Design and Synthetic Development of New Multifunctional Anti-cancer Agents

新型多功能抗癌药物的设计与合成开发

基本信息

批准号：
60470146
负责人：
NAGAO Yoshimitsu
金额：
$ 1.41万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1985
资助国家：
日本
起止时间：
1985 至 1986
项目状态：
已结题

项目摘要

1) We designed a guideline for the development of new multifunctional anti-cancer agents based on much information on the thiol chemistry, DNA-binding drugs, the relationship between chemical structure and toxicity, and radiosencitizing chemistry of DNA.2) According to our own guideline, we synthesized various thiazolidine-2-thiones, nitrofurazanes, 3-nitrotriazoles, and 2-nitroimidazoles, respectively. These new compounds and a Rabdosia diterpenoid, oridonin, were subjected to biological screening tests in vitro and in vivo system. From the results, the following facts were disclosed. Some thiazolidine-2-thione carboxylic acids having a weak immuno activity, exhibited fairly strong aldose reductase inhibition being concerned with the therapeutic agents for the chronic complications of diabetes. Nitrofurazanes, 3-nitrotriazoles, and 2-nitroimidazoles would be hopeful radiosencitizers in cancer radiotherapy. A tumor-inhibitor, oridonin showed an additive effect on the radiosencitizing activities of misonidazole to hypoxic cells. Thus, oridonin may be available for cancer radiotherapy.3) In order to clarify active mechanism of a clinically useful anti-cancer drugs: camptotecin derivatives and bleomycin A2, polyamine-containing radiosencitizers, and benzo[C]-phenanthridine alkaloids, interaction between drugs and DNA was investigated utilizing the Tm measurement, UV difference spectum, and <^1H> - and <^(13)C> -NMR spectrum. It was revealed that benzo[C]-phenanthridine alkaloids clearly form strong charge-transfer complexes with the nucleic bases in double and and single strand DNA.

1）我们设计了一项针对新的多功能抗癌剂的指南，基于许多有关硫醇化学，DNA结合药物，化学结构与毒性之间的关系以及DNA的放射性化学的关系。分别为2-硝基咪唑。这些新化合物和二萜类化合物（Oridonin）在体外和体内进行了生物学筛查测试。从结果中，披露了以下事实。一些具有弱免疫活性的噻唑烷-2-噻酮羧酸，表现出相当强的醛糖还原酶抑制作用，与治疗剂有关糖尿病的慢性并发症的治疗剂。硝基呋喃子，3-硝基二唑和2-硝基咪唑将是癌症放射疗法中有希望的放射线剂。肿瘤抑制剂Oridonin对Misonidazole对低氧细胞的放射固定活性显示出累加作用。 3）为了阐明临床上有用的抗癌药物的主动机制：camptotecin衍生物和博来霉素A2，含多胺放射性固定剂，含多胺的放射性固定剂，以及苯并[c] - 苯恐怖烯醇烷基的苯甲酸烷基和DNA之间的差异，并在dna之间进行了研究。 <^1H> - 和<^（13）C> -NMR频谱。据表明，苯并[C] - 苯雄氨酸生物碱清楚地形成了具有双重和单链DNA的核碱基的强电荷转移复合物。