Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: Discovery of a novel neuroinflammation inhibitor

Yang, Yaxi; Zheng, Longtai; Shi, Jingjing; Gao, Bo; Chen, Yan-Ke; Yang, Hui-Chi; Chen, Hongli; Li, Yuanchao; Zhen, Xuechu

doi:10.1016/j.bmcl.2013.12.055

Cited by 19 publications

(37 citation statements)

References 31 publications

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“…The overall yield of 7 is increased from 68% to 96.8%. The physical properties and spectroscopic data (IR and 1 H-NMR) of compounds 6 and 7 were consistent with those previously reported [8,[30][31][32]. The 13 C-NMR spectroscopic data for compound 7 has been informed but not assigned [32].…”

Section: Resultssupporting

confidence: 89%

“…Subsequent treatment of compound 9 with the Li 2 CO 3 /LiBr system at 80 • C in dimethylformamide (DMF) produces the alquene 10 with 74.9% yield [33] (Scheme 2). The 1 H-NMR spectroscopic data of alquene 10 was consistent with that previously reported [8,32]. Additionally, in the 13 C-NMR spectrum the signals at δ C = 124.49 (C-2) and 124.95 (C-3) ppm are observed.…”

Section: Resultssupporting

confidence: 89%

“…Compound 11 was obtained with 51% yield by stereospecific α-face hydroxylation of olefin 10 using a catalytic amount of osmium tetraoxide (4.0%) in a mixture of (CH3)2CO-H2O (3:1) and 2.0 mL of pyridine, and in the presence of N-methylmorpholine N-oxide [33]. The 1 H-and 13 C-NMR spectroscopic data of diol 11 were consistent with those reported [8,32]. In addition, the spatial orientations of The reaction of compound 8 with methanesulfonyl chloride (mesyl chloride) in CH 2 Cl 2 /DMAP produces the mesylated derivative 9 with 61% yield [28].…”

Section: Resultssupporting

confidence: 83%

“…Thus, to get 8, an additional esterification reaction was carried out with 94% yield. The physical properties, IR, and 1 H-NMR spectroscopic data of compound 8 have been previously reported, but the signals of 13 C-NMR were not assigned [32]. The change of the 5β-cholestan to 5α-cholestan skeleton (A/B ring cis for trans fusion) implies a very important structural modification, and therefore a detailed analysis of NMR spectroscopic data for compounds 7 and 8 must be performed.…”

Section: Resultsmentioning

confidence: 98%

“…Compound 7 was readily isomerized (94.4% yield) under acid conditions (2.5% HCl/MeOH) to give the derivative 8 possessing 5α-cholestan-6-one skeleton [8,13,32]. This isomerization reaction can be performed under alkaline conditions as well, but under these conditions the obtained compound was isomerized and hydrolyzed (carboxylic acid) with 84% yield [31].…”

Section: Resultsmentioning

confidence: 99%

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Structural Modifications of Deoxycholic Acid to Obtain Three Known Brassinosteroid Analogues and Full NMR Spectroscopic Characterization

et al. 2016

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An improved synthesis route for obtaining known brassinosteroid analogues, i.e., methyl 2α,3α-dihydroxy-6-oxo-5α-cholan-24-oate (11), methyl 3α-hydroxy-6-oxo-7-oxa-5α-cholan-24-oate (15) and methyl 3α-hydroxy-6-oxa-7-oxo-5α-cholan-24-oate (16), from hyodeoxycholic acid (4) maintaining the native side chain is described. In the alternative procedure, the di-oxidized product 6, obtained in the oxidation of methyl hyodeoxycholate 5, was converted almost quantitatively into the target monoketone 7 by stereoselective reduction with NaBH 4 , increasing the overall yield of this synthetic route to 96.8%. The complete 1 H-and 13 C-NMR assignments for all compounds synthesized in this work have been made by 1D and 2D heteronuclear correlation gs-HSQC and gs-HMBC techniques. Thus, it was possible to update the spectroscopic information of 1 H-NMR and to accomplish a complete assignment of all 13 C-NMR signals for analogues 5-16, which were previously reported only in partial form.

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Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Structural Modifications of Deoxycholic Acid to Obtain Three Known Brassinosteroid Analogues and Full NMR Spectroscopic Characterization

et al. 2016

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Inhibition of Neuroinflammation by Synthetic Androstene Derivatives Incorporating Amino Acid Methyl Esters on Activated BV‐2 Microglia

et al. 2015

ChemMedChem

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Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.

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Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: Discovery of a novel neuroinflammation inhibitor

Cited by 19 publications

References 31 publications

Structural Modifications of Deoxycholic Acid to Obtain Three Known Brassinosteroid Analogues and Full NMR Spectroscopic Characterization

Structural Modifications of Deoxycholic Acid to Obtain Three Known Brassinosteroid Analogues and Full NMR Spectroscopic Characterization

Inhibition of Neuroinflammation by Synthetic Androstene Derivatives Incorporating Amino Acid Methyl Esters on Activated BV‐2 Microglia

Inducible nitric oxide synthase inhibitors: A comprehensive update

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