3-Aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione for circumvention of anticancer drug resistance

  • Shchekotikhin A
  • Shtil A
  • Luzikov Y
 et al. 
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Abstract

A series of 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f] indole-5,10-dione was synthesized by Mannich reaction or by the transamination of 3-dimethylaminomethyl 4,11-dihydroxy- or 4,11-dimethoxynaphtho[2,3-f]indole- 5,10-dione. The potency of novel derivatives was tested on a National Cancer Institute panel of 60 human tumor cell lines as well as in cells with genetically defined determinants of cytotoxic drug resistance, P-glycoprotein (Pgp) expression, and p53 inactivation. Mannich derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione with an additional amino function in their side chain, demonstrated equal cytotoxicity against the parental K562 leukemia cells and their Pgp-positive subline, whereas the latter showed ∼7-fold resistance to adriamycin, a Pgp transported drug. 3-(1-Piperazinyl)methyl and 3-(quinuclidin-3-yl)aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione killed HCT116 colon carcinoma cells (carrying wild type p53) and their p53-null variant within the similar range of concentrations. We conclude that Mannich modification of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione, especially when cyclic diamine (e.g., piperazine, quinuclidine) is used, confers an important feature to the resulting compounds, namely, the potency for tumor cells otherwise resistant to a variety of anticancer drugs. © 2004 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • Circumvention of anticancer drug resistance
  • Mannich reaction
  • Naphthoindolediones

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Authors

  • Andrey E. Shchekotikhin

  • Alexander A. Shtil

  • Yuri N. Luzikov

  • Tatyana V. Bobrysheva

  • Vladimir N. Buyanov

  • Maria N. Preobrazhenskaya

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