- Investigation of liver alcohol dehydrogenase catalysis using an NADH biomimetic and comparison with a synthetic zinc model complex
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We have compared the catalytic activity of horse liver alcohol dehydrogenase (LADH) with a synthetic zinc model complex in the presence of N-benzyl-1,4-dihydronicotinamide (BNAH), a cofactor which serves as a biomimetic for the natural cofactor NADH. We have used five different substrates (benzaldehyde, p-anisaldehyde, 4-nitrobenzaldehyde, 2-pyridine carboxaldehyde, and 5-pyrimidine carboxaldehyde) in this study. These substrates vary in their substituent inductive effect, which is the ability to donate or withdraw electron density away from their carbonyl-functional group. Our results reveal that in the presence of NADH, geometric factors (induced fit of the substrate and cofactor in the enzyme active site) are vital. However, reactivity assays show that in the presence of BNAH, there is a strong correlation between substrate electronic environment and the observed catalytic rate, i.e. the more electron withdrawn the substrate, the greater the speed at which the reduction reaction occurs. NMR spectroscopy reveals that a synthetic zinc model complex catalyzes the reduction of substrates in a manner consistent with LADH enzyme.
- Sunderland, James R.,Tao, Xingjian,Butrick, Elizabeth E.,Keilich, Lauren C.,Villa, Christine E.,Miecznikowski, John R.,Jain, Swapan S.
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Read Online
- Controlled meta-Selective C-H Mono- And Di-Olefination of Mandelic Acid Derivatives
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Mandelic acids represent a key structural motif present in many drug molecules. Herein, we report the controlled meta-selective mono- and diolefination of mandelic acids by the careful design of the substrate and oxidant. Furthermore, free meta-functional
- Muthuraja, Perumal,Usman, Rahamdil,Sajeev, Revathy,Gopinath, Purushothaman
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supporting information
p. 6014 - 6018
(2021/08/03)
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- CANCER TREATMENTS TARGETING CANCER STEM CELLS
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Disclosed are compounds, methods, compositions, and kits that allow for treating cancer by, e.g., targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in the disclosure are of Formula (0), (O'), and (I):
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Paragraph 0331; 0391-0392
(2019/11/19)
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- cGAS ANTAGONIST COMPOUNDS
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Disclosed are novel compounds of Formula (I) that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.
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Paragraph 0216; 0225; 0236
(2017/11/06)
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- AMIDO-BENZYL SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment of an NAMPT-mediated disease or condition in a subject, selected from solid or liquid tumor, rheumat
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Paragraph 0218
(2013/09/12)
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- COMPOUNDS AND METHODS
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The present invention relates to novel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.
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Page/Page column 41
(2013/03/26)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 144; 145
(2013/09/12)
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- PYRIDINYL AND PYRIMIDINYL SULFOXIDE AND SULFONE DERIVATIVES
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Disclosed are certain pyridinyl and pyrimidinyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds and methods of treatment using such compounds.
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Page/Page column 95; 96
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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Page/Page column 69; 70
(2013/09/12)
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- ALKYL-AND DI-SUBSTITUTED AMIDO-BENZYL SULFONAMIDE DERIVATIVES
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The present invention relates to certain alkyl- and di-substituted amido-benzyl sulfonamide compounds, pharmaceutical compositions comprising such compounds, and to methods of treatment of NAMPT-mediated disorders, such as diabetes, rheumatoid arthritis,
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Paragraph 0226
(2013/09/12)
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- SUBSTITUTED DIHYDROISOQUINOLINONE AND ISOQUINOLINEDIONE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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A series of disubstituted dihydroisoquinolinone and isoquinolinedione derivatives represented by Formula I, or pharmaceutically acceptable salts thereof are presented. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, calcium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, epilepsy, diabetic neuropathy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, sleep disorder, bipolar disorder and stroke, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds.
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Page/Page column 32-33
(2010/04/03)
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- N-SUBSTITUTED OXINDOLINE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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A series of N-substituted oxindole derivatives represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more othe
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Page/Page column 29-30
(2009/05/29)
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- N-SUBSTITUTED OXINDOLINE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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A series of N-substituted oxindole derivatives represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more othe
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Page/Page column 32-33
(2009/05/29)
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- Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
- Kempf, Dale J.,Sham, Hing L.,Marsh, Kennan C.,Flentge, Charles A.,Betebenner, David,Green, Brian E.,McDonald, Edith,Vasavanonda, Sudthida,Saldivar, Ayda,Wideburg, Norman E.,Kati, Warren M.,Ruiz, Lisa,Zhao, Chen,Fino, Lynnmarie,Patterson, Jean,Molla, Akhteruzzaman,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 602 - 617
(2007/10/03)
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