Design and Synthetic Development of New Multifunctional Anti-cancer Agents

1)我们在充分了解巯基化学、DNA结合药物、DNA的化学结构与毒性的关系以及DNA的放射增敏化学的基础上，设计了一个新的多功能抗癌药物的开发指南。2）根据我们自己的指南，我们分别合成了噻唑烷-2-硫酮、硝基呋咱、3-硝基三唑和2-硝基咪唑。对这些新化合物和香茶菜属二萜化合物冬凌草甲素进行了体内外生物筛选试验。从结果中可以看出以下事实。某些噻唑烷-2-羧酸类化合物具有较弱的免疫活性，但对醛糖还原酶有较强的抑制作用，可作为糖尿病慢性并发症的治疗药物。硝基呋咱类、3-硝基三唑类和2-硝基咪唑类化合物有望成为肿瘤放射治疗的放射增敏剂。肿瘤抑制剂冬凌草甲素对米索硝唑对乏氧细胞的放射增敏作用有相加作用。3）为了阐明临床上有用的抗癌药物喜树碱衍生物、博来霉素A2、多胺类放射增敏剂和苯并[C]-菲啶生物碱的作用机制，利用Tm测量、UV差谱和<^1 H> -和<^（13）C> -NMR谱研究了药物与DNA的相互作用。结果表明，苯并[C]-菲啶生物碱与双链和单链DNA中的核酸碱基形成了强的电荷转移复合物。

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.