- Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase
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Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to L-homocysteine, yielding dimethylglycine and L-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH3), or N(CH 3)2 groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH3) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.
- Vaněk, Václav,Budě?ínsky, Milo?,Kabeleová, Petra,?anda, Miloslav,Koz?í?ek, Milan,Han?lová, Ivona,Mládková, Jana,Brynda, Ji?í,Rosenberg, Ivan,Koutmos, Markos,Garrow, Timothy A.,Jirá?ek, Ji?í
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supporting information; experimental part
p. 3652 - 3665
(2010/04/30)
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- 2-SULFONYLAMINO-4-HETEROARYL BUTYRAMIDE ANTAGONISTS OF CCR10
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This invention relates to a compound of formula (I) and the pharmaceutically acceptable salts thereof wherein R1, R2, R4. Ar and Het are as defined herein. The invention also relates to methods of using the compound of for
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Page/Page column 134-135
(2009/11/29)
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- Cyclic hydroxamates, especially multiply substituted [1,2]oxazinan-3-ones
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Routes to putative N-acyl-D-ala-D-ala surrogates, beginning with the conversion of 4-, 5-, and 6-membered lactones into 5-, 6-, and 7-membered cyclic hydroxamates, are reported. The key step of the synthesis is trimethylaluminium-promoted cyclization of an ω-aminooxyester. The 7-membered cyclic hydroxamate crystallizes in a chair conformation. Extension of the reaction sequence to homoserine or homoserine lactone leads to cyclocanaline and N-acylated cyclocanalines. The 4-phenylacetamido derivative of cyclocanaline crystallizes in a boat conformation. The attachment of a 2-carboxypropyl substituent to the ring nitrogen of a 4-acylaminocyclocanaline has been effected, prior to cyclization, by coupling of the acyclic aminooxyester precursor to the triflate of benzyl lactate or, after cyclization, by coupling to tert-butyl α-bromopropionate in the presence of potassium fluoride - alumina, followed by removal of the protecting group in each case. A six-membered homolog of the antibiotic lactivicin has been synthesized by the reaction of 4-phenylacetamidocyclocanaline with benzyl 2-oxoglutarate in the presence of carbodiimide, followed by hydrogenolysis. Starting with methyl 2,4-dibromo-2,4-dideoxy-L-erythronate, which is available in two steps from L-ascorbic acid, these reaction sequences have been applied to the stereospecific synthesis of a D-alanine derivative whose nitrogen atom is enclosed within a 3,4-disubstituted [1,2]oxazinan-3-one.
- Wolfe, Saul,Wilson, Marie-Claire,Cheng, Ming-Huei,Shustov, Gennady V.,Akuche, Christiana I.
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p. 937 - 960
(2007/10/03)
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- Efflux pump inhibitors
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Compounds are described which have efflux pump inhibitor activity. Also described are methods of using such efflux pump inhibitor compounds and pharmaceutical compositions which include such compounds.
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- Platelet aggregation inhibitors
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This invention relates to compounds having the following formula STR1 or a pharmaceutically acceptable salt thereof which are useful in the inhibition of platelet aggregation, to pharmaceutical compositions of such phenylamidines derivatives, and to a method of inhibiting platelet aggregation in mammals by administering such compounds and compositions.
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- Synthesis of (+/-)-Thienamycin based on a New Approach to β-Lactams via 4-Exo-trig Cyclisation of Carbamoylcobalt Salophens
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A series of N-propenyl substituted N-benzylcarbamoylcobalt(III) salophens, i.e., 11, 20 and 30, have been prepared, and have been shown to be useful precursors in a new approach to β-lactams (viz. 12 - 16, 21 and 31) via 4-exo-trig-modes of cyclisation of
- Pattenden, Gerald,Reynolds, Stephen J.
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p. 379 - 386
(2007/10/02)
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- Lithiation of N-Boc-2-methyltetrahydro-1,3-oxazine: A Synthetic Equivalent for 1-Lithio-3-hydroxy-1-propylamine
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A α-metalo amine synthetic equivalent of an unactivated primary amine, 1-lithio-3-hydroxy-1-propylamine (7) is provided by the lithiation of N-Boc-2-methyltetrahydro-1,3-oxazine (8) to give 9 which on reaction with electrophiles and hydrolysis gives derivatives of 1-substituted 3-hydroxy-1-propylamines 10-24.
- Beak, Peter,Yum, Eul Kgun
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p. 823 - 824
(2007/10/02)
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