AMINE-BORANES AS NEW TOPOISOMERASE II INHIBITORS

这项研究的主要目的是开发一种新的 拓扑异构酶II（Topo II）抑制剂作为抑制剂。 在 初步研究表明，杂环胺-羧基硼烷 对许多鼠和人肿瘤具有细胞毒活性 组织培养系，例如P388、L1210、Tmolt 3、HeLa-S3、肺 支气管源性、KB鼻咽、神经胶质瘤和骨肉瘤。 这些化合物 已显示在100 μ M浓度下抑制HeLa-S3 Topo II，但 未在此浓度下进行测试。 第一阶段的目标是综合更多的选择， 胺-羧基硼烷，以评价刘易斯碱部分对 生物活性 建议进行研究以确定体外 这些化合物的细胞毒性和体内抗肿瘤活性。 模式 作用研究将限于Topo II抑制、DNA抑制 合成和DNA稳定性。 第二阶段研究将进一步集中于结构-活性 在分子建模的帮助下。 此外，详细 作用方式、急性毒性、组织分布和药代动力学 将确定参数。 拟议的项目预计将导致确定和 开发一种或多种有效的抗肿瘤剂以治疗一种或多种疾病， 更多的人类肿瘤

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.