Novel Indoline-Based Acyl-CoA:Cholesterol Acyltransferase Inhibitor with Antiperoxidative Activity: Improvement of Physicochemical Properties and Biological Activities by Introduction of Carboxylic Acid

Takahashi, Kenji; Kasai, Magosaburo; Ohta, Masaru; Shoji, Yasuhiro; Kunishiro, Kazuyoshi; Kanda, Mamoru; Kurahashi, Kazuyoshi; Shirahase, Hiroaki

doi:10.1021/jm800248r

Cited by 27 publications

(14 citation statements)

References 31 publications

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“…Ca 2+ -free DMEM medium was purchased from Gibco (Carlsbad, CA). K-604 ( 24 ) and CS-505 ( 25 ) were provided by Kowa Pharmaceutical, Daiichi Sankyo and Kyoto Pharmaceutical Industries, respectively. Pyripyropene A (PPPA) was purifi ed from a culture broth of the fungus, Aspergillus fumigatus FO-1289 ( 26,27 ).…”

Section: Methodsmentioning

confidence: 99%

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Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Sekiya

Yamamuro

Ohshiro

et al. 2014

Journal of Lipid Research

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Atherosclerotic cardiovascular diseases are the leading cause of mortality in industrialized countries, despite advances in the management of coronary risk factors. Heart attacks arise from the thrombotic occlusion of coronary arteries following the rupture of plaques. Characteristic of these rupture-prone plaques is their lipid-rich nature due to the presence of cholesteryl ester (CE)-laden macrophage foam cells ( 1 ).The hydrolysis of intracellular CE, the initial step of reverse cholesterol transport, is catalyzed by multiple enzymes: neutral cholesterol ester hydrolase 1 (NCEH1) ( 2 ), also known as KIAA1363 or arylacetamide deacetylase-like 1 (AADACL1) ( 3 ), hormone-sensitive lipase (LIPE) ( 4 ), and possibly carboxylesterase 1 (CES1) ( 5, 6 ). NCEH1 is a microsomal protein tethered to the endoplasmic reticulum (ER) membrane by its N terminus with the rest of the protein containing the catalytic domain residing in the ER Abbreviations: acLDL, acetyl-LDL; Bip, immunoglobulin heavy chain-binding protein; CE, cholesteryl ester; CHOP, CCAAT/enhancer-binding protein-homologous protein; ER, endoplasmic reticulum; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; Hmgcs1 , 3-hydroxy-3-methylglutaryl-CoA synthase 1; 7-KC, 7-ketocholesterol; LD, lipid droplet; LIPE, hormone-sensitive lipase; LPDS, lipoprotein defi cient serum; LXR, liver X receptor; NCEH1, neutral cholesterol ester hydrolase 1; PPPA, pyripyropene A; Srebp, sterol regulatory element binding protein; TEM, transmission electron microscopy; TGEM, thioglycollate-elicited peritoneal macrophage; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Xbp-1, X-box-binding protein 1 . This work was supported by a grant-in-aid from Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists, a grant-in-aid for Scientifi c Research from the Ministry of Education and Science, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and JKA through its promotion funds from KEIRIN RACE, and MEXT-Supported Program for the Strategic Research

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Section: Methodsmentioning

confidence: 99%

“…After reaction, 25-HC oleate was purifi ed by preparative TLC on silica gel (10:1 hexane:ethyl acetate). Chemical structure was determined by the NMR analysis and MS. 25 Lipoproteins acLDL and lipoprotein defi cient serum (LPDS) were prepared as described previously ( 28 ).…”

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confidence: 99%

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Sekiya

Yamamuro

Ohshiro

et al. 2014

Journal of Lipid Research

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“…7) Pactimibe exerted inhibitory effects on macrophage ACAT activities and was efficiently absorbed orally, suggesting that it would have potent anti-atherosclerotic effects; however, clinical studies failed to show a plaque-reducing effect in CAD patients.…”

Section: Resultsmentioning

confidence: 99%

“…Compound 27 (Pactimibe) with a carboxymethyl moiety, and compounds 28 (KY-455) and 29 with no substituents at the 5-position were synthesized according to the methods previously reported. 7,11) …”

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confidence: 99%

Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: Indoline-Based Sulfamide Derivatives with Low Lipophilicity and Protein Binding Ratio

Takahashi

Ohta

Shoji

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Sulfur-containing compounds such as thioamides and thioesters have been found to be better reactants in the preparation of several heterocycle-tethered peptidomimetics and other related compounds compared to their oxygenated analogues. 38,39 Furthermore, some thioformamides show antifungal 40 and antibacterial activity, 41 and they have been employed in the synthesis of thiazoles via the Hantzsch protocol. 42 We envisaged the use of Nurethane-protected amino alkyl thioformamides for the synthesis of the corresponding isonitriles through a dehydrosulfurization reaction.…”

Section: Methodsmentioning

confidence: 99%

Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of Nβ-Fmoc-Amino Alkyl Isonitriles from Nβ-Fmoc-Amino Alkyl Thioformamides

Vishwanatha¹,

Hemantha²,

Sureshbabu³

2010

Synlett

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Synthetically useful N b -Fmoc amino alkyl isonitriles are prepared conveniently from N b -Fmoc amino alkyl thioformamides via a cyanogen bromide mediated dehydrosulfurization. The reaction is fast, clean, and yields are good.Key words: N b -Fmoc-amino alkyl thioformamides, isonitriles, dehydrosulfurization, cyanogen bromideIn recent years, the synthetic utility of isonitriles 1 in organic reactions has been exploited. Compounds containing an isocyano group find use as antibiotics, 2 antineoplastics, 3 and antianaesthetics. 4 The synthetic utility of isonitriles arises from their divergent character 5 and this functionality has wide utility, such as in the preparation of isothiocyanates, 6 N,N-dialkylcarbodiimides, 7 1-substituted tetrazoles, 8 [16][17][18][19][20] has been well demonstrated.In peptide chemistry, the application of isonitrile derivatives of amino acids has led to a variety of peptidomimetics 21 and other useful products such as blactams, 22 glycopeptides, 23 depsipeptides, 24 peptide nucleic acids, 25 and N-hydroxy peptides. 26 Amino acid ester derived isonitriles are the known entities, which are prepared from corresponding formyl amino acid esters. 27A recent entry into this new class of amino acid derived isonitriles has been described by our group wherein N bFmoc amino alkyl isonitriles were obtained through carboxyl group modification. 28Of the many methods available for the preparation of isonitriles, dehydration of formamides is the widely followed route in amino acid chemistry, showing general applicability and reproducibility. 29 Reaction of alkyl halides with heavy metal cyanide salts, 30 addition of dichlorocarbene to amines, 31 reduction of isocyanates and isothiocyanates 32 are other available routes. Dehydration of formamides has been carried out by using tosyl chloride, phosphorus oxychloride (POCl 3 ) in the presence of a base, cyanuric chloride, triphenyl phosphine-CCl 4 , phosgene, diphosgene, and triphosgene. 33 The method employing POCl 3 being quite harsh is found to cause racemization and therefore is not applicable in peptide chemistry, and isolation of enantiomerically pure isonitriles is always challenging and demanding. Danishefsky and co-workers have isolated enantiomerically pure aisocyanoesters 34 derived from formyl amino acid esters, employing triphosgene/N-methylmorpholine (NMM) at -78°C. Nenajdenko's group has synthesized the amino acid derived nonracemic isonitriles employing the less commonly used 4-methyl-2,6,7-trioxabicyclo[2.2.2] octyl-protected formyl amino ester.35 Sureshbabu et al. reported the synthesis and isolation of enantiomerically pure N-Fmoc-amino alkyl isonitriles by the dehydration of the corresponding N b -Fmoc amino alkyl formamides under neutral conditions employing Burgess' reagent.28 In a continuation of our current studies on isonitriles, we sought a simple and economically viable route involving dehydrosulfurization of N b -Fmoc amino alkyl thioformamides using cyanogen bromide (CNBr, Scheme 1). Scheme 1There has been a sur...

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Novel Indoline-Based Acyl-CoA:Cholesterol Acyltransferase Inhibitor with Antiperoxidative Activity: Improvement of Physicochemical Properties and Biological Activities by Introduction of Carboxylic Acid

Cited by 27 publications

References 31 publications

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: Indoline-Based Sulfamide Derivatives with Low Lipophilicity and Protein Binding Ratio

Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of Nβ-Fmoc-Amino Alkyl Isonitriles from Nβ-Fmoc-Amino Alkyl Thioformamides

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