STRUCTURAL INVESTIGATIONS OF MODE OF ACTION OF DRUGS

本研究计划的目的是(I)阐明 香豆素的理化性质与化学结构的关系 要研究的药物，以及(Ii)也要了解确切的分子 这些药物抑制核酸和蛋白质合成的机制。 这些研究选择的药物是蒽环类药物，例如阿克拉霉素， 诺卡霉素、硬脂霉素等；利福霉素；DNA的共价结合物，例如 安息香素、西比洛霉素、托迈霉素、新硫霉素等； 环肽类抗生素，如棘球菌素、平链霉素、放线菌素、 等；核苷类抗生素，如葛根素、尼克霉素；以及 抗肿瘤多肽抗生素。此外，这些药物与其他药物的络合物 将对核酸和蛋白质的碎片进行调查。这些方法 主要用于研究的是X射线结晶学、核磁共振和 计算机图形学。这些调查的结果将有助于揭示 这些药物与靶分子的相互作用部位，从而 药物-受体相互作用的模型是可以假定的。另外， 可以假定，对药物结构的修改可以增强 他们的治疗选择性。

The objectives of this research program are (i) to elucidate the relationship between physicochemical properties and chemical structures of the drugs to be studied, and (ii) also to understand the exact molecular mechanism by which these drugs inhibit nucleic acid and protein synthesis. The drugs chosen for these studies are Anthracyclines, e.g. aclacinomycin, nogalamycin, steffimycin, etc.; Rifamycins; Covalent binders of DNA, e.g. anthramycin, sibiromycin, tomaymycin, neothramycin, etc.; Mitoxantrones; Cyclic peptide antibiotics, e.g. echinomycin, ostreogrycin, actinomycin, etc.; Nucleoside antibiotics, e.g. gougerotin, nikkomycin; as well as Antitumor polypeptide antibiotics. Also, complexes of these drugs with fragments of nucleic acids and proteins will be investigated. The methods used for investigations will be mainly X-ray crystallography, NMR, and computer graphics. The results of these investigations will help reveal the sites of interaction of these drugs to the target molecules and thus models for drug-receptor interaction can be postulated. Also, modifications to the structures of the drugs can be postulated to enhance their therapeutic selectivity.