NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS

这项研究计划的长期目标是(I)探索和 开发新的有效的方法来合成各种 有药用价值的化合物和(Ii)发现和开发新的 以及有效的抗癌药作为MDR逆转剂。这项研究 该计划是非常跨学科的，已经并将继续实施 与每一学科的世界领先专家合作。那里 有三个具体目标：(1)开发有效的方法 手性非蛋白质氨基酸、多肽类和类肽的合成 具有药用价值的相关化合物。它是发展和发展的关键 建立高效可靠的新的综合方法学 攻克药物化学和分子科学中的重大问题 医药。作为实现这一具有挑战性的目标的途径，国际和平研究所将进一步 促进我们在非对称合成方面卓有成效的研究 蛋白质氨基酸、二肽异构体及相关化合物。新的 将开发适用于组合化学的方法。(2) 新一代紫杉类抗肿瘤药物的开发(2.1) 紫杉醇生物活性构象的测定。这是非常重要的 重要的是要找出紫杉醇，一种强大的抗癌药物是如何 与微管相互作用以稳定它，然后抑制它 细胞分裂。PI非常接近于揭示微管结合 紫杉醇的氟探针法首次构象 紫杉醇的固体~(19)F-核磁共振分析 激子手性CD法。(2.2)二次和二次合成的设计与合成 第三代紫杉类抗肿瘤药物。私家侦探将继续 在SAR研究的基础上开发第二代紫杉类化合物。《少年派》 将找出紫杉醇、埃博西酮和紫杉醇的共同药效团 根据在特定目的中获得的信息进行盘状皮质化 (2.1.)、合成孔径雷达研究和分子模拟。曾经常见的药效团 一旦确定，PI将设计第三代紫杉类抗肿瘤药物 可能不再具有紫杉烷结构的药物。(2.3)研究：关于 巨噬细胞代谢的光亲和标记 被紫杉醇激活。PI将执行光亲和标记 微管和P-糖蛋白及其代谢研究 P-450使用策略性的氟化紫杉醇 特定的氧化部位。私家侦探还将考察 紫杉醇激活巨噬细胞产生一氧化氮和/或肿瘤坏死因子α。(3) 利用巴卡菌素开发新的多药耐药逆转剂。抗药性 在癌症中，化疗是一个严重的问题。为了解决这个问题 问题，PI将继续他的成功方法来发展 基于巴卡菌素的战略修饰的多药耐药逆转剂。

The long-term objectives of this research program are (i) to explore and develop new and efficient methodologies for the syntheses of a variety of compounds of medicinal interest and (ii) to discover and develop new and effective anticancer agents as MDR reversal agents. 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) Development of efficient methods for the synthesis of enantiopure non-protein amino acids, peptidomimetics and related compounds of medicinal interest. It is essential to develop and establish efficient and reliable new synthetic methodologies in order to attack important problems in medicinal chemistry and molecular medicine. As an approach to this challenging goal, the PI will further promote our very productive research on the asymmetric synthesis of non- protein amino acids, dipeptide isosteres and related compounds. New methods applicable to combinatorial chemistry will be developed. (2) Development of new generation taxoid antitumor agents (2.1.) Determination of bioactive conformation of paclitaxel. It is extremely important to find out how paclitaxel, a powerful anticancer drug, interact with microtubules in order to stabilize it and then to inhibit the cell division. The PI is very close to reveal the microtubule-bound conformation of paclitaxel for the first time using fluorine probe of paclitaxel by means of the solid state 19FNMR analysis as well as exciton chirality CD method. (2.2.) Design and synthesis of second and third generation taxoid antitumor agents. The PI will continue to develop the second generation taxoids based on the SAR study. The PI will find out the common pharmacophore of paclitaxel, epothilones, and discodermoride based on the information obtained in the specific aim (2.1.), SAR study, and molecular modeling. Once the common pharmacophore is defined, the PI will design the third generation taxoid antitumor agents that may not have taxane structure anymore. (2.3.) Studies on the photoaffinity labeling with, the metabolism of and macrophage activation by taxoids. The PI will perform photoaffinity labeling of microtubules and P-glycoprotein as well as the metabolic study of taxoids by P-450s using strategically fluorinated taxoids that can block specific oxidation sites. The PI will also look at the ability of taxoids to activate macrophages producing NO and/or TNFalpha. (3) Development of new MDR reversal agents from baccatins. Drug resistance in cancer chemotherapy is a serious problem. In order to solve this problem, the PI will continue his successful approach to the development of MDR reversal agents based on the strategic modification of baccatins.