TY - JOUR
T1 - Welwitindolinone analogues that reverse P-glycoprotein-mediated multiple drug resistance
AU - Smith, Charles D.
AU - Zilfou, Jack T.
AU - Stratmann, Klemens
AU - Patterson, Gregory M.L.
AU - Moore, Richard E.
PY - 1995/2
Y1 - 1995/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0028944619
UR - https://www.scopus.com/inward/citedby.url?scp=0028944619&partnerID=8YFLogxK
U2 - 10.1016/s0026-895x(25)08534-7
DO - 10.1016/s0026-895x(25)08534-7
M3 - Article
C2 - 7870031
AN - SCOPUS:0028944619
SN - 0026-895X
VL - 47
SP - 241
EP - 247
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 2
ER -