Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction.

Bader, John P.; McMahon, James B.; Schultz, Robert J.; Narayanan, V. L.; Pierce, J. B.; Harrison, W.A.; Weislow, Owen S.; Midelfort, C. F.; Stinson, Sherman F.; Boyd, Michael R.

doi:10.1073/pnas.88.15.6740

Cited by 60 publications

(52 citation statements)

References 18 publications

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“…Following 6 days of incubation at 37ЊC, the viability of the cells in each well was determined spectrophotometrically by the metabolic reduction of XTT to a soluble colored formazan (12). The effect of michellamine B on chronically infected cells was assessed by the determination of supernatant RT, core p24, and CEM-SS infectivity as previously described (1,12).…”

Section: Methodsmentioning

confidence: 99%

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

McMahon

Currens

Gulakowski

et al. 1995

Antimicrob Agents Chemother

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108

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Section: Methodsmentioning

confidence: 99%

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

McMahon

Currens

Gulakowski

et al. 1995

Antimicrob Agents Chemother

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108

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“…UC781 has been identified as an extremely potent inhibitor of HIV-1 in cell culture [50% effective concentration (EC 50 ), approximately 3.0 ng/mL] (1-3). It belongs to the class of thiocarboxanilide derivatives, the prototype of which (UC-84) was originally reported by Bader et al (4). UC781 can neutralize several laboratory and clinical strains of HIV-1 (2), including both syncytium-and nonsyncytium-inducing phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781

Yang

Parniak

Isaacs³

et al. 2008

AAPS J

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Abstract. The highly potent anti-HIV agent UC781 is being evaluated for use in topical microbicides to prevent HIV transmission. However, UC781 is extremely hydrophobic with poor water solubility, a property that may complicate appropriate formulation of the drug. In this study, we examined the ability of several cyclodextrins, beta-cyclodextrin (βCD), methyl-beta-cyclodextrin (MβCD), and 2-hydroxylpropyl-beta-cyclodextrin (HPβCD), to enhance the aqueous solubility of UC781. Each of the cyclodextrins provided dramatic increases in UC781 aqueous solubility, the order being MβCD>HPβCD>βCD. The complexation constants (K 1:1 ) of the inclusion complexes were determined via a phase solubility technique using high-performance liquid chromatography and showed that UC781 solubility increased linearly as a function of cyclodextrin concentration. Ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and 2D 1 H ROESY NMR spectroscopy were used to further characterize these UC781/cyclodextrin complexes. The inhibitory potency of UC781 and its HPβCD inclusion complex were evaluated using an in vitro HIV-1 reverse transcriptase inhibition assay The inhibitory potency of the UC781/HPβCD complex was 30-fold greater than that of UC781 alone, showing that the complexed drug is able to provide substantial inhibition of its target. The enhancement of UC781 aqueous solubility is essential for the development of a useful vaginal microbicide dosage form, and our data suggest that UC781/cyclodextrin inclusion complexes may be useful in this context.

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“…Since then, numerous other classes of HIV-1-specific RT inhibitors, now referred to as NNRTls (non-nucleoside reverse transcriptase inhibitors), have been reported (for an overview, see De Clercq, 1993). The oxathiin carboxanilide 1-methylethyl 2-chloro-S· [[(S,6-dihydro-2-methyl-1,4-oxathiin-3-yl) carbonyljamlnojbenzoate (NSC 61S98S, UC84) was discovered as a specific HIV-1 inhibitor in 1991 (Bader et al, 1991) through the AIDS screening programme of the National Institutes of Health (National Cancer Institute), and its conformational properties were revealed by X-ray studies (Bader et al, 1991;Silverton et al, 1991). A common property of the NNRTls is the high potenoy and specificity of their inhibitory effect against HIV-1 strains but not HIV-2 or other RNA or DNA viruses.…”

mentioning

confidence: 99%

Oxathiin Carboxanilide Derivatives: A Class of Non-Nucleoside HIV-1-Specific Reverse Transcriptase Inhibitors (NNRTIs) that are Active against Mutant HIV-1 Strains Resistant to other NNRTIs

Balzarini

Jonckheere

Harrison³

et al. 1995

Antivir Chem Chemother

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The HIV-1-specific oxathiin carboxanilide derivative 1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designated UC84) has potent activity against HIV-1(IIIB) (50% effective concentration: 0.015 μg ml−1). UC84 was found to select for a 138-Lys mutant virus strain in HIV-1-infected CEM cell cultures. When the 138-Lys mutation was introduced solely in the p51 subunit of the p51/p66 reverse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT heterodimer. These data provided clear evidence for a structural and functional role of the p51 subunit in the sensitivity/resistance of the enzyme to UC84. UC84 also proved to be virtually inactive against mutant HIV-1 strains containing the 100-lle, 106-Ala, 138-Lys or 181-Cys mutation in their RT. However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or the isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains. For example, compound 131 (1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)thioxomethyl]amino]benzoate was only 2-fold more active than the parent compound UC84 against wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mutant strains that contained the 100-11e, 106-A1a, 138-Lys or 181-Cys in their RT. These findings should be taken into account when selecting suitable drug candidates for the treatment of HIV-1 infections, particularly those that have developed resistance to other non-nucleoside RT inhibitors (NNRTIs).

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Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction.

Cited by 60 publications

References 18 publications

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781

Oxathiin Carboxanilide Derivatives: A Class of Non-Nucleoside HIV-1-Specific Reverse Transcriptase Inhibitors (NNRTIs) that are Active against Mutant HIV-1 Strains Resistant to other NNRTIs

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