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

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

Research output: Contribution to journalArticle

111 Citations (Scopus)

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 1 1995

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Multiple Drug Resistance
P-Glycoprotein
Verapamil
Aptitude
Vinblastine
Paclitaxel
Daunorubicin
MCF-7 Cells
Colchicine
Cyanobacteria
Dactinomycin
Biological Products
Alkaloids
Cisplatin
Membranes
Pharmaceutical Preparations
isothiocyanic acid

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Smith, C., 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.
Smith, Charles ; Zilfou, Jack T. ; Stratmann, Klemens ; Patterson, Gregory M.L. ; Moore, Richard E. / Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance. In: Molecular pharmacology. 1995 ; Vol. 47, No. 2. pp. 241-247.
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Smith, C, Zilfou, JT, Stratmann, K, Patterson, GML & Moore, RE 1995, 'Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance', Molecular pharmacology, vol. 47, no. 2, pp. 241-247.

Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance. / Smith, Charles; Zilfou, Jack T.; Stratmann, Klemens; Patterson, Gregory M.L.; Moore, Richard E.

In: Molecular pharmacology, Vol. 47, No. 2, 01.02.1995, p. 241-247.

Research output: Contribution to journalArticle

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Smith C, Zilfou JT, Stratmann K, Patterson GML, Moore RE. Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance. Molecular pharmacology. 1995 Feb 1;47(2):241-247.