Structural Necessity of Indole C5-O-Substitution of seco-Duocarmycin Analogs for Their Cytotoxic Activity

Abstract

A series of racemic indole C5-O-substituted seco-cyclopropylindole (seco-CI) compounds 1-5 were prepared by coupling in the presence of EDCI of 1-(tert-butyloxycarbonyl)-3-(chloromethyl)indoline (seg-A) with 5-hydroxy-, 5-O-methylsulfonyl, 5-O-aminosulfonyl, 5-O-(N,N-dimethylaminosulfonyl)- and 5-O-benzyl-1H-indole-2-carboxylic acid as seg-B. Compounds 1-5 were tested for cytotoxic activity against four human cancer cell lines (COLO 205, SK-MEL-2, A549, and JEG-3) using a MTT assay. Compounds 2 and 3 with small sized sulfonyl substituents like 5-O-methylsulfonyl and 5-O-aminosulfonyl exhibit a similar level of activity as doxorubicin against all cell lines tested.

Keywords

• duocarmycin
• Indole C5-O-substituted seco-CI
• cytotoxicity
• DNA minor groove alkylation