Synthesis and Cytotoxicity of 5-Amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2- dihydro-3H-benz[e]indole (Amino-s eco-CBI-TMI) and Related 5-Alkylamino Analogues:  New DNA Minor Groove Alkylating Agents

• Published in: Journal of organic chemistry Vol. 63; no. 25; pp. 9414 - 9420
• Main Authors: Atwell, Graham J, Tercel, Moana, Boyd, Maruta, Wilson, William R, Denny, William A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.12.1998; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; REAGENT; CELLS; PRODRUG; CC-1065; DUOCARMYCINS; FEATURES
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo981395w

The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen substituents 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-dimethylamino analogues, while resolution of an intermediate by chiral HPLC allowed preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was about 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-dimethylamino 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 of relatively stable amine-based prodrugs.