Hydroxyl-directed regioselective monodemethylation of polymethoxyarenes

Lal, K.; Ghosh, Subrata; Salomon, Robert G.

doi:10.1021/jo00382a018

Cited by 48 publications

(21 citation statements)

References 2 publications

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“…Slightly deviating from the procedure depicted in Scheme 2 , pyridine-2-amine 10a has been synthesized by a S N 2 reaction of single Boc-protected 2-amino-4-methylpyridine and 1-(3-bromopropyl)-2,4-dimethoxybenzene ( 9 ) followed by subsequent formation of the 4,5-diaryl-imidazole scaffold using the procedure developed for synthesis of 6 . Alkyl halide 9 was synthesized from 3-(2,4-dimethoxyphenyl)propionic acid by reduction [ 39 ] followed by an Appel reaction using triphenylphosphine and N -bromosuccinimide ( Scheme 3 ) [ 40 ]. Detailed information about the synthesis of 10a is presented in the Supporting Information.…”

Section: Resultsmentioning

confidence: 99%

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

et al. 2017

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The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α.

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Section: Resultsmentioning

confidence: 99%

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

et al. 2017

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“…The IR absorption showed the presence of hydroxyl group signal at 3502 cm -1 and carboxyl group at 1721 cm -1 . The 1 H-NMR spectrum showed the presence of aromatic proton at position H-5 (δ H 6.52, 1H, dd, J = 8.1, 2.5 Hz) having ortho and meta coupling with H-6 (δ H 7.06, 1H, d, J = 8.1 Hz) and H-4 (δ H 6.45, 1H, d, J = 2.5 Hz), respectively, quite identical to compound 2 ( Lal et al, 1987 ). In addition, the methyl group resonated at δ H 1.30 (3H, d, J = 7.8Hz, CH 3 ) and methine signal centered at δ H 3.29 (1H, m, H-3′).…”

Section: Resultsmentioning

confidence: 83%

“…Similarly, the methylene signal bearing hydroxyl group resonated at δ H 3.39 (1H, m, H-1′), δ H 3.68 (1H, m, H-1′) and the other methylene signal appeared at δ H 1.53 (1H, m, H-2′), δ H 2.01 (1H, m, H-2′). Methylene proton (H-5) showed ortho coupling with H-6 at δ H 7.06 (1H, d, J = 8.1 Hz) and meta coupling with H-3 at δ H 6.44 (1H, d, J = 2.4 Hz) characteristic of aromatic ring ( Lal et al, 1987 ).…”

Section: Resultsmentioning

confidence: 99%

Isolation and Characterization of Two New Secondary Metabolites From Quercus incana and Their Antidepressant- and Anxiolytic-Like Potential

et al. 2018

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The ethyl acetate fraction of Quercus incana yielded two new compounds [1 and 2]. The characterization and structure elucidation of these compounds were carried out through various spectroscopic techniques such as mass spectrometry along with one- and two-dimensional NMR techniques. The structural formula was deduced to be 2-(4-hydroxybutan-2-yl)-5-methoxyphenol [1] and 4-hydroxy-3-(hydroxymethyl) pentanoic acid [2]. The elevated plus maze (EPM) and light–dark box (LDB) tests (classical mouse models) were performed in order to reveal the anxiolytic potential of both compounds [1 and 2]. Both compounds displayed dose-dependent increases in open-arm entries and time spent in open arms in EPM (∗P < 0.05, ∗∗P < 0.01), and increased the time spent in the lit compartment and increased transitions between the two compartments in LDB test (∗P < 0.05, ∗∗P < 0.01). Co-administration of selective benzodiazepine (BZP) receptor antagonist, flumazenil (2.5 mg/kg) with compounds [1 and 2] decreased the anxiolytic-like activity of both compounds in the EPM indicating BZP-binding site of GABA-A receptors are involved in the anxiolytic-like effect. Similarly, both compounds at the dose level of 10 and 30 mg/kg, i.p. exerted pronounced antidepressant-like effect in both forced swimming as well as tail suspension tests (∗P < 0.05, ∗∗P < 0.01; ANOVA followed by Dunnett’s post hoc test). The effect at 30 mg/kg was comparable to the reference drug imipramine (60 mg/kg).

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“…Accordingly,2 ,5-dimethoxyphenyla cetic acid (23)w as reduced into alcohol 24, [9] which was subsequently converted into iodide 25 under Appel-type conditions (Ph 3 P, I 2 )i n8 3% yield (Scheme5). [10] Thea lkylation of ethyl 2-oxocyclopentane-1-carboxylate (14)b yu sing K 2 CO 3 in DMF worked reasonably well.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Lingzhiol and its Analogues through the Wittig Reaction of an Oxocyclopentane Carboxylate

Rengarasu

Maier

2016

Asian J Org Chem

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The biosynthesis of polycyclic natural product lingzhiol (1)t hrough an intramolecular Friedel-Crafts alkylation reaction of an aryl-substituted cyclopentane epoxide (22)w as attempted.T he synthesis of this endocyclic epoxide involved the alkylation of cyclopentane carboxylate 14 with alkyl iodide 25 to afford ketoester 26.S ubsequentW ittig olefination led to exocyclic alkene exo-15 in good yield. Epoxidation, opening of the epoxide to generate allyl alcohol 29,a nd as econd epoxidation reaction afforded compounds 22 and 31.H owever,p resumably owing to stereoelectronic effects, the cyclization of these substrates into polycycles 17 and 32,r espectively,w as unsuccessful. Nevertheless, the Wittig reaction to afford exo-15 allowed us to converge with the previouslyr eported route of Qin et al.,w hich featured the cyclization of spiro epoxide 16.T hus, lingzhiol is now availablei no nly nine steps. Various analogueso fl ingzhiol were also prepared, includingd esoxy derivative 37,q uinone 38,m ono-methoxy-deoxy derivative 39,and ketone 40.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under http://dx. Scheme2.Previously proposed biosynthesis of lingzhiol by Birman and coworkers.Scheme3.Summary of the previously published synthetic routes to lingzhiol. TFA = trifluoroaceticacid, TMSOTf = trimethylsilyl trifluoromethanesulfonate.Scheme4.Our strategy for the synthesis of lingzhiol.Scheme5.Alkylation of b-ketoester 14 with iodide 25 and conversion of ketoester 26 into alkene exo-15 through aWittig reaction.Scheme6.Conversion of exocyclic alkene exo-15 into epoxides 22 and 31 and their attempted intramolecular cyclization. mCPBA = meta-chloroperoxybenzoic acid, pyr = pyridine,A c 2 O = acetic anhydride.Scheme8.Synthesis of fourlingzhiol analogues (37-40). DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, IBX = 2-iodoxybenzoica cid.

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Hydroxyl-directed regioselective monodemethylation of polymethoxyarenes

Cited by 48 publications

References 2 publications

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK

Isolation and Characterization of Two New Secondary Metabolites From Quercus incana and Their Antidepressant- and Anxiolytic-Like Potential

Total Synthesis of Lingzhiol and its Analogues through the Wittig Reaction of an Oxocyclopentane Carboxylate

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