NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS

非蛋白质氨基酸和紫杉烷抗肿瘤剂

• 批准号: 2900722
• 负责人: IWAO OJIMA
• 金额: $ 26.33万
• 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 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900722
• 关键词: P glycoprotein; affinity labeling; aminoacid analog; antibiotics; antineoplastics; chemical structure function; combinatorial chemistry; cytochrome P450; drug design /synthesis /production; leukocyte activation /transformation; macrophage; microtubules; multidrug resistance; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; paclitaxel; peptide hormone analog; pharmacokinetics; stereochemistry

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.

该研究计划的长期目标是（i）探索和 开发新的和有效的方法来合成各种 （二）发现和开发新的药物; 和作为MDR逆转剂的有效抗癌剂。 本研究 该计划是非常跨学科的，已经并将进行 与各学科的世界领先专家合作。那里 有三个具体目标：（1）发展有效的方法， 对映体纯非蛋白质氨基酸、肽模拟物和 相关的药用化合物。 必须制定和 建立有效和可靠的新合成方法， 解决药物化学和分子生物学中的重要问题 药 作为实现这一具有挑战性目标的方法，PI将进一步 促进我们对非对称合成的非常富有成效的研究， 蛋白质氨基酸、二肽电子等排体和相关化合物。 新 将开发适用于组合化学的方法。（二） 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。 是极其 重要的是要找出紫杉醇，一种强大的抗癌药物， 与微管相互作用以稳定它， 细胞分裂 PI非常接近于显示微管结合 紫杉醇的构象首次使用氟探针 紫杉醇的固态19 FNMR分析以及 激子手性CD方法。（2.2.）设计和合成第二和 第三代紫杉类抗肿瘤药物。 PI将继续 在SAR研究的基础上开发第二代紫杉醇。的PI 将找出紫杉醇、埃博霉素和 discodermoride基于在特定目的中获得的信息， （2.1.），SAR研究和分子建模。一旦共同药效团 定义，PI将设计第三代紫杉烷类抗肿瘤药物 可能不再具有紫杉烷结构的药剂。 （2.3.）研究 光亲和标记，巨噬细胞代谢 通过紫杉醇活化。 PI将进行光亲和标记， 微管和P-糖蛋白以及代谢研究 P-450使用策略性氟化紫杉烷， 特定的氧化位点。 PI还将查看 紫杉烷类以激活产生NO和/或TNF α的巨噬细胞。 （三） 从浆果赤霉素开发新的MDR逆转剂。 耐药性 在癌症中，化疗是一个严重的问题。 为了解决这一 问题，PI将继续他的成功方法的发展， 基于对浆果赤霉素的策略性修饰的MDR逆转剂。