Glutathione and Mercapturic Acid Conjugates of Sulofenur and Their Activity against a Human Colon Cancer Cell Line

Abstract

ABSTRACT: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.

Quercetin Selectively Inhibits Bioreduction and Enhances Apoptosis in Melanoma Cells That Overexpress Tyrosinase

“…Therefore, increased activity or abundance of GST may facilitate the formation and subsequent accumulation of such compounds. It is also important to note that quercetin can inhibit GST through the formation of oquinone (18,31) and other GSH, and mercapturic conjugates inhibit GSH reductase (28). Therefore, in tyrosinase expressing cells, quercetin may have multiple modes of interaction with drug detoxification proteins and may provide a means to interfere with drug resistance.…”

“…Therefore, Tyr + cells may also display elevated GST activity and a higher capacity to form conjugates. Various GSH and mercapturic acid conjugates have anticarcinogenic activity (28) and chemopreventative properties (29). The role of conjugate toxicity is further demonstrated by the induction of apoptosis in cells after the depletion of ralA binding protein 1, a transporter of GSH conjugates (30).…”

Glutathione S-conjugates as prodrugs to target drug-resistant tumors

“…However, it was clearly demonstrated that SCPG is further processed through the mercapturic acid pathway to the corresponding N-acetylcysteine conjugate [ N -acetyl- S -( p -chlorophenylcarbamoyl)cysteine, NACC], which possesses comparable anticancer activity to the parent compound. The GSH- and cysteine-conjugates produced are susceptible to thiol exchange reactions and may act as carbamoylating agents towards biomacromolecules (Day et al, 1996; Guan et al, 2002). NACC, whose mechanism of action remains unclear, demonstrated selective anticancer activity, and low toxicity, which make NACC and its analogs promising anticancer agents (Chen et al, 2011).…”

Analyses of representative biomarkers of exposure and effect by chromatographic, mass spectrometric, and nuclear magnetic resonance techniques: Method development and application in life sciences

“…Therefore, though urinary MAs are frequently used as biomarkers of internal dose, they are sometimes also classified as biomarker of effect [22]. Several recent and older examples of MAs used in the BM of human exposure or in biotransformation studies are: N-acetyl-S-(9,10-dihydro-9-hydroxy-10-phenanthryl)-L-cysteine, which originates from a polycyclic aromatic hydrocarbon, phenanthrene, present in cigarette smoke [23], four structurally different mercapturates derived from the herbicides atrazine, acetochlor, metolachlor, and alachlor [24], S-acetamidomethylmercapturic acid, in response to exposure to the industrial solvent N,N-dimethylacetamide [25], N-acetyl-S-(p-chloro- phenylcarbamoyl)cysteine, derives from the anticancer agent sulofenur [26], phenyl mercapturic acid, in response to benzene exposure in industry [27], 3,4-dihydroxybutylmercapturic acid as an environmental and biological monitoring indicator of non-occupational exposure to 1,3-dichloropropene [28], 3-chloro-2-hydroxypropylmercapturic acid and allylmercapturic acid as urinary biomarkers of human exposure to allyl chloride [29], and N-acetyl-S-(Z-and E-3-chloropropenyl-2)-L-cysteine as a biomarker for agricultural soil fumigant 1,3-dichloropropene [30]. In the first part of the studies summarized in this Review, attention is paid to MA derivatives of volatile anesthetics in humans, and whether they are applicable as biomarkers of effect.…”