NON-PROTEIN AMINO ACIDS AND TAXOID ANTITUMOR AGENTS

拟议研究的目标之一是开发和开发 建立有效和可靠的新方法来合成 药用多种非蛋白质氨基酸及其相关化合物 对立体化学有完美控制的兴趣。这些方法包括 非常有益于(I)生物功能的研究 无法获得的非蛋白质氨基酸及其相关化合物 通过与自然来源隔离而获得足够数量的，以及(Ii) 酶抑制剂、抗肿瘤药物、抗生素和 多肽激素。作为实现这一具有挑战性的目标的途径，我们将 进一步推动我们对不对称有机化合物的卓有成效的研究 手性纯N-酰基-β-内酰胺类药物的转化。那些非- 这样获得的蛋白质氨基酸及其衍生物将提供 酶抑制剂、抗肿瘤药物、抗生素、植物成分 代谢物和多肽激素类似物，碳水化合物，手性 大环，不对称试剂和催化剂的手性配体 综合。 拟议研究的另一个目标是发现和发展 新的有效的抗肿瘤药物，特别是对乳腺癌和肺癌， 通过对紫杉醇骨架和结构进行系统的修饰- 活动关系研究。这些新的紫杉类抗肿瘤药物种类繁多 肿瘤类型不同于紫杉醇和紫杉醇。我们将专注于 从新紫杉烷14-羟基-10-羟基衍生的新紫杉醇类抗肿瘤药物的研究 华中红豆杉中的脱乙酰巴卡菌素III(140DAB) (喜马拉雅红豆杉)。紫杉醇的严重缺点之一是它的水很差。 溶解度，这会在其配方中造成实际问题，例如 需要有其副作用的特殊车辆，并且 最大剂量可能受其溶解度的限制。泰索帝有一些 更好的溶解性，从而比 紫杉醇，但这种抗肿瘤药物仍有其他不良副作用。 由于在C-14位增加了一个羟基，14-OH-DAB具有 事实证明，它具有比通常的10- 脱乙酰巴卡菌素III(DAB)，目前用于生产 紫杉醇和紫杉醇。因此，新的抗肿瘤紫杉醇类化合物来源于 14-羟基-DAB的水溶性有望显著提高 以及作为治疗剂的药理特性。这些改进 药理特性很可能与黄连的修饰有关 针对不同癌症的不良毒性和独特的活性谱 耐药类型和多重耐药。这些新类似物的抗肿瘤活性 将通过与肿瘤科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.