Comparison of metabolism and toxicity to the structure of the anticancer agent sulofenur and related sulfonylureas

Abstract

The metabolic formation of p-chloroaniline from the oncolytic agent sulofenur [N-(5-indanesulfonyl)-N'-(4-chlorophenyl)urea, LY186641,] and from similar diaryl-substituted sulfonylureas, and its possible relevance to the compound's toxicity, was studied. In previous studies it was found that significant amounts of metabolites such as 2-amino-5-chlorophenyl sulfate (II), which is also a metabolite of p-chloroaniline, are formed from sulofenur in mice, rats, monkeys, and humans. The metabolism of N-(4-tolyl)-N'-(2-hydroxy-4-chlorophenyl)-urea (V) was studied, and V was not found to be an intermediate in the metabolic formation of II from the sulfonylurea N-(4-tolyl)-N'-(4-chlorophenyl)urea (LY181984, III). The amounts of this p-chloroaniline metabolite (II) formed in C3H mice from a series of diarylsulfonylureas were found to correlate with the compound's propensities to form methemoglobin, one notable toxicity of p-chloroaniline. This metabolism was also found to correlate with the structure of the arylsulfonyl moiety of the sulfonylurea. Other evidence supports the hypothesis that p-chloroaniline is directly formed by metabolism of sulfofenur and similar diarylsulfonylureas as well. Metabolic formation of p-chloroaniline thus appears to be a plausible explanation for the methemoglobinemia and anemia found to be dose-limiting toxicities of sulofenur in Phase I trials.

Interference by metabolites and the corresponding troubleshooting during the LC–MS/MS bioanalysis of G004, a bromine-containing hypoglycemic agent

“…2B). Moreover, the fragmentation patterns of M1 are quite similar with those of the hydroxylation metabolites from the other sulphonylureas [23][24][25][26][27], and the proposed fragmentation pathway of M1 was shown in Fig. 2C.…”

Sulfonimidamide Analogs of Oncolytic Sulfonylureas,1

“…The p -chloroaniline could be quantitated by the measurement of its oxidation product, 2-amino-5-chlorophenyl sulfate 65 in the urine. Previous work had shown that, in mice, after oral dosing of various substituted sulfonylureas, the urinary excretion of 65 correlated to the degree of methemoglobinemia measured, strongly suggesting, along with other evidence, that the dose-limiting toxicities of sulofenur were caused by the release and metabolism of p -chloroaniline …”

“…The sulfonamide hydrogen atom in the sulfonylurea structure is weakly acidic (p K a ≈ 6.1), and at a pH ≤ p K a , the sulfonylurea undergoes significant hydrolysis. For example, in 2% acetonitrile/25 mM sodium phosphate buffer at 37 °C, there is observed about 25% decomposition of sulofenur to form p -chloroaniline and indan-5-sulfonamide over 24 h at pH = 5. , In contrast, these diarylsulfonimidamides do not undergo detectable hydrolysis in the pH range of 2−8 over 24 h…”

“…These diarylsulfonylureas display broad spectrum antitumor activity against syngeneic and human xenograft tumors carried in mice through a thoroughly investigated but as yet unidentified mechanism of action. , Phase I studies of sulofenur defined the dose-limiting toxicity of this agent as methemoglobenemia and hemolytic anemia, non-life-threatening toxicities more commonly associated with aniline metabolism rather than nonspecific cytotoxicity. − The unpredictable onset of these toxicities, however, complicated the clinical study of sulofenur. Recently published sulofenur metabolism studies identified p -chloroaniline and its o -sulfate 65 as urinary metabolites in mice, rats, monkeys, and humans, providing direct evidence for the in vivo liberation of p -chloroaniline from sulofenur. , …”

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

“…The primary metabolic pathways of sulofenur in humans and other species are oxidation of the saturated carbons in the indane ring (Ehlhardt, 1991(Ehlhardt, , 1992. Other reported metabolites include p-chloroaniline and its metabolites, 2-amino-5-chlorophenyl sulfate and pchloro-oxanilic acid (Ehlhardt, 1991).…”