Synthesis and cytotoxicity evaluation of 2-amino- and 2-hydroxy-3-ethoxycarbonyl-N-substituted-benzo[f]indole-4,9-dione derivatives

Abstract

Reaction between 2,3-dichloronaphthoquinone (I) and ethyl cyanoacetate or diethyl malonate under different conditions gave the starting materials, 2-chloro-3-(alpha-cyano-alpha-ethoxycarbonyl-methyl)-1,4-naphthoquinone (A) or 2-chloro-3-(diethoxycarbonyl-methyl)-1,4-naphthoquinone (B). The 2-amino-3-ethoxycarbonyl-N-substituted-benzo[f]indole-4,9-dione derivatives [A-(1-10)] and 2-hydroxy-3-ethoxycarbonyl-N-substituted-benzo[f]indole-4,9-dione derivatives [B-(1-12)] were prepared from compounds A and B, respectively, by using various alkyl-, and arylamines. The cytotoxic activities of the prepared compounds were evaluated by SRB (Sulforhodamine B) assay against the following tumor cell lines: A459 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human melanoma), XF498 (human CNS), and HCT 15 (human colon). Many of the derivatives mentioned exhibited more potent cytotoxic effects against SK-OV-3 and XF498 than etoposide. Significantly, 2-amino-3-ethoxycarbonyl-N-(3-methyl-phenyl)-benzo[f]indole-4,9-dione (A-8) showed potent activity against all tumor cell lines, and in particular, its cytotoxic effect against SK-OV-3 was much higher than doxorubicin. (C) 2003 Elsevier Science Ltd. All rights reserved.