Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

Abstract

10-Chloromethyl-11-demethyl-12-oxo-calanolide (F18), an analog of calanolide A, is a novel potent nonnucleoside reverse transcriptase inhibitor against HIV-1. Here, we report the metabolic profile and the results of associated biochemical studies of F18 in vitro and in vivo. The metabolites of F18 were identified based on liquid chromatography-electrospray ionization mass spectrometry and/or nuclear magnetic resonance. Twenty-three metabolites of F18 were observed in liver microsomes in vitro. The metabolism of F18 involved 4-propyl chain oxidation, 10-chloromethyl oxidative dechlorination and 12-carbonyl reduction. Three metabolites (M1, M3-1, and M3-2) were also found in rat blood after oral administration of F18 and the reduction metabolites M3-1 and M3-2 were found to exhibit high potency for the inhibition of HIV-1 in vitro. The oxidative metabolism of F18 was mainly catalyzed by cytochrome P450 3A4 in human microsomes, whereas flavin-containing monooxygenases and 11β-hydroxysteroid dehydrogenase were found to be involved in its carbonyl reduction. In human cytosol, multiple carbonyl reductases, including aldo-keto reductase 1C, short-chain dehydrogenases/reductases and quinone oxidoreductase 1, were demonstrated to be responsible for F18 carbonyl reduction. In conclusion, the in vitro metabolism of F18 involves multiple drug metabolizing enzymes, and several metabolites exhibited anti-HIV-1 activities. Notably, the described results provide the first demonstration of the capability of FMOs for carbonyl reduction.

Coumarin and Its Derivatives

“…Due to the length of this general overview, synthetic strategies for obtaining new coumarins have not been discussed in detail. To find information on the most recent synthetic pathways, we recommend the manuscripts by Molnar and co-authors [81] and Kovač and co-authors [82], both from 2020. To find an overview of the wide range of biological activities of coumarins, a 2020 review by Pinto and co-authors [1] is strongly recommended.…”

“…The Suzuki-Miyaura cross coupling of bromoarylcarboxylates and o-hydroxy(methoxy) arylboronic acids is one of the methods that plays an important role in the preparation of 4H-thieno[2, 3-c] 91 and 4H-thieno [3,4-c]benzopyran-4-ones 92 (Scheme 26) [ [81][82][83].…”

“…The released NK-κB is promptly translocated into the nucleus to activate specific response elements in DNA, triggering a transcriptional activity with high production of diverse inflammatory mediators, mainly TNF-α, IL-1β, COX-2, IL-6, IL-8, IL-12, and IL-23 (Figure 9) [ [77][78][79][80][81]. In several studies, the peroxisome proliferator-activated receptor gamma (PPAR-γ) has been associated with the inflammatory response coordinated by the NF-κB signaling pathway [82,83]. PPAR-γ and other PPARs, such as PPARα and PPARβ are a group of nuclear receptors that modulates glucose metabolism, adipogenesis, fatty acid synthesis as well as inhibit the NF-κB inflammatory response [83].…”

“…Under receptor activation by ligands, the co-repressor molecule displaced, whereas PPARγ/RXRα free complex binding with coactivator molecules [83].This activated complex binding to PPAR-γ response elements (PPRE) inducing transcription and protein synthesis (Figure 9). It has been reported that activated PPAR-γ/RXRα/coactivators complex can also bind with NF-κB repressing its transcriptional function with consequent reduction of pro-inflammatory cytokines production and consequent anti-inflammatory effects [81][82][83][84][85]. Several exogenous and endogenous PPAR-γ ligands have been reported, including fatty acids (linoleic, palmitoleic, and oleic acids), eicosanoids (eicosapentaenoic and docosahexaenoic acids, and prostaglandins), thiazolidinediones (rosiglitazone and pioglitazone), non-steroidal anti-inflammatory drugs (indomethacin and ibuprofen) as well as short-chain fatty acids, mainly butyrate and propionate, which are produced from the fermentative process of dietary fiber and other food products by intestinal microbiota [83,86,87].…”

Naturally Occurring Calanolides: Occurrence, Biosynthesis, and Pharmacological Properties Including Therapeutic Potential

“…In 2006, Craun Research (Kuching, Malaysia), a company established by the Sarawak Government, acquired Sarawak MediChem, and in 2016, Craun Research announced the completion of Phase I clinical trials for calanolide A (1) with doses of 200 to 800 mg, which initially started in 2013 [77]. In 2017, F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide A), a synthetic structural analog of calanolide A (1) was shown to have more potent anti-HIV activity than original molecule, calanolide A (1) [81,82]. This compound showed better druggable profile with 32.7% oral bioavailability in rat, tolerable oral single-dose toxicity in mice, and suppressed both the wild type HIV-1 and Y181C mutant HIV-1 at an EC 50 of 7.4 nM and 0.46 nM, respectively [83].…”