- Design, synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors
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We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC50 = 31 μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50 = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3h in vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.
- Shibuya, Kimiyuki,Kawamine, Katsumi,Miura, Toru,Ozaki, Chiyoka,Edano, Toshiyuki,Mizuno, Ken,Yoshinaka, Yasunobu,Tsunenari, Yoshihiko
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p. 4001 - 4013
(2018/06/26)
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- RENEWABLY DERIVED POLYAMIDES AND METHODS OF MAKING THE SAME
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Methods of making polyamides from renewable materials, such as natural oils, are generally disclosed herein. In some embodiments, the polyamides are nylon-10. In some such embodiments, nylon-10 is made by polymerizing 10-aminodecanoic acid, or esters thereof. In some further such embodiments, the 10-aminodecanoic acid monomers (or esters thereof) are derived from natural oils via the metathesis of unsaturated fatty acid moieties of the natural oil.
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- Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl- 4(1H)-quinolones
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A series of 23 new 1-methyl-2-alkenyl-4(1H)quinolones have been synthesized and evaluated in vitro for their antimycobacterial activities against fast growing species of mycobacteria, such as Mycobacterium fortuitum, M. smegmatis and M. phlei. The compounds displayed good to excellent inhibition of the growth of the mycobacterial test strains with improved antimycobacterial activity compared to the hit compound, evocarpine. The most active compounds, which possessed chain length of 11-13 carbons at position-2 displayed potent inhibitory effects with an MIC value of 1.0 mg/L. In a human diploid embryonic lung cell line, MRC-5 cytotoxicity assay, the alkaloids showed weak to moderate cytotoxic activity. Biological evaluation of these evocarpine analogues on the less pathogenic fast growing strains of mycobacteria showed an interesting antimycobacterial profile and provided significant insight into the structure-activity relationships.
- Wube, Abraham A.,Hüfner, Antje,Thomaschitz, Christina,Blunder, Martina,Kollroser, Manfred,Bauer, Rudolf,Bucar, Franz
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experimental part
p. 567 - 579
(2011/03/17)
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- Syntheses and physical properties of ferrocene derivatives (XIII)
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Two monosubstituted ferrocene derivatives, 8-[4-(4-methoxyphenoxycarbonyl)phenoxycarbonyl]octyl 4-ferrocenylbenzoate (MPAF-8) and 9-[4-(4-methoxyphenoxycarbonyl)phenoxycarbonyl] nonyl 4-ferrocenylbenzoate (MPAF-9), were synthesized and their phase transition behavior was studied using a differential scanning calorimeter, a polarizing microscope and an X-ray diffractometer. MPAF-8 exhibited two liquid crystalline phases in both heating and cooling processes at approximately room temperature. In the heating process, a crystal-crystal phase transition behavior was ascertained. The phase transition behavior of MPAF-9 was very similar to that of MPAF-8 except for the behavior of the crystal-crystal phase transition in the heating process. In MPAF-8, one crystalline phase was transformed into another crystalline phase completely. On the other hand, this transformation was observed in part in MPAF-9, and as a result, the melting behavior was observed two times in the heating process.
- Nakamura,Setodoi,Hanasaki
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- Cyclo-depolymerisation of polyundecanoate and related polyesters: Characterisation of cyclic oligoundecanoates and related cyclic oligoesters
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The cyclo-depolymerisation of linear polyundecanoate has been studied in detail. The cyclic oligomers produced were characterised by gel permeation chromatography, 1H NMR spectroscopy and mass spectroscopy in comparison with the corresponding linear oligomers. A sample of the cyclic dimer was isolated and its crystal structure determined. Cyclic oligooctanoates, oligodecanoates and oligododecanoates were prepared similarly. The ring-opening polymerisation of the cyclic oligoundecanoates was briefly investigated.
- Ruddick, Clare L.,Hodge, Philip,Zhuo, Yang,Beddoes, Roy L.,Helliwell, Madeleine
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p. 2399 - 2405
(2007/10/03)
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- Identification and biosynthesis of (E,E) -10,12-Tetradecadienyl acetate in spodoptera littoralis female sex pheromone gland
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A miner component of the sex pheromone gland of the Egyptian cotton leafworm, Spodoptera littoralis, has been identified as (E,E)-10,12-tetradecadienyl acetate. Structural elucidation has been carried out by isobutane-chemical ionization mass spectrometry of the fatty acyl biosynthetic precursor-derived methyl ester. To assign the stereochemistry of the double bonds, the four isomers of both 10,12-tetradecadienyl acetates and methyl 10,12-tetradecadienoates have been synthesized and their gas chromatography retention times and mass spectra have been compared to those of the corresponding natural compounds. Mass-labeling experiments showed that the (E,E)-10,12-tetradecadienoyl moiety is biosynthetically derived from (Z)-11-tetradecenoic acid in the insect pheromone gland.
- Navarro, Isabel,Mas, Esther,Fabrias, Gemma,Camps, Francisco
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p. 1267 - 1274
(2007/10/03)
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- Synthesis of Very Long Fatty Acid Methyl Esters
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Phosphoranes, produced by treating alkyltriphenylphosphonium bromides with lithium hexamethyldisilazide, reacted with ω-oxo esters to give modest yields of the corresponding methyl cis-alkenoates.By an alternative method, treatment of ω-iodo esters with the complexes formed from reactions of alkylcopper(I) and Grignard reagents gave methyl alkanoates, cis-alkenoates, and methylene-interrupted cis,cis-alka-dienoates and cis,cis,cis-trienoates.The stereochemical integrity of the esters was determined by 13C NMR spectroscopy.
- Kling, Marcel R.,Easton, Christopher J.,Poulos, Alf
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p. 1183 - 1190
(2007/10/02)
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- Cyclization of 9-Substituted Decanoic Acid Derivatives to 9-Decanolide and 9-Decanelactam
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Several standard and some novel cyclization reactions have been applied to 9-substituted decanoic acids to establish which are the optimum procedures for lactonization and lactamization at 80 deg C under identical high-dilution conditions.The methods of Galli-Mandolini and Kellogg (cyclization of 9-bromodecanoate ion), Gerlach (cyclization of S-2-pyridyl 9-hydroxydecanethioate in the presence of AgClO4), and Yamaguchi (activation of the carboxyl group as a mixed anhydride) in the presence of an excess of DMAP appear to be the most useful for the preparation of the 10-membered lactone, phoracantolide I, under these conditions.Analogously, treatment of S-2-pyridyl 9-azidodecanethionate with Sn(SePh)3(1-) afforded the best yield of the 10-membered lactam.The mixed anhydrides RCOOCOAr (Ar = 2,4,6-trichlorophenyl) are more reactive than thioesters RCOSPy (Py = 2-pyridyl) with benzyl alcohol or benzylamine; it is confirmed that the addition of DMAP activates the reaction of alcohols with mixed anhydrides much more than with pyridyl thioesters, while the addition of Ag(1+) strongly activates RCOSPy in relation to either RCOOCOAr or RCOOSO2Mes.
- Bartra, Marti,Vilarrasa, Jaume
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p. 5132 - 5138
(2007/10/02)
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