the intermolecular carbon-carbon coupling of alkenes with activated substrates; (4) the highly-convergent synthesis of seven-membered rings through tandem sequential Heck- type olefinations with activated heteroaromatic ester-type compounds. Study design: The design requirements of this method are dictated by the mechanism for Heck-t5T)e cyclization.. To launch investigations, a simple substrate will be employed to optimize carbon-carbon cross- couplings. Optimal conditions will be applied to more complex substrates to construct the structural scaffolds of potential cancer treatments, including dehydrocostuslactone, thapsigargin and sargassinone. PUBLIC HEALTH RELEVANCE: Carbon-based small molecules are essential tools to prevent, understand, diagnose, and treat disease. A major obstacle to these efforts is our inability to construct these chemicals rapidly and in a cost-effective manner. We plan to develop a new process to connect carbons, which should enable us to assemble currently inaccessible drugs, and chemical probes.