- Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
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Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
- Osko, Jeremy D.,Porter, Nicholas J.,Narayana Reddy, Poli Adi,Xiao, You-Cai,Rokka, Johanna,Jung, Manfred,Hooker, Jacob M.,Salvino, Joseph M.,Christianson, David W.
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- Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent
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Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg-1 dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 104 M-1 and ΔG of -100.3 kJ mol-1 in comparison to a Ka 0.41 × 103 ± 0.09 M-1 and ΔG of -19.2 ± 0.06 kJ mol-1 for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg-1 dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
- Singh, Palwinder,Kaur, Sukhmeet,Kaur, Jagroop,Singh, Gurjit,Bhatti, Rajbir
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p. 3920 - 3934
(2016/05/24)
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- Zinc-catalyzed amide cleavage and esterification of β- hydroxyethylamides
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Snipping tool: Zn(OTf)2 is an efficient catalyst for selective cleavage of amides bearing a β-hydroxyethyl group on the nitrogen atom. The mechanism involves an N,O-acyl rearrangement and transesterification. This new catalytic system can be applied to sequence-specific peptide bond scission at the amine side of a serine residue. Tf=trifluoromethanesulfonyl. Copyright
- Kita, Yusuke,Nishii, Yuji,Higuchi, Takafumi,Mashima, Kazushi
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supporting information; body text
p. 5723 - 5726
(2012/08/07)
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- METHOD FOR PRODUCING BIVALIRUDIN
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A method for producing bivalirudin using solid phase peptide synthesis by: a) condensing Fmoc-Asn(Trt)-Gly-OH with a peptide resin of Asp(OtBu)11-Phe12-Glu(OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu(OtBu)18-Tyr(tBu)19-Leu20-Resin; b) removing Fmoc-; c) condensing Fmoc-Gly-Gly-Gly-Gly-OH with the peptide resin; d) separately condensing Pro, Arg, Pro, and Phe with the peptide resin from C-terminal to N-terminal to yield a peptide resin of Boc-D-Phe1-Pro2-Arg(Pbf)3-Pro4-Gly5-Gly6-Gly7-Gly8-Asn(Trt)9-Gly10-Asp(OtBu)11-Phe12-Glu(OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu(OtBu)18-Tyr(tBu)19-Leu20-Resin; and e) in the presence of a cleavage agent, separating a peptide from the peptide resin to yield bivalirudin represented by Formula VI. The method is low in cost and the resultant bivalirudin has high purity.
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- Synthesis and transformation of N,N-dimethylamino-methylidene derivatives of indolylglycines and some other dipeptides
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Indolyl glycinates (3, 7, and 11) were transformed with t-butoxybis(dimethylamino)methane (Bredereck's reagent) into 3-[(dimethylamino)methylidene]-2,3-dihydropyrazino[1,2-a]indole-1,4-dione (4),3-(dimethylamino)-2-[(1H-indol-3-ylcarbonyl)amino]propenoate
- Jakse, Renata,Golic, Ljubo,Meden, Anton,Groselj, Uros,Svete, Jurij,Stanovnik, Branko
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p. 293 - 307
(2008/09/17)
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- Peptide synthesis in room temperature ionic liquids
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We demonstrate that chemical peptide coupling using modern coupling agents is efficient in rt ionic liquids. This new approach presents some advantages, especially in the case of hindered amino acids, which are not easy to couple under standard conditions
- Vallette, Hélène,Ferron, Laurent,Coquerel, Gérard,Gaumont, Annie-Claude,Plaquevent, Jean-Christophe
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p. 1617 - 1619
(2007/10/03)
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- Polymer-bound N-hydroxysuccinimide as a solid-supported additive for DCC-mediated peptide synthesis
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Polymer-supported N-hydroxysuccinimide (P-HOSu) has been prepared from a styrene/maleic anhydride co-polymer and used as an easily removable activating and racemization-reducing additive for the peptide coupling of amino acid derivatives using DCC.
- Chinchilla, Rafael,Dodsworth, David J.,Nájera, Carmen,Soriano, José M.
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p. 4487 - 4489
(2007/10/03)
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- Intermolecular Aminolyses of 1-Thioglycosyl Esters of N-Acylamino Acids
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Fully acetylated 1-thioglycopyranosyl esters of N-acylamino acids (1-3), comprising different 1-thio sugars, undergo aminolysis with glycine methyl ester in dichloromethane at 40° to form the corresponding N-acyldipeptide methyl esters. The relative reactivity of the C-1 thioester bond towards aminolysis depends inter alia on the structure of the sugar moiety. Acylating efficiency of the 1-thioesters was additionally demonstrated by aminolysis of 2,3,4,6-tetra-O-acetyl-1-S-(N-tert-butyloxycarbonyl-L-tyrosyl)-1-thio-β-D- glucopyranose (3h) with peptidoglycan monomer (PGM, a disaccharide-pentapeptide) in N,N-dimethylformamide at room temperature to give the corresponding disaccharide-hexapeptide.
- Ljevakovic, Durdica,Tomic, Srdanka,Tomasic, Jelka,Horvat, Jaroslav
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p. 1329 - 1337
(2007/10/03)
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- A novel and versatile route to mixed p-toluenesulphonic carboxylic anhydrides
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A versatile route to the mixed p-toluenesulphonic carboxylic anhydrides (1) via the reaction of tetra-n-butylammonium carboxylate (2) with p-toluenesulphonyl chloride in a neutral medium is described.Some of the synthetic applications of the proposed method are described.
- Kumar, Arvind,Srivastava, Nivedita,Mital, Alka
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p. 606 - 607
(2007/10/02)
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- KINETICS OF THE ALKALINE HYDROLYSIS OF SEVERAL N-BENZYLOXYCARBONYLDIPEPTIDE METHYL AND ETHYL ESTERS
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The reaction rates of the alkaline hydrolysis of synthesized N-protected dipeptide methyl and ethyl esters were studied systematically.From the kinetic data the energies of activation, the pre-exponential factors and the reference values at 40 deg C were calculated.The rate of hydrolysis shows to be strongly dependent on the C-terminal amino acid in the sequence Gly >> Ala/Met/Phe > Leu >> Val/Pro.Surprisingly the N-terminal amino acid also exerts an effect, but in a different sequence.N-Terminal Phe in particular shows a relative accelerating effect.Remarkable is the significantly faster ester hydrolysis of glycine containing dipeptide ethyl esters in ethanol/water compared to the corresponding methyl esters in methanol/water.
- Hoogwater, D. A.,Peereboom, M.
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p. 5325 - 5332
(2007/10/02)
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- Synthesis of Peptides with α,β-Dehydroamino Acids, V. - Coupling Experiments with C-terminal Dehydrophenylalanine and Dehydroalanine Residues
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N-Protected model dipeptides of C-terminal (Z)-ΔPhe and ΔAla couple with glycine esters after activation with either diphenyl phosphorazidate (DPPA), N-cyclohexyl-N'-carbodiimide p-toluenesulfonate (WSC), N,N'-dicyclohexylcar
- Makowski, Maciej,Rzeszotarska, Barbara,Kubica, Zbigniew,Pietrzynski, Grzegorz,Hetper, Jacek
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p. 980 - 991
(2007/10/02)
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- PEPTIDE BOND FORMATION BY INTERMOLECULAR AMINOLYSIS OF D-GLUCOPYRANOSYL ESTERS OF AMINO ACIDS
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The reaction of HO-protected and -unprotected D-glucopyranosyl esters of N-acylamino acids (Gly, Ala, Phe) with glycine and phenylalanine methyl esters in N,N-dimethylformamide at 38 deg C and dichloromethane at 40 deg C, respectively, led to repture of the C-1 ester bond and formation of the corresponding N-acyldipeptide methyl ester.The relative reactivity of the C-1 ester bond toward aminolysis was greatly influenced by the structure of the amino acid nucleophile, the nature of the aglycon side-chain group, and the anomeric configuration of the D-glucopyranosyl ester involved.Evidence for a substantially lower acylating efficiency of the ester at C-2, as compared to that at C-1, was obtained by aminolysis of two fully acetylated 2-O-(acylaminoacyl)-β-D-glucopyranoses.Treatment of 1-O-(glycylglycylglycyl)-β-D-glucopyranose with phenylalanine methyl ester in N,N-dimethylformamide led to parallel hydrolysis and intermolecular aminolysis, to give the tripeptide and tetrapeptide methyl ester.
- Horvat, Stefica,Keglevic, Dina
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