Rhodamine inhibitors of P-glycoprotein: an amide/thioamide "switch" for ATPase activity.

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Gannon MK 2nd, Holt JJ, Bennett SM, Wetzel BR, Loo TW, Bartlett MC, Clarke DM, Sawada GA, Higgins JW, Tombline G, Raub TJ, Detty MR

Rhodamine inhibitors of P-glycoprotein: an amide/thioamide "switch" for ATPase activity.

J Med Chem. 2009 May 28;52(10):3328-41. doi: 10.1021/jm900253g.

PubMed ID

19402665 [ View in PubMed

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Abstract

We have examined 46 tetramethylrosamine/rhodamine derivatives with structural diversity in the heteroatom of the xanthylium core, the amino substituents of the 3- and 6-positions, and the alkyl, aryl, or heteroaryl group at the 9-substituent. These compounds were examined for affinity and ATPase stimulation in isolated MDR3 CL P-gp and human P-gp-His(10), for their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant MDCKII-MDR1 cells, and for transport in monolayers of MDCKII-MDR1 cells. Thioamide 31-S gave K(M) of 0.087 microM in human P-gp. Small changes in structure among this set of compounds affected affinity as well as transport rate (or flux) even though all derivatives examined were substrates for P-gp. With isolated protein, tertiary amide groups dictate high affinity and high stimulation while tertiary thioamide groups give high affinity and inhibition of ATPase activity. In MDCKII-MDR1 cells, the tertiary thioamide-containing derivatives promote uptake of calcein AM and have very slow passive, absorptive, and secretory rates of transport relative to transport rates for tertiary amide-containing derivatives. Thioamide 31-S promoted uptake of calcein AM and inhibited efflux of vinblastine with IC(50)'s of approximately 2 microM in MDCKII-MDR1 cells.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Verapamil	P-glycoprotein 1	IC 50 (nM)	14000	N/A	N/A	Details