Synthesis and cytotoxicity of amino-seco-DSA: An amino analogue of the DNAalkylating agent duocarmycin SA

This paper describes the synthesis of methyl 5-amino-1-(chloromethyl)-3-[(5 ,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-c arboxylate 8, an amino analogue of the anticancer antibiotic and potent DNA minor groove alkylating agent seco-duocarmycin SA. Key points in the synth esis are sequential radical cyclization and Hemetsberger reaction steps to construct the indoline and indole rings of the target compound from a 1,2,3 -trisubstituted benzene precursor. An intermediate has been resolved by chi ral chromatography to provide the separate enantiomers of 8. Racemic 8 alky lates DNA at adenine in AT rich sequences, similar to seco-duocarmycin SA a nd the previously reported amino-seco-CBI 7, but is 15-60 times less potent than 7 in an in vitro cytotoxicity test. Derivatives of 8 in which the ami no group is replaced by an electron-withdrawing nitro or nitrobenzylcarbama te substituent are considerably less toxic and may have application as prod rugs to be activated selectively in a tumor environment.