Glutathione and mercapturic acid conjugates of sulofenur and their activity against a human colon cancer cell line.
Sulofenur is one of the diarylsulfonylureas developed as an anticancer agent. Sulofenur possesses a broad spectrum of activity in several solid tumor models and has undergone extensive clinical trials based on its impressive preclinical activity. However, the clinical response of sulofenur has been disappointing because of the side effect of anemia. Furthermore, the anticancer mechanism of sulofenur and its diarylsulfonylurea analogs still remains unknown. Elucidation of the metabolic fates of sulofenur may help to delineate the mechanism and provide information to guide the structural modification for more potent anticancer agents with less side effects. We have identified a glutathione conjugate and a mercapturic acid conjugate from sulofenur-dosed rats with the aid of liquid chromatography/mass spectrometry. The fraction of the dose of sulofenur as the glutathione conjugate in the dosed-rat bile over 5 h was 0.12 +/- 0.03%, and the mercapturic acid conjugate in urine over 24 h was 1.4 +/- 0.7%. Protein binding of the glutathione conjugate and mercapturic acid conjugate was determined to be 20 +/- 3 and 84 +/- 2%, respectively, as opposed to >99% of sulofenur. The high protein binding of sulofenur requires a higher than in vitro dose, which is believed to cause the side effect of anemia. The significance of this metabolic pathway is that both conjugates were found to be glutathione reductase inhibitors and to possess anticancer activity comparable to sulofenur against human colon adenocarcinoma GC(3)/c1 cells, a sulofenur-sensitive cell line. These conjugates may serve as new leads for the development of novel anticancer agents.
Guan
Xiangming
X
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, South Dakota 57007, USA. Xiangming_Guan@sdstate.edu
Hoffman
Brianna N
BN
McFarland
Douglas C
DC
Gilkerson
Kysa K
KK
Dwivedi
Chandradhar
C
Erickson
Angela K
AK
Bebensee
Scott
S
Pellegrini
Jill
J
D000111:Acetylcysteine / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D001646:Bile / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013453:Sulfonylurea Compounds / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C454682:N-acetyl-S-(4-chlorophenylcarbamoyl)cysteine; C454681:S-(4-chlorophenylcarbamoyl)glutathione; D013453:Sulfonylurea Compounds; D012710:Serum Albumin, Bovine; D005980:Glutathione Reductase; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine; C058179:sulofenur