Initial chemical events caused by carcinogenic heterocyclic amines and molecular design of anti-tumor agents

Abstract

Initial chemical events caused by carcinogenic 2-amino-6-methyldipyrido [1, 2 -a: 3', 2'-d]-imidazole (Glu-P-1) and molecular design of antitumor agents on the basis of the intercalative ability of Glu-P-1 skeleton are reviewed.Glu-P-1 binds to deoxyribonucleic acid (DNA) at the 8-position of guanine residues after metabolic activations. Structures of modified nucleic acid base and the activated metabolites were confirmed by alternative synthesis. The pathway of chemical modification of DNA with Glu-P-1 is established chemicaly, and found to occur in vivo. The chemical modification of oncogene proto-ras caused transforming activity of the gene toward NIH3T3 cells. In other words, chemical modification of DNA with Glu-P-1 results in cell transformation. The established pathway of the DNA modification provides a fundamental standpoint in the study of chemical carcinogenesis caused by Glu-P-1.Glu-P-1 possesses intercalative ability toward double stranded DNA. We designed and synthesized polyamino-Glu-P derivatives and Hemin-Glu-P-1 derivatives. Polyamino-Glu-P derivatives were found to possess extremely high affinity toward DNA. Hemin-Glu-P-1 derivatives cleaved DNA efficiently. Hemin-Glu-P-1 derivatives were suggested to cleave DNA in the same mode of reaction as bleomycin: Hemin-Glu-P-1's are functional analogs of bleomycin. The results suggested the possibility of the method of molecular design described might be served for the development of new antitumor agents.