RESUMEN

We report the combination of organo-photocatalysis with transition metal (TM) catalysis for directed ortho-hydroxylation of substituted anilides for the synthesis of α-aminophenol derivatives under mild conditions. The developed metallaphotocatalysis utilizes N-pivaloyl as a directing group and phenyl iodine(III) bis(trifluoroacetate) (PIFA) in the combination of the 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) photocatalyst and [RuCl2(p-cymene)]2 TM catalyst under visible-light irradiation at room temperature. The hydroxylation reaction works well for a wide range of substrates containing electron-withdrawing substituents and could be applied to late-stage functionalization and ortho-hydroxyl metabolite generation for drug compounds-containing anilides with electron-withdrawing substituents in a single mild reaction.

RESUMEN

The human hepatocyte suspension model has been a valuable tool to study covalent binding (CVB) for compounds that form reactive metabolites. However, accurately measuring CVB values with the suspension model becomes challenging for metabolically low turnover compounds. In this study, we evaluated the HµREL human hepatocyte coculture model relative to existing literature using human hepatocyte suspension for drugs of known drug-induced liver injury category. Our results indicate that this coculture model provides ample metabolic turnover to reproducibly measure CVB. It is sufficiently robust to apply a predefined 1 mg/day CVB body burden threshold for risk assessment to guide our discovery programs, allowing for expanded coverage to include metabolically low turnover compounds.

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RESUMEN

Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-ß-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR). 3-((4-Nitronaphthalen-1-yl)amino)benzoic acid 1 is a "first-in-class" AKR1C3 competitive inhibitor and AR antagonist. Compound 1 was compared in a battery of in vitro studies with structurally related N-naphthyl-aminobenzoates, and AKR1C3 targeted therapeutics e.g. GTx-560 and ASP9521, as well as with R-bicalutamide, enzalutamide and abiraterone acetate. Compound 1 was the only naphthyl derivative that was a selective AKR1C3 inhibitor and AR antagonist in direct competitive binding assays and in AR driven reporter gene assays. GTx-560 displayed weak activity as a direct AR antagonist but had high potency in the AR reporter gene assay consistent with its ability to inhibit the co-activator function of AKR1C3. By contrast ASP9521 did not act as either an AR antagonist or block AR reporter gene activity. Compound 1 was the only compound that showed comparable potency to inhibit AKR1C3 and act as a direct AR antagonist. Compound 1 blocked the formation of testosterone in LNCaP-AKR1C3 cells, and the expression of PSA driven by the AKR1C3 substrate (4-androstene-3,17-dione) and by an AR agonist, 5α-dihydrotestosterone consistent with its bifunctional role. Compound 1 blocked the nuclear translocation of the AR at similar concentrations to enzalutamide and caused disappearance of the AR from cell lysates. R-biaclutamide and enzalutamide inhibited AKR1C3 at concentrations 200x greater than compound 1, suggesting that its bifunctionality can be explained by a shared pharmacophore that can be optimized.

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RESUMEN

Irradiation of a 1,3-enyne tethered to a 2-pyridone, in the presence of oxygen, leads to formation of a seven-membered ring product, an overall [4+4-1] reaction. This transformation involves two unstable intermediates and a sequence of unusual reactions. An initial [4+4] photocycloaddition of the enyne with the pyridone yields a 1,2,5-cyclooctatriene. Photooxidation of this triene forms a cyclopropanone and subsequent photoextrusion of carbon monoxide gives the observed 1,4-cycloheptadiene product. The first-formed cyclooctatriene and the cyclopropanone could be observed and characterized spectroscopically. The cyclopropanone underwent CO extrusion both photochemically and thermally to give the cycloheptadiene product. Addition of fluoride or acetylide to the most stable cyclopropanone occurred chemoselectively at the two different silicon groups rather than the carbonyl group. The resulting cyclopropanone ring openings gave unsaturated aldehydes.

RESUMEN

Intramolecular [4 + 4] photoreaction of 2-pyrones with a 1,3-enyne yields an unstable 1,2,5-cyclooctatriene product. Without a C4 pyrone substituent, 1,3-hydrogen migration converts the allene to a 1,3-diene, with a skeleton related to dactylol. With methoxy substitution, Cope rearrangement yields a nine-membered ring fused to a cyclobutane. Both structures were confirmed by X-ray crystallography. The Cope rearrangement is apparently reversible, reforming the allene which undergoes a proton shift to the more stable 1,3-diene product.

RESUMEN

Reactive 1,2,5-cyclooctatrienes, formed by photocycloaddition of 2-pyridones with enynes, are stabilized by steric shielding, slowing or preventing an otherwise facile [2 + 2]-dimerization reaction. Diisopropylsilyl ether-tethered reactants paired with an alkene substituent (R) produce allenes that are stable (R = TMS) or that isomerize to 1,3-dienes by hydrogen migration (R = alkyl). Under acidic conditions, hydrolysis of the photoproduct's silyl ether can lead to a [3,3]-sigmatropic rearrangement.