- Substrate-Tuned Catalysis of the Radical S-Adenosyl- L -Methionine Enzyme NosL Involved in Nosiheptide Biosynthesis
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NosL is a radical S-adenosyl-L-methionine (SAM) enzyme that converts L-Trp to 3-methyl-2-indolic acid, a key intermediate in the biosynthesis of a thiopeptide antibiotic nosiheptide. In this work we investigated NosL catalysis by using a series of Trp analogues as the molecular probes. Using a benzofuran substrate 2-amino-3-(benzofuran-3-yl)propanoic acid (ABPA), we clearly demonstrated that the 5′-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction in NosL catalysis is not from the indole nitrogen but likely from the amino group of L-Trp. Unexpectedly, the major product of ABPA is a decarboxylated compound, indicating that NosL was transformed to a novel decarboxylase by an unnatural substrate. Furthermore, we showed that, for the first time to our knowledge, the dAdo radical-mediated hydrogen abstraction can occur from an alcohol hydroxy group. Our study demonstrates the intriguing promiscuity of NosL catalysis and highlights the potential of engineering radical SAM enzymes for novel activities.
- Ji, Xinjian,Li, Yongzhen,Ding, Wei,Zhang, Qi
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p. 9021 - 9024
(2015/08/03)
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- Azepinoindole derivatives as pharmaceutical agents
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Compounds, compositions and methods for modulating the activity of receptors are provided. In particular, compounds and compositions are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder directly or indirectly related to the activity of the receptors.
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- N-phenpropylcuclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
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The invention relates to compounds of formula (I) for treating for example sexual dysfunction, wherein R1 is optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6alkoxy, —NR2 R3 or —NR4SO2R5; X is the linkage —(CH2)n— or —(CH2)q—O— (wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C1-4alkoxy; hydroxy; hydroxy(C1-3alkyl); C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6 or 7; and q is 2, 3, 4, 5 or 6; and Y is phenyl or pyridyl, each of which may be substituted; or two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused optionally substituted 5- or 6-membered carbocyclic or heterocyclyic ring.
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- AZEPINOINDOLE AND PYRIDOINDOLE DERIVATIVES AS PHARMACEUTICAL AGENTS
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The present invention is directed to compounds of formula (I) and formula (II): formula (I) and (II), wherein R1-R8, A and n are as described in the description. These compounds are used in pharmaceutical compositions and methods for modulating the activity of orphan nuclear receptors.
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- Substituted hexahydroarylquinolizines
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Certain substituted hexahydroarylquinolizines and pharmaceutically acceptable salts thereof are peripherally selective α2 -adrenoceptor antagonists. The compounds are adapted to be employed for the treatment of certain pathological disorders such as hypertension, diabetes, disorders involving platelet aggregation and the like without side effects attributable to effect on the central nervous system.
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- Enantioselective synthesis of 1,3,4,6,7,12b(S)-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one
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An enantioselective synthesis of 1,3,4,6,7,12b(S)-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one provides a key intermediate for the preparation of the α2 -adrenergic antagonist (2R,12bS)-N-(1,3,4,6,7,12-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide hydrochloride, useful as an anti-depressant.
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- Preparation of n-formamidoyl[(s)-1-t-butoxy-3-methyl-2-amino)]1,2,3,4 tetrahydrobenzo [b]furo [2,3-c]pyridine and derivatives
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The present invention is directed to an enantioselective synthesis of 1,3,4,6,7,12b(S)-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one which is an intermediate in the production of the α2 -adrenergic antagonist (2R,12bS)-N-(1,3,4,6,7,12-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxy-ethanesulfonamide hydrochloride.
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- SUBSTITUTED HEXAHYDROARYLQUINOLIZINES
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Certain substituted hexahydroarylquinolizines and pharmaceutically acceptable salts thereof are peripherally selective α 2-adrenoceptor antagonists. The compounds are adapted to be employed for the treatment of certain pathological disorders such as hypertension, diabetes, disorders involving platelet aggregation and the like without side effects attributable to effect on the central nervous system.
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- Substituted benzo[b]furo- and benzo[b]thieno quinolizines
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Substituted hexahydro arylquinolizines and pharmaceutically acceptable salts thereof are selective α 2 -adrenergic receptor antagonists and thereby useful as antidepressants, antihypertensives, ocular antihypertensives, antidiabetics, antiobesity and platelet aggregation inhibitors and modifiers of gastrointestinal motility.
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- α2 -adrenergic receptor antagonists as modifiers of gastrointestinal motility
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Selective α 2 -adrenergic receptor antagonists are effective in modifying gastrointestinal motility in a manner useful in the treatment of colonic spasm, irritable bowel syndrome and constipation.
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- ANTI-DEPRESSANT SPIRO HEXAHYDRO ARYLQUINOLIZINE DERIVATIVES, COMPOSITION, AND METHOD OF USE THEREFOR
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Substituted hexahydro arylquinolizines and pharmaceutically acceptable salts thereof are selective α 2-adrenergic receptor antagonists and thereby useful as antidepressants, antihypertensives, ocular antihypertensives, antidiabetics, platelet aggregation inhibitors, antiobesity agents, and modifiers of gastrointestinal motility.
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- SUBSTITUTED HEXAHYDRO ARYLQUINOLIZINES AS ALPHA 2 BLOCKERS
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Substituted hexahydro arylquinolizines and pharmaceutically acceptable salts thereof are selective α 6-adrenergic receptor antagonists and thereby useful as antidepressants, antihypertensives, antidiabetics, antiobesity and platelet aggregation inhibitors.
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