Synthesis, Characterization And In Vitor Cytotoxicity Of Chloromethyl Indole Derivatives As DNA Minor Groove Alkylator

Malignant tumor is a common disease that threatens the human heath. The study of anticancer drugs with high selectivity and low toxicity become a research hotspot. In the anti-tumor drugs, alkylating agent such as nitrogen mustard, nitrosourea, ethylene imines, sulfonic esters and hydrazines, were the earliest and most widely used cytotoxic drugs. However, their disadvantages of high toxicity, poor selectivity and drug resistance limit its application in clinical.CC-1065 is a DNA alkylating agent which has a strong anti-tumor activity. However, the poor selectivity and high toxicity for liver and kidney, limit its application in clinical. In view of the low selectivity of CC-1065 to DNA, in order to enhance the combination of compounds and sequence of DNA minor groove area capacity and reduce the side effects, chloromethyl indole derivatives as DNA minor groove alkylator was designed and synthesized, using chlorine methyl indole as alkylation group, increasing aromatic conjugation system by introduction cinnamic acid and benzyl.Applying 4-aminosalicylic acid and substituted cinnamic acid as raw material, a novel series of chlorine methyl indole analogues have been synthesized through nucleophilic substitution reaction, free radical reaction and amidation reaction. These compounds have been characterized by ¹HNMR, ¹³ CNMR, HRMS and IR. The effects of the reaction temperature, reaction time, solvent and condensing agent on the yields of intermediates and products were investigated. The cytotoxicity against HeLa and A549 cell lines was investigated via MTT test. The cellular apoptosis and morphological changer of cell nucleus of compounds 7f against HeLa cell line tested by AnnexinV-FITC/PI. The results showed that the compound 7a-7f are equal to cisplatin with inhibition of the A549 cell lines. Compound 7f can induce cell apoptosis. The morphological changes of cell nuclei indicate compound 7f cause some of damage to the nucleus, with the increase of concentration of compound, the nucleus damage degree increased.