Taxane and Taxoid Chemotherapeutic Agents

描述（由申请人提供）：本研究计划的长期目标是结合有机合成、药物化学、现代光谱方法、化学生物学和分子药理学的新方法，发现和开发新的有效的抗癌化疗药物，包括基于紫杉烷、类紫杉烷及其同系物的细胞毒性药物、免疫偶联物和多药耐药（MDR）逆转药物，将转化研究与医学和临床肿瘤学联系起来。该研究项目是跨学科的，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：一般来说，广泛使用的细胞毒性化疗药物存在严重的缺陷，即无法区分癌细胞和正常细胞，这一不幸的特点是导致各种不良副作用的主要原因。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，以及肿瘤细胞寻找的特殊脂肪酸，作为肿瘤特异性递送高细胞毒性类taxoid抗癌药物的载体。1.2. 紫杉烷类药物在癌症耐药中的应用研究PI计划对癌症的各种耐药进行系统的研究，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，以及新一代抗耐药肿瘤的类紫杉抗癌药物的开发，以及高效的紫杉烷-耐多药逆转药物（TRAs）。1.3. 新微管稳定抗肿瘤药物的设计和开发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类taxoid结构，PI将设计和合成新的构象受限类taxoids以及稳定微管的新生抗肿瘤药物。

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.