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
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-dimethy...
Saved in:
Published in | Journal of organic chemistry Vol. 63; no. 25; pp. 9414 - 9420 |
---|---|
Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
11.12.1998
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | istex:D83FC95DBC9793A6FDB444E043986C71C47D54B9 ark:/67375/TPS-GNSKPSF8-K |
ISSN: | 0022-3263 1520-6904 |
DOI: | 10.1021/jo981395w |