Traceless solid-phase synthesis and biological evaluation of purine analogs as inhibitors of multidrug resistance protein 4.
The traceless solid-phase syntheses of 6-oxopurines and pyrazolo[3,4-d]pyrimidines are presented. The effects of these compounds on multidrug resistance protein 4 (MRP4/ABCC4) facilitated efflux was examined. Four of the compounds, 7b, 7c, 15a, and 17e, were active in inhibiting MRP4-mediated efflux of the bimane-glutathione conjugate. In addition, all four compounds were also able to reverse MRP4-mediated resistance to the anticancer drug 6-thioguanine. In the presence of 25 microM 15a or 17e, there was complete reversal. The reversal of resistance was achieved without any effects on the uptake and metabolism of 6-thioguanine.
Tan
Theresa May Chin
TM
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597. bchtant@nus.edu.sg
Yang
Fei
F
Fu
Han
H
Raghavendra
Makam S
MS
Lam
Yulin
Y
D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011687:Purines; C073492:ABCC4 protein, human