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Thiorhodamines containing amide and thioamide functionality as inhibitors of the ATP-binding cassette drug transporter P-glycoprotein (ABCB1).


ABSTRACT: 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.

SUBMITTER: Orchard A 

PROVIDER: S-EPMC3400123 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Thiorhodamines containing amide and thioamide functionality as inhibitors of the ATP-binding cassette drug transporter P-glycoprotein (ABCB1).

Orchard Alexandra A   Schamerhorn Gregory A GA   Calitree Brandon D BD   Sawada Geri A GA   Loo Tip W TW   Claire Bartlett M M   Clarke David M DM   Detty Michael R MR  

Bioorganic & medicinal chemistry 20120607 14


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)  ...[more]

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