Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance

Charles D. Smith, Jack T. Zilfou, Klemens Stratmann, Gregory M.L. Patterson, Richard E. Moore

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Abstract

Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii as a part of our effort to identify new compounds that overcome multiple drug resistance. The abilities of three structurally similar members of this family to interact with P- glycoprotein have been compared. Similarly to the effects of verapamil, N- methylwet-witindolinone C isothiocyanate (compound 1) attenuated the resistance of MCF-7/ADR cells to natural product anticancer drugs, including vinblastine, taxol, actinomycin D, daunomycin, and colchicine, without affecting the cytotoxicity of cisplatin. These effects of compound I were apparent at doses as low as 0.1 μM, indicating that it is considerably more potent than verapamil for reversal of resistance. Welwitindolinone C isothiocyanate (compound 3) demonstrated weaker reversing activity, whereas an analogue of compound 1 in which the isothiocyanate group is replaced by an isonitrile group (compound 2) was inactive. The accumulation of [3H]vinblastine in SK-VLB-1 cells was increased by compound 1 > compound 3 > verapamil >> compound 2. Interestingly, only compound 1 and verapamil enhanced [3H]taxol accumulation by these cells. Photoaffinity labeling of P- glycoprotein with [3H]azidopine in membranes from SK-VLB-1 cells was inhibited by compounds 1 and 3, but not by compound 2. Therefore, the differences in the size and/or the electronegativity of the isothiocyanate and isonitrile moieties appear to dramatically affect the abilities of the compounds to interact with P-glycoprotein.

Original languageEnglish (US)
Pages (from-to)241-247
Number of pages7
JournalMolecular pharmacology
Volume47
Issue number2
StatePublished - Feb 1995

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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    Smith, C. D., Zilfou, J. T., Stratmann, K., Patterson, G. M. L., & Moore, R. E. (1995). Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance. Molecular pharmacology, 47(2), 241-247.