AMINE-BORANES AS NEW TOPOISOMERASE II INHIBITORS

本研究的主要目的是开发一类新型的

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.