Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Abstract

Many xenobiotics containing a furan ring are toxic and/or carcinogenic. The harmful effects of these compounds require furan ring oxidation. This reaction generates an electrophilic intermediate. Depending on the furan ring substituents, the intermediate is either an epoxide or a cis-enedione with more ring substitution favoring epoxide formation. Either intermediate reacts with cellular nucleophiles such as protein or DNA to trigger toxicities. The reactivity of the metabolite determines which cellular nucleophiles are targeted. The toxicity of a particular furan is also influenced by the presence of competing metabolic pathways or efficient detoxification routes. GSH plays an important role in modulating the harmful effects of this class of compound by reacting with the reactive metabolite. However, this may not represent a detoxification step in all cases.

Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic

“…Furan has received attention since 1995 because it was classified as "possibly carcinogenic to humans" by the International Agency for Research on Cancer (International Agency for Research on Cancer 1995). DIOB is a furan-containing compound, and many furan compounds have been reported to be toxic and/or carcinogenic (Peterson 2013), such as 4-ipomeanol (Rowinsky et al 1993;Boyd et al 1974), furosemide (Mitchell et al 1974(Mitchell et al , 1976Wong et al 2000;Williams et al 2007), 3-methylfuran (Haschek et al 1984), and menthofuran (Sullivan et al 1979;Anderson et al 1996). We speculated that the furan moiety might be the critic functional group responsible for DIOB-induced hepatotoxicities.…”

Cytochrome P450–Mediated Metabolic Activation of Diosbulbin B

“…A number of furanoid compounds have been linked to adverse events, including hepatotoxicity, pulmonary toxicity, and carcinogenesis, possibly in part resulting from the in situ formation of cis-enedial (Peterson, 2013). These reactive species are capable of alkylating key cellular proteins and/or DNA.…”

“…Many furan compounds are reported to be toxic or carcinogenic (Peterson, 2013), such as 4-ipomeanol (Boyd et al, 1974), furosemide (Mitchell et al, 1974(Mitchell et al, , 1976Wong et al, 2000;Williams et al, 2007), 3-methylfuran (Haschek et al, 1984;Morse et al, 1984), teucrin A (Larrey et al, 1992), and menthofuran (Sullivan et al, 1979;Anderson et al, 1996). The toxic effects elicited by these furans are suggested to attribute to their cis-enedial oxidative metabolite (Peterson, 2013). We hypothesized that DIOB is metabolized to a cis-enedial, an electrophilic species, which may play an important role in hepatotoxicity induced by DIOB.…”

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

“…However, compound 20 also had increased lipophilicity compared to compound 11, so we did not see any advantage in using this group in subsequent compounds and, whilst compounds 19 and 21 did not substantially increase lipophilicity, they still did not achieve our target potency. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Unable to significantly improve on the indole moiety at the 6-position of the indazole template, we turned our attention back to the 4-position. Careful re-evaluation of SAR, coupled with closer examination of compounds modeled into PI3Kδ, indicated that there was potentially space to substitute on the heteroaryl ring to search for further interactions.…”