Taxane and Taxoid Chemotherapeutic Agents

紫杉烷和紫杉烷类化疗药物

• 批准号: 7092254
• 负责人: IWAO OJIMA
• 金额: $ 30.84万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092254
• 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）：该研究计划的长期目标是结合有机合成、药物化学、现代光谱学方法、化学生物学、生物化学、生物化学等新方法，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性药物、免疫缀合物和多药耐药逆转剂，和分子药理学，将转化研究与医学和临床肿瘤学联系起来。该研究计划是非常跨学科的，已经并将与各学科的世界领先专家合作开展。 有三个具体目标：作为新化疗剂的高度肿瘤特异性的紫杉烷-缀合物的设计和开发通常，广泛使用的细胞毒性化疗剂具有严重的缺点，即，这些药物不能将癌细胞与正常细胞区分开，并且这种不幸的特征构成了各种不希望的副作用的主要基础。为了克服这些缺点，PI将探索肿瘤激活的前药策略，使用识别特定肿瘤表面抗原的适当抗体以及肿瘤细胞寻求的特殊脂肪酸作为高细胞毒性紫杉烷类抗癌剂的肿瘤特异性递送的载体。 1.2.开发可克服癌症耐药性的紫杉烷类药物PI计划对癌症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。这一特定目标包括P-糖蛋白的光亲和标记和新一代紫杉烷类抗癌剂的开发，这些抗癌剂对耐药肿瘤以及高效的紫杉烷MDR逆转剂（TRAs）有效。 1.3.重新设计和开发微管稳定抗癌药物PI将继续研究几种微管稳定抗癌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。