Iodination increases the activity of verapamil derivatives in reversing PGP multidrug resistance.
Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.
Barattin
Regis
R
University of Grenoble I, Department of Molecular Chemistry, UMR CNRS 5250, F-38041, Grenoble Cedex 9, France.
Gerby
Bastien
B
Bourges
Kevin
K
Hardy
Gaëlle
G
Olivares
Jose
J
Boutonnat
Jean
J
Arnoult
Christophe
C
D'Hardemare
Amaury D U Moulinet
AD
Ronot
Xavier
X
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020112:Rhodamine 123; D016572:Cyclosporine; D014700:Verapamil; D003630:Daunorubicin