- Design and synthesis of several small-size HTLV-I protease inhibitors with different hydrophilicity profiles
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The human T cell leukemia/lymphotropic virus type 1 (HTLV-I) is clinically associated with adult T cell leukemia/lymphoma, HTLV-I associated myelopathy/tropical spastic paraparesis, and a number of other chronic inflammatory diseases. To stop the replication of the virus, we developed highly potent tetrapeptidic HTLV-I protease inhibitors. In a recent X-ray crystallography study, several of our inhibitors could not form co-crystal complexes with the protease due to their high hydrophobicity. In the current study, we designed, synthesized and evaluated the HTLV-I protease inhibition potency of compounds with hydrophilic end-capping moieties with the aim of improving pharmaceutic and pharmacokinetic properties.
- Nguyen, Jeffrey-Tri,Kato, Keiko,Hidaka, Koushi,Kumada, Henri-Obadja,Kimura, Tooru,Kiso, Yoshiaki
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supporting information; experimental part
p. 2425 - 2429
(2011/06/17)
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- A practical and convenient synthesis of the protease inhibitor epibestatin
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A convenient synthesis of the protease inhibitor epibestatin, a useful component in protease inhibition cocktails for use in proteomics research, is described. The synthesis sequence consists of seven steps, starting from phenylacetaldehyde, yielding enantiopure epibestatin in 8% overall yield. A regioselective Mitsunobu transformation of a diol is the key step in the sequence. Georg Thieme Verlag Stuttgart.
- Richter, Anja,Hedberg, Christian
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experimental part
p. 2039 - 2042
(2010/08/13)
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- PROCESSES FOR PRODUCING OXAZOLIDINONE DERIVATIVE OF BETA-HYDROXYETHYLAMINE COMPOUND AND FOR PRODUCING BETA-HYDROXYETHYLAMINE COMPOUND
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The present invention provides a process of starting from N-alkoxycarbonyl-ethylamine compounds having a leaving group at the β-position to prepare oxazolidinone derivatives of β-hydroxyethylamine compounds having an inverted steric configuration at the β
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- PROCESS FOR PRODUCING 3-AMINO-2-HYDROXYPROPIONIC ACID DERIVATIVES
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The present invention provides a process for preparing 3-amino-2-hydroxypropionic acid derivatives (1) which does not use dangerous reagents, is economically advantageous, and is suitable for an industrial production, which process comprises:treating N-protected-3-amino-2-hydroxypropionic acid derivatives (2) having a steric configuration at 2-position carbon reverse to that of derivatives (1) with a leaving group-introducing agent to convert into N-protected-3-aminopropionic acid derivatives (3),then treating the derivatives with a basic substance to convert into substituted-3-amino-2-hydroxypropionic acid derivatives (4) having an inverted steric configuration at 2-position carbon,and then converting the derivatives into 3-amino-2-hydroxypropionic acid derivatives (1).
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- Production method of beta-amino-alpha-hydroxycarboxylic acid
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The present invention provides a production method of an optically active β-amino-α-hydroxycarboxylic acid, which includes the following steps (a)-(c): (a) treating an optically active N-carbamate protected β-amino epoxide with an acid to give an optically active 5-hydroxymethyl-2-oxazolidinone; (b) oxidizing the resulting compound in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy and hypochlorite to give an optically active 4-benzyl-2-oxo-5-oxazolidinecarboxylic acid; and (c) treating the 4-benzyl-2-oxo-5-oxazolidinecarboxylic acid with a base, and a production method of an optically active N-carbamate protected β-amino-α-hydroxycarboxylic acid which includes protection of the amino group with a carbamate type protecting group. The industrial production method of the present invention can produce these compounds efficiently.
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- Process for producing alpha-aminoketone derivatives
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A process for producing α-amino-dihalogenated methyl ketone derivatives by reacting an N-protected α-amino acid ester with a dihalomethyl lithium is provided. This process is suitable for the production on an industrial scale and by this process, α-amino-
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- A concise synthesis of (2S,3S)-BocAHPBA and (R)-BocDMTA, chiral building blocks for peptide-mimetic HIV protease inhibitors
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Scalable syntheses of (2S,3S)-3-N-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (BocAHPBA) 1 and (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid (BocDMTA) 2 have been developed. Both 1 and 2 can serve as chiral building blocks in assembling JE-2147 (KNI-764) 3, a potent HIV protease inhibitor. The synthesis of (2S,3S)-BocAHPBA 1 is achieved in 41% overall yield from (S)-2-N,N-dibenzylamino-3-phenylpropanal 4 in five steps where Tamao's reagent [Me2(i-PrO)SiCH2MgCl] is employed for a one-carbon homologation, and Zhao's oxidation protocol (TEMPO, NaClO2, NaClO) is applied to convert a 1,2-glycol moiety into an α-hydroxy acid motif. (R)-BocDMTA 2 is synthesized with 99.4% ee in 24% yield via enantioselective hydrolysis of methyl (±)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate 8b by a Klebsiella oxytoca hydrolase; the unreacted (S)-ester 8b can be recovered and racemized with NaOMe to afford (±)-8b in 46% yield for another round of the enzymatic processing.
- Ikunaka, Masaya,Matsumoto, Jun,Nishimoto, Yukifumi
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p. 1201 - 1208
(2007/10/03)
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- Dihalomethylation of N-protected phenylalanine esters
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Dihalomethylation of several N-protected amino acid esters gave N-protected α-aminoalkyl-α′-dihalomethylketones, which are useful intermediates for the synthesis of erythro β-amino-α-hydroxycarboxylic acids, in good yield. The dihalomethylketones were successfully converted to N-protected α-aminoalkyl-α′-halomethylketones by selective catalytic hydrogenation.
- Onishi, Tomoyuki,Otake, Yasuyuki,Hirose, Naoko,Nakano, Takashi,Torii, Takayoshi,Nakazawa, Masakazu,Izawa, Kunisuke
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p. 6337 - 6340
(2007/10/03)
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- Synthesis of di- and tripeptide analogues containing α-ketoamide as a new core structure for inhibition of HIV-1 protease
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Di- and tripeptide analogues containing α-ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert·butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective α-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The α-keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu1 with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 μM and 50 nM levels of the di- and tripeptides respectively. The α-ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Sheha, Mahmoud M.,Mahfouz, Nadia M.,Hassan, Hoda Y.,Youssef, Adel F.,Mimoto, Tsutomu,Kiso, Yoshiaki
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p. 887 - 894
(2007/10/03)
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- Process for preparing beta -amino- alpha -hydroxy acid derivatives
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PCT No. PCT/JP97/02844 Sec. 371 Date May 14, 1999 Sec. 102(e) Date May 14, 1999 PCT Filed Aug. 18, 1997 PCT Pub. No. WO98/07687 PCT Pub. Date Feb. 26, 1998An object of the present invention is to provide a process for producing a beta -amino- alpha -hydro
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- Development of selective tight-binding inhibitors of leukotriene A4 hydrolase
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Leukotriene A4 hydrolase is a zinc-containing enzyme which exhibits both epoxide hydrolase and aminopeptidase activities. Since the enzyme product leukotriene B4 is an inflammatory mediator, it is of interest to develop selective inh
- Yuan,Munoz,Wong,Haeggstrom,Wetterholm,Samuelsson
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p. 211 - 220
(2007/10/02)
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