The synthesıs of (+)-Duocarmycın antıbıotıc analogs and theır effects on DNA

Binding studies of small molecules to DNA are very important in the development of DNA molecular probes and new therapeutic reagents. In recent years, small molecules that interact with DNA through recognition, binding, modifying, cleaving and crosslinking have attracted great interest and had been challenging project in the research fields of chemistry, biology, and medicine. Therefore, the design of small compounds able to bind and cleave DNA at physiological conditions is of great interest for the development of novel therapeutic agents. CC-1065 and duocarmycin antitumor antibiotics are specifically bind to double strand DNA. Duocarmycin have similar structure to the CC-1065. However it is not very toxic. In this study, three water-soluble DNA-binding subunits, indole-2-carboxylic acid hydrochlorides bearing a substituent with a tertiary amino functionality at C-5 were synthesised. DNA cleavege aktivity of this ligands were checked in the absence and presence of Cu (II) ions on pBluescript M13+ plazmid DNA (3.2 kb) and Calf Thymus DNA (8-15 kb). The ligands (1-3) showed concentration and time dependent DNA cleavage activity. The DNA cleavage activity of 1 is significantly better than the ligands (2, 3). To verify if reactive oxygen species involved in the mechanism of DNA cleavage, the experiments were carried out in the presence of histidine, thiourea, TEMPO and DMSO. It has been found that DNA cleavage was inhibited in the presence of these radical scavengers. This finding indicated that ROS plays a key role in the DNA cleavage.