Rhodamine inhibitors of P-glycoprotein: an amide/thioamide "switch" for ATPase activity.
Rhodamine inhibitors of P-glycoprotein: an amide/thioamide "switch" for ATPase activity.
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DOI：
10.1021/jm900253g
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发表时间：
2009-05-28
影响因子：
7.3
通讯作者：
Detty MR
中科院分区：
文献类型：
--
作者：
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
我们研究了46个四甲基罗萨胺/罗丹明衍生物，它们的结构多样性存在于黄体芯的杂原子、3-位和6-位的氨基以及9-位的烷基、芳基或杂芳基。这些化合物在分离的MDR3 CL P-gp和人P-gp-His10上的亲和力和ATPase刺激作用，以及它们促进多药耐药MDCKII-MDR1细胞摄取钙黄素AM和长春花碱的能力，以及在MDCKII-MDR1细胞单层的转运能力。硫代酰胺31-S测得人P-gp的KM为0.087μM。这组化合物之间结构上的微小变化影响了亲和力和转运速率(或通量)，尽管所有被检查的衍生物都是P-gp的底物。对于分离的蛋白质，叔胺基团具有高亲和力和高刺激性，而叔基硫代酰胺基团具有高亲和力和抑制ATPase活性。在MDCKII-MDR1细胞中，含有叔硫酰胺的衍生物促进钙调素AM的摄取，相对于含有叔胺的衍生物的转运速率，被动的、吸收的和分泌的转运速率非常慢。硫代酰胺31-S可促进MDCKII-mdr1细胞摄取钙黄素AM，抑制长春花碱的外流，其IC50‘S为~2μM。
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 KM 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.
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影响因子：
2.9
作者：
Aanismaa, Paivi;Gatlik-Landwojtowicz, Ewa;Seelig, Anna
通讯作者：
Seelig, Anna
影响因子：
3.6
作者：
BEAK, P;BROWN, RA
通讯作者：
BROWN, RA
影响因子：
2.8
作者：
Calitree, Brandon;Donnelly, David J.;Detty, Michael R.
通讯作者：
Detty, Michael R.
影响因子：
2.8
作者：
Del Valle, DJ;Donnelly, DJ;Detty, MR
通讯作者：
Detty, MR
DOI：
10.1073/pnas.94.20.10594
发表时间：
1997-09-30
影响因子：
11.1
作者：
Dey, S;Ramachandra, M;Ambudkar, SV
通讯作者：
Ambudkar, SV