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

抗癌工具：利用赫克型烯化来锻造中环

• 批准号: 8212434
• 负责人: Jennifer L Roizen
• 金额: $ 5.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-08 至 2013-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212434
• 关键词: Address; Alkenes; Alzheimer' s Disease; Antineoplastic Agents; Architecture; Cancer cell line; Carbon; Cell Death; Cells; Chemicals; Cisplatin; Complex; Coupling; Cyclization; Development; Diagnosis; Disease; Esters; Guaianolide Sesquiterpenes; Health; Investigation; Malignant Neoplasms; Metals; Methods; Molecular; Pharmaceutical Preparations; Process; Research Design; Research Methodology; Structure; Sulfides; Technology; Thapsigargin; analog; androgen independent prostate cancer; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cost effective; cytotoxic; cytotoxicity; design; fighting; forging; member; molecular mass; prevent; scaffold; small molecule; thioester; tool

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.

描述（由申请人提供）：背景和相关性：开发包含中型环的潜在抗癌药物的主要障碍是无法有效地生产这七到十名的carbocycles。该提案解决了形成中型环的策略的不足。该提案为具有广泛但选择性的抗癌和抗阿尔茨海默氏症活性的一类分子开发了收敛的方法：瓜伊亚诺伊德曲甲苯苯甲酸酯。瓜伊亚诺伊德倍半萜包括脱氢乳肠酮和硫甘醇。脱氢可肝乳酮显示出与几种关键癌细胞系中顺铂相当的细胞毒性。 Thapsigargin促进了包括雄激素独立的前列腺癌细胞，包括对常规化学疗法反应的增殖和静止细胞中的细胞死亡。 thiapsigargin类似物已经通过29步合成访问，并且比thiapsigargin更有效。需要更好的合成方法来生产这些分子体系结构，以开发具有成本效益的癌症治疗。我们此处开发的工具将与构建中型环的一系列无关的细胞毒性化合物的构建有关。具体目的：这些调查将开发出较高的碳 - 碳交叉偶联，涉及碳激活因子键的金属催化分裂，这是一种迄今未报告的技术。该提案的具体目的是开发（1）激活的酰基化合物的分子内heck型烯烃以锻造中型碳纤维； （2）分子内heck烯烃用活化的杂瘤化学组装中等大小的环； （3）烯烃与活化底物的分子间碳碳偶联； （4）通过串联顺序的heck-型烯烃与活化的异源酯型化合物通过串联顺序heck-type烯烃的高度结合合成。研究设计：该方法的设计要求取决于Heck-t5t）e环化的机制。为了启动调查，将采用简单的基板来优化碳碳交叉耦合。最佳条件将应用于更复杂的底物，以构建潜在的癌症治疗的结构支架，包括脱氢链氨甲酮，thapsigargin和sargassinone。公共卫生相关性：基于碳的小分子是预防，理解，诊断和治疗疾病的重要工具。这些努力的主要障碍是我们无法以具有成本效益的方式快速构建这些化学物质。我们计划开发一个连接碳的新过程，这应该使我们能够组装目前无法接近的药物和化学探针。

项目成果

Selective intermolecular amination of C-H bonds at tertiary carbon centers.

• DOI: 10.1002/anie.201304238
• 发表时间: 2013-10-18
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Roizen JL;Zalatan DN;Du Bois J
• 通讯作者: Du Bois J

Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C-H bonds.

• DOI: 10.1021/ar200318q
• 发表时间: 2012-06-19
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Roizen JL;Harvey ME;Du Bois J
• 通讯作者: Du Bois J

Analyzing site selectivity in Rh2(esp)2-catalyzed intermolecular C-H amination reactions.

• DOI: 10.1021/ja5015508
• 发表时间: 2014-04-16
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Bess, Elizabeth N.;DeLuca, Ryan J.;Tindall, Daniel J.;Oderinde, Martins S.;Roizen, Jennifer L.;Du Bois, J.;Sigman, Matthew S.
• 通讯作者: Sigman, Matthew S.