AMINE-BORANES AS NEW TOPOISOMERASE II INHIBITORS

拟议研究的主要目标是开发一类新的 拓扑异构酶II(Topo II)抑制剂作为抗肿瘤药物。在……里面 初步研究表明，杂环胺-羧基硼烷 对多种小鼠和人肿瘤具有细胞毒活性 组织培养系，如P388、L1210、Tmolt3、HeLa-S3、肺 支气管瘤、鼻咽癌、神经胶质瘤和骨肉瘤。这些化合物 已被证明在100mM浓度下抑制HeLa-S3 Topo II，但 没有在低于该浓度的情况下进行测试。 第一阶段的目标是综合更多的选择 用胺-羧基硼烷评价Lewis碱对人血清白蛋白的影响 生物活性。建议在体外进行研究，以确定 这些化合物的细胞毒性和体内抗肿瘤活性。模式 行动研究将限于TOPO II抑制，DNA的抑制 I期合成及DNA稳定性研究 第二阶段的研究将进一步集中在结构活性上。 在分子模型的帮助下，它们之间的关系。此外，详细介绍了 作用方式、急性毒性、组织处置和药代动力学 参数将被确定。 预计拟议的项目将导致确定和 开发一种或多种有效的抗肿瘤药物来治疗一种或多种 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.