Rhodamine Inhibitors of P-Glycoprotein: An Amide/Thioamide “Switch” for ATPase Activity

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• 作者：Michael K. Gannon ; ; Jason J. Holt ; Stephanie M. Bennett ; Bryan R. Wetzel ; Tip W. Loo ; M. Claire Bartlett ; David M. Clarke ; Geri A. Sawada ; J. William Higgins ; Gregory Tombline ; Thomas J. Raub ; Michael
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3328-3341
• 全文大小：298K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

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-His₁₀, 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 μM 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 IC₅₀’s of 2 μM in MDCKII−MDR1 cells.