AMINE-BORANES AS NEW TOPOISOMERASE II INHIBITORS

胺硼烷作为新的拓扑异构酶 II 抑制剂

• 批准号: 3493267
• 负责人: BERNARD F SPIELVOGEL
• 金额: $ 5万
• 依托单位: BORON BIOLOGICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1993-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3493267
• 关键词: DNA replication; DNA topoisomerases; antineoplastics; boranes; chemical synthesis; cyclic amine; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; laboratory mouse; neoplasm /cancer pharmacology; tissue /cell culture

The main objective of the proposed research is to develop a new class of topoisomerase II (Topo II) inhibitors as antineoplastic agents. In preliminary studies, heterocyclic amine-carboxyboranes have been shown to possess cytotoxic activity against a number of murine and human tumor tissue culture lines, e.g. P388, L1210, Tmolt3, HeLa-S3, lung brochogenic, KB nasopharynx, glioma, and osteosarcoma. These compounds have been shown to inhibit HeLa-S3 Topo II at 100 mu M concentration, but have not been tested below this concentration. The phase I objectives are to synthesize a larger selection of amine-carboxyboranes to evaluate the effect of Lewis base moiety on biological activity. Studies are proposed to determine in vitro cytotoxicity and in vivo antitumor activity of these compounds. Mode of action studies will be limited to Topo II inhibition, inhibition of DNA synthesis and DNA stability in phase I. Phase II studies will concentrate further on structure-activity relationship with the help of molecular modeling. In addition, detailed mode of action, acute toxicity, tissue disposition, and pharmacokinetic parameters will be determined. The proposed project is expected to result in the identification and development of one or more potent antineoplastic agents to treat one or more human tumors.

拟议的研究的主要目的是开发新的一类 拓扑异构酶II（TOPO II）抑制剂作为抗塑剂。 在 初步研究，杂环胺 - 羧基硼烷已显示为 对许多鼠和人类肿瘤具有细胞毒性活性 组织培养线，例如P388，L1210，TMOLT3，HELA-S3，肺 小脑膜，鼻咽，神经胶质瘤和骨肉瘤。 这些化合物 已显示以100 mu M浓度抑制HeLa-S3 Topo II，但 尚未在此浓度以下测试。 I期目标是合成更大的选择 胺 - 羧基硼烷以评估刘易斯基部部分对 生物活性。 提出了研究以确定体外 这些化合物的细胞毒性和体内抗肿瘤活性。 模式 作用研究将仅限于TOPO II抑制，DNA的抑制作用 阶段I的合成和DNA稳定性。 第二阶段研究将进一步集中于结构活动 与分子建模的帮助。 另外，详细 作用方式，急性毒性，组织处置和药代动力学 将确定参数。 预计拟议的项目将导致身份证明和 开发一种或多种有效的抗塑剂来治疗一种或 更多的人类肿瘤。