Thiorhodamines containing amide and thioamide functionality as inhibitors of the ATP-binding cassette drug transporter P-glycoprotein (ABCB1).
Twelve thiorhodamine derivatives have been examined for their ability to stimulate the ATPase activity of purified human P-glycoprotein (P-gp)-His(10), to promote uptake of calcein AM and vinblastine into multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells, and for their rates of transport in monolayers of multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells. The thiorhodamine derivatives have structural diversity from amide and thioamide functionality (N,N-diethyl and N-piperidyl) at the 5-position of a 2-thienyl substituent on the thiorhodamine core and from diversity at the 3-amino substituent with N,N-dimethylamino, fused azadecalin (julolidyl), and fused N-methylcyclohexylamine (half-julolidyl) substituents. The julolidyl and half-julolidyl derivatives were more effective inhibitors of P-gp than the dimethylamino analogues. Amide-containing derivatives were transported much more rapidly than thioamide-containing derivatives.
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, United States.
Alexandra
A
Orchard
Gregory A
GA
Schamerhorn
Brandon D
BD
Calitree
Geri A
GA
Sawada
Tip W
TW
Loo
M
M
Claire Bartlett
David M
DM
Clarke
Michael R
MR
Detty
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D012235:Rhodamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000737:chemistry*; D014747:Vinblastine / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D005452:Fluoresceins; D012235:Rhodamines; D013854:Thioamides; C085925:calcein AM; D014747:Vinblastine