NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS

拟议研究的目标之一是开发和 建立有效和可靠的新方法， 各种非蛋白质氨基酸和有关化合物的药用 对立体化学的完美控制。 这种方法学 （一）研究生物学功能; 无法获得的非蛋白质氨基酸和相关化合物 （二）从自然资源中分离出足够的数量; 开发酶抑制剂、抗肿瘤剂、抗生素， 肽激素 为了实现这一具有挑战性的目标，我们 进一步促进我们对不对称有机物的富有成效的研究， 对映体纯的N-酰基-β-内酰胺的转化。 这些非- 由此获得的蛋白质氨基酸及其衍生物将提供 酶抑制剂成分，抗肿瘤剂，抗生素，植物 代谢物和肽激素类似物，碳水化合物，手性 大环和手性配体的试剂和催化剂的不对称 合成. 研究的另一个目的是发现和开发 新的和有效的抗肿瘤剂，特别是用于乳腺癌和肺癌， 通过系统地改变紫杉醇的骨架和结构， 活动关系研究。 这些新的紫杉烷类抗肿瘤剂 肿瘤类型不同于紫杉醇和泰索帝。 我们将重点 新的紫杉烷类抗肿瘤药物，14-羟基-10- 脱乙酰浆果赤霉素III（140 DAB），分离自红豆杉（Taxus Wallichiana Zucc （喜马拉雅红豆杉）。 紫杉醇的一个严重缺点是它的水分少 溶解性，这在其配制中引起实际问题，例如，一 需要特殊的车辆，这有其自身的副作用， 最大剂量可能受到其溶解度的限制。 泰索帝在某种程度上 改善的溶解度和因此更好的药理学性质 紫杉醇，但这种抗肿瘤剂仍然具有其它不希望的副作用。 由于在C-14位上的额外羟基，14-OH-DAB具有 被证明具有比通常的10- 10%高得多的水溶性。 脱乙酰浆果赤霉素III（DAB），目前用于生产 紫杉醇和泰索帝。 因此，新的抗肿瘤紫杉烷衍生自 预期14-OH-DAB具有显著改善的水溶性 和作为治疗剂的药理学性质。 这些改进的 药理学性质可能与修饰 不希望的毒性和针对不同癌症的独特活性谱 类型和多药耐药。 这些新类似物的抗肿瘤活性 将通过与肿瘤学的持续合作进行评估 实验室

One of the objectives of the proposed research is to develop and establish efficient and reliable new methodologies for the synthesis of various non-protein amino acids and related compounds of medicinal interest with perfect control of stereochemistry. Such methodologies are very beneficial for (i) the investigation of the biological functions of non-protein amino acids and related compounds which cannot be obtained in sufficient quantity by isolation from natural sources, and (ii) the development of enzyme inhibitors, antitumor agents, antibiotics, and peptide hormones. As an approach to this challenging goal, we will further promote our very productive research on the asymmetric organic transformations of enantiomerically pure N-acyl-Beta-lactams. Those non- protein amino acids and their derivatives, thus obtained, will furnish components of enzyme inhibitors, antitumor agents, antibiotics, plant metabolites, and peptide hormone analogs, carbohydrates, chiral macrocycles, and chiral ligands for reagents and catalysts for asymmetric synthesis. The other objective of the proposed research is to discover and develop new and potent antitumor agents, especially for breast and lung cancers, through systematic modifications of the taxol skeleton and the structure- activity relationship studies. These new taxoid antitumor agents various tumor types different from those of taxol and taxotere. We will focus on new taxoid antitumor agents derived from a new taxane, 14-hydroxy-10- deacetylbaccatin III (140DAB), isolated from Taxus Wallichiana Zucc (Himalayan yew). One of the serious drawbacks of taxol is its poor water solubility, which causes practical problems in its formulation, e.g., a special vehicle is required which has its own side effects, and the maximum dose may be limited by its solubility. Taxotere has somewhat improved solubility and thus better pharmacological properties than taxol, but this antitumor agent still has other undesirable side effects. Because of an extra hydroxyl group at the C-14 position, 14-OH-DAB has proven to possess much higher water solubility than the usual 10- deacetylbaccatin III (DAB) which is currently used for the production of taxol and taxotere. Therefore, the new antitumor taxoids derived from 14-OH-DAB are expected to have substantially improved water solubility and pharmacological properties as therapeutic agents. These improved pharmacological properties may well be related to the modification of undesired toxicity and unique activity spectra against different cancer types and multi drug resistance. Antitumor activity of these new analogs will be evaluated through ongoing collaboration with an oncology laboratory.