2-(2-Pyridyl)-1,2-diarylalkanols as Hypocholesteremic Agents

Burckhalter, J. H.; Dixon, William D.; Black, Martin L.; Westland, Roger D.; Werbel, Leslie M.; DeWald, Horace A.; Dice, John R.; Rodney, Gertrude; Kaump, D. H.

doi:10.1021/jm00316a013

Cited by 9 publications

(9 citation statements)

References 3 publications

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“…32 2,6-Bis(3,4-dihydroxybenzylidene)cyclohexanone (7b). A mixture of 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde (3.1 g, 10.2 mmol), cyclohexanone (0.5 g, 5.1 mmol), and barium hydroxide octahydrate (4.8 g, 15.2 mmol) in methanol (100 mL) was stirred at 50°C for 7 h. After cooling the solvent was evaporated, and the residue was treated with 1 M hydrochloric acid (100 mL) and extracted with ethyl acetate (3 × 50 mL).…”

Section: 4-bis(tetrahydropyran-2-yloxy)benzaldehydementioning

confidence: 99%

Geometrically and Conformationally Restrained Cinnamoyl Compounds as Inhibitors of HIV-1 Integrase: Synthesis, Biological Evaluation, and Molecular Modeling

et al. 1998

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Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

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Section: 4-bis(tetrahydropyran-2-yloxy)benzaldehydementioning

confidence: 99%

Geometrically and Conformationally Restrained Cinnamoyl Compounds as Inhibitors of HIV-1 Integrase: Synthesis, Biological Evaluation, and Molecular Modeling

et al. 1998

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“…The Z / E ratio of cross-coupling products depended on both coupling partners and varied from 1.9/1 to 10/1. It is worth noting that several coupling products such as 5c , 7c , 10c , and 17c are important scaffolds in drug molecules. − …”

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confidence: 99%

Metal–Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis

et al. 2020

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Here we report the design of an enzyme-inspired metal–organic framework (MOF), 1-OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF (1), with mixed 2,2′-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy)2(dcbpy)]+ (ppy = 2-phenylpyridine) sites to afford 1-OTf-Ir with both Lewis acid and photoredox sites. 1-OTf-Ir effectively catalyzed reductive cross-coupling of N-hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives. 1-OTf-Ir enabled catalytic synthesis of anticholinergic drugs Pheniramine and Chlorpheniramine.

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“…pyridine)ethanol (8a) has been synthesized and found to be the major urinary metabolite following intraperitoneal administration of l-(3-chlorophenyl)-l-methyl-2-phenyl-2-(2-pyridine)ethanol (1) to rats. This metabolite has a hypocholesteremic effect in rats similar to that of the parent drug.…”

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confidence: 99%

“…The one exception in this regard was that a high percent of 3H activity remained in the peritoneal cavity encapsulated in numerous white masses. This material was identified by TLC as compound 1 which had not been absorbed. Also included in Figure 1 are cumulative excretion rates.…”

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confidence: 99%

Metabolic formation and synthesis of 1-(3-chlorophenyl)-2-(4-hydroxyphenyl)-1-methyl-2-(2-pyridine)ethanol. A potential hypocholesteremic agent

Sinsheimer¹,

Eeckhout²,

Hewitt³

et al. 1976

J. Med. Chem.

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2-(2-Pyridyl)-1,2-diarylalkanols as Hypocholesteremic Agents

Cited by 9 publications

References 3 publications

Geometrically and Conformationally Restrained Cinnamoyl Compounds as Inhibitors of HIV-1 Integrase: Synthesis, Biological Evaluation, and Molecular Modeling

Geometrically and Conformationally Restrained Cinnamoyl Compounds as Inhibitors of HIV-1 Integrase: Synthesis, Biological Evaluation, and Molecular Modeling

Metal–Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis

Metabolic formation and synthesis of 1-(3-chlorophenyl)-2-(4-hydroxyphenyl)-1-methyl-2-(2-pyridine)ethanol. A potential hypocholesteremic agent

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