Synthesis and cytotoxicity of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole (amino-seco-CBI-TMI) andrelated 5-alkylamino analogues: New DNA minor groove alkylating agents

The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen subst ituents is reported. The parent 5-amino compound was prepared in a 15-step synthesis from 1-hydroxynaphthalene-2-carboxylic acid. Reductive alkylation of the 5-amino compound gave the corresponding 5-methylamino and 5-dimethy lamino analogues, while resolution of an intermediate by chiral HPLC allowe d preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was a bout 65-fold more cytotoxic than the R enantiomer in cell line assays. The 5-amino and 5-methylamino compounds had in vitro cytotoxicities comparable to that of the known 5-hydroxy analogue (0.2-0.5 nM), while the 5-dimethyla mino derivative was about 10-fold less potent. The high potencies of the 5- amino and 5-methylamino analogues make them of interest for the formation o f relatively stable amine-based prodrugs.