PABA/NO

We have continued to synthesize and diversify libraries of O²-arylated diazeniumdiolates designed to release nitric oxide (NO) upon reaction with glutathione catalyzed in the pocket of selective isoforms of glutathione S-transferase (GST). This has led to the promising drug, PABA/NO, that was more π-selective than JS-K.

PABA/NO has shown tumoristatic activity against A2780 human ovarian cancer xenografts in female SCID mice with a potency comparable to that of cisplatin.  Its cytotoxicity was shown to increase with increases in the intracellular expression levels of GSTπ.  In the absence of multidrug resistance-associated protein 1 (MRP1), a key component of the cellular efflux pump system, PABA/NO and/or its metabolites caused the activation of the extracellular-regulated and stress-activated protein kinases. The study suggested that cells with high levels of GSTπ, but low content of MRP1, may be ideal targets for induction of cytotoxicity.

Shami, P. J.; Saavedra, J. E.; Bonifant, C. L.; Chu, J.; Udupi, V.; Malaviya, S.; Carr, B. I.; Kar, S.; Wang, M.; Jia, L.; Ji, X.; Keefer, L. K. J. Med. Chem. 2006, 49, 4356-4366.

Saavedra, J. E.; Srinivasan, A.; Buzard, G. S.; Davies, K. M.; Waterhouse, D. J.; Inami, K.; Wilde, T. C.; Citro, M. L.; Cuellar, M.; Deschamps, J. R.; Parrish, D.; Shami, P. J.; Findlay, V. J.; Townsend, D. M.; Tew, K. D.; Singh, S.; Jia, L.; Ji, X.; Keefer, L. K. J. Med. Chem. 2006, 49, 1157-1164.

Findlay, V. J.; Townsend, D. M.; Saavedra, J. E.; Buzard, G. S.; Citro, M. L.; Keefer, L. K.; Ji, X.; Tew, K. D.Mol. Pharmacol. 2004, 65, 1070-1079.