Total Synthesis and Evaluation of Taumycin A and Analogs as Chemotherapeutics for

陶霉素A及其类似物作为化疗药物的全合成及评价

• 批准号: 8619639
• 负责人: William A Maio
• 金额: $ 14.6万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619639
• 关键词: 3-hydroxybutanal; Acetals; Action Potentials; Address; Adverse effects; Affect; Alkynes; Architecture; Biological; Biological Factors; Blood; Bone Marrow Transplantation; Cancer cell line; Cell Line; Cells; Chemicals; Chronic; Clinical Trials; Combined Modality Therapy; Complex; Coupling; Development; Diagnosis; Disease; Dose; Elements; Enzymes; Evaluation; FDA approved; Future; Gemtuzumab Ozogamicin; Generations; Genetic; Gleevec; Goals; Harvest; Hematopoietic Neoplasms; Hour; Hybrids; Inhibitory Concentration 50; Laboratories; Lead; Light; Literature; Macrolides; Madagascar; Malignant Neoplasms; Marines; Mediating; Metals; Methods; Molecular; Monoclonal Antibodies; Nature; Operative Surgical Procedures; Oxazoles; Palladium; Pathway interactions; Patients; Personal Communication; Pharmaceutical Preparations; Phase; Porifera; Radiation therapy; Reaction; Regimen; Reporting; Research; Route; Secure; Solid Neoplasm; Structure-Activity Relationship; Time; United States; United States National Institutes of Health; Work; analog; base; cancer therapy; cell growth; chemical synthesis; chemotherapeutic agent; clinically relevant; cytotoxic; cytotoxicity; design; dosage; drug candidate; esterase; innovation; interest; ketene; leukemia; non-ribosomal peptide synthase; novel; programs; public health relevance; resilience; stereochemistry; treatment duration

DESCRIPTION (provided by applicant): The goal of this NIH SCORE proposal is to develop several novel synthetic methods to transform a cytotoxic marine-derived secondary metabolite into a potent chemotherapeutic agent for the treatment of leukemia. Worldwide, it is estimated that more than six people die every hour from some form of blood cancer. As a result of being a cancer that affects the blood, surgery is not an effective option, and modern-day therapies include radiation therapy and/or the administration of several chemotherapeutic agents. Since many patients cannot tolerate the high-dose regimen of drugs over time, new and effective agents that can be utilized in combination therapy and administered in low dosages over time are needed, especially in light of recent reports that question both the side-effects and efficacies of current drugs and drug-candidates used treat blood cancers. Recently, (+)-Taumycin A was isolated from a Madagascar sponge of genus Fascaplysinopsis and shown to inhibit UT-7 cell growth in the micromolar range (IC50=1¿M). In order to address the need for new blood- cancer treatments, a goal of this research program is to utilize total synthesis to supply a clinically-relevant amoun of this potent metabolite for further biological evaluation. The specific aims of this proposal are (1) to determine the unknown, absolute stereochemistry of (+)-taumycin A via total synthesis. This synthetic effort will lead to, (2) the development of a novel, one-pot metal-catalyzed method to regioselectively introduce a methyl substituent and an oxazole ring cis across a terminal alkyne by exploiting a carboalumination / paladium- mediated Suzuki cross coupling strategy. In addition, we will also explore (3) the stereoselective generation of a silyl ketene acetal and its use in an enantioselective vinylogous aldol reaction to establish two key stereocenters as well as to facilitate the final macrocyclic ring closure. Finally, (4) the synthetic route will offer acess to several analogs, and structural mimics that will assist in the determination of the unknown biological mode of action of this potential chemotherapeutic. Importantly, these novel methods will have application beyond the scope of the current proposal and are envisioned to be exploited in future total syntheses by the Maio laboratory, as our long-term goal is to be known as a strong and regular contributor to the chemical literature with a focus on the total synthesis of complex natural products that display both interesting molecular architecture and promising biological activity.

描述（由申请人提供）： 该NIH得分建议的目的是开发几种新型的合成方法，以将细胞毒性海洋衍生的二次代谢产物转化为潜在的化学治疗剂，以治疗白血病。在全球范围内，据估计，每小时有超过六人死于某种形式的血液癌。由于是影响血液的癌症，手术不是一个有效的选择，现代疗法包括放射治疗和/或给药几种化学治疗剂。由于许多患者无法随着时间的推移忍受药物的高剂量方案，因此需要在组合疗法中使用的新和有效药物随着时间的推移而在低剂量中使用，尤其是鉴于最近的报道质疑当前药物和药物习惯的副作用和有效性，并使用了药物习惯。最近，（+） - 陶霉素A从马达加斯加的fastaplysinopsis属的赞助商中分离出来，并显示可抑制微摩尔范围内的UT-7细胞生长（IC50 = 1？m）。为了满足对新血液治疗的需求，该研究计划的目标是利用总合成来提供与该潜在代谢产物相关的临床上的AMOUN，以进行进一步的生物学评估。该提案的具体目的是（1）确定（+） - taumycin a通过总合成的未知，绝对立体化学。这种合成的努力将导致（2）一种新型的单蛋白金属催化方法的发展，以区域选择性地在末端碱中引入甲基微生物和恶唑环顺序，从而利用碳浮肿 / paladium介导的suzuki suzuki suzuki交叉耦合策略。此外，我们还将探讨（3）甲硅烷基酮乙烯的立体选择性生成及其在对映选择性vinyllogous aldol反应中的使用，以建立两个关键的立体中心，并促进最终的大环环闭合。最后，（4）合成途径将为几个类似物提供ACESS，以及结构模仿，这将有助于确定这种潜在化疗的未知生物学作用方式。重要的是，这些新颖的方法将具有超出当前提案范围的应用，并设想将在未来的总合成中探索Maio实验室，因为我们的长期目标是被称为化学文献的强大和定期贡献者，重点是对复杂天然产物的全合成，既表现出有趣的分子结构又表现出有益的生物学活动。