Taxane and Taxoid Chemotherapeutic Agents

紫杉烷和紫杉烷类化疗药物

• 批准号: 6781078
• 负责人: IWAO OJIMA
• 金额: $ 31.58万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781078
• 关键词: Taxane; Taxoid; Chemotherapeutic; Agents

DESCRIPTION (provided by applicant): The long-term objective of this research program is to discover and develop new and effective chemotherapeutic agents for fight against cancer, including cytotoxic agents, immunoconjugates, and multidrug resistance (MDR) reversal agents based on taxanes, taxoids and their congeners by combining new methodology in organic synthesis, medicinal chemistry, modern spectroscopic methods, chemical biology, and molecular pharmacology, connecting translational research to medical and clinical oncology. This research program is very interdisciplinary and has been and will be carried out in collaboration with world leading experts in each discipline. There are three specific aims: 1.1. Design and development of highly tumor specific taxoid-conjugates as new chemotherapeutic agents In general, widely used cytotoxic chemotherapeutic agents have serious drawbacks, i.e., these drugs cannot distinguish cancer cells from normal cells and this unfortunate feature constitutes major basis for a variety of undesirable side effects. In order to overcome these drawbacks, the PI will explore tumor activated prodrug strategy with the use of appropriate antibodies that recognize particular tumor surface antigens as well as special fatty acid that tumor cells seek for as vehicle for tumor-specific delivery of highly cytotoxic taxoid anticancer agents. 1.2. Development of taxane-based agents that can overcome drug-resistance in cancer The PI plans to undertake a systematic study on various drug-resistance in cancer and explore new approaches to overcoming this problem. This specific aim includes photoaffinity labeling of P-glycoprotein and development of new generation taxoid anticancer agents that are effective against drug-resistant tumors as well as highly effective taxane-MDR reversal agents (TRAs). 1.3. Design and development of de novo microtubule-stabilizing antitumor agents The PI will continue to investigate the microtubule-bound conformations of several microtubule-stabilizing anticancer agents and their common pharmacophore. Based on the tubulin-bound paclitaxel and taxoid structures, the PI will design and synthesize novel conformationally restricted taxoids as well as de novo antitumor agents that stabilize microtubules.

描述（申请人提供）：本研究项目的长期目标是通过结合有机合成、药物化学、现代光谱方法、化学生物学和分子生物学的新方法，发现和开发新的、有效的抗癌化疗药物，包括基于紫杉烷类、紫杉烷类及其同系物的细胞毒剂、免疫偶联物和多药耐药（MDR）逆转剂。 药理学，将转化研究与医学和临床肿瘤学联系起来。该研究项目具有很强的跨学科性，已经并将与各个学科的世界领先专家合作进行。 具体目标有以下三个： 1.1．设计和开发高度肿瘤特异性的紫杉烷缀合物作为新的化疗药物一般来说，广泛使用的细胞毒性化疗药物具有严重的缺点，即这些药物无法区分癌细胞和正常细胞，这种不幸的特征构成了各种不良副作用的主要基础。为了克服这些缺点，PI将探索肿瘤激活的前药策略，使用适当的抗体来识别特定的肿瘤表面抗原以及肿瘤细胞寻求的特殊脂肪酸，作为肿瘤特异性递送高细胞毒性紫杉烷抗癌药物的载体。 1.2.开发能够克服癌症耐药性的紫杉烷类药物 PI计划对癌症中的各种耐药性进行系统研究，并探索克服这一问题的新方法。这一具体目标包括P-糖蛋白的光亲和标记和开发可有效对抗耐药肿瘤的新一代紫杉烷抗癌药物以及高效紫杉烷-MDR逆转剂（TRA）。 1.3.从头设计和开发微管稳定抗肿瘤药物 PI将继续研究几种微管稳定抗肿瘤药物的微管结合构象及其共同药效团。基于微管蛋白结合的紫杉醇和紫杉烷结构，PI将设计和合成新型构象限制的紫杉烷以及稳定微管的从头抗肿瘤药物。