- Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1S,2R)-tranylcypromine
-
Primary amidations of carboxylic acids 1 or 3 with NH4Cl in the presence of ClCO2Et and Et3N were developed to afford the corresponding primary amides in 22% to quantitative yields. Additionally, we have applied the amidation to the preparation of various amides containing hydroxamic acids and achieved the synthesis of (1S,2R)-tranylcypromine as an antidepressant medicine via Lossen rearrangement.
- Ezawa, Tetsuya,Kawashima, Yuya,Noguchi, Takuya,Jung, Seunghee,Imai, Nobuyuki
-
p. 1690 - 1699
(2017/11/14)
-
- β,γ-Diamino acid: An original building block for hybrid α/γ-peptide synthesis with extra hydrogen bond donating group
-
Using a β,γ-diamino acid, several small hybrid α/γ peptides have been synthesized and their conformations investigated through extensive NMR studies and molecular dynamics. A tripeptide and a tetrapeptide have thus shown several hydrogen bonds in solution, including a 13-membered ring involving the β-nitrogen.
- Stanovych, Andrii,Guillot, Rgis,Kouklovsky, Cyrille,Miclet, Emeric,Alezra, Valrie
-
p. 2753 - 2757
(2015/02/19)
-
- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
-
A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
-
supporting information; experimental part
p. 248 - 254
(2010/08/19)
-
- AmIno Acid Homologation by the Blaise Reaction: A new entry into nitrogen heterocycles
-
(Chemical Equation Presented) A general strategy for the amino acid homologation via Blaise reaction and subsequent reduction is presented. This strategy involves the preparation of protected α-amino nitriles from the corresponding amino acids, followed by the zinc-mediated condensation of tert-butyl bromoacetate, to give the imidazolidones after iminozincate cyclization. Reduction gave the saturated imidazolidinones with cis or trans stereochemistry, depending on the reduction conditions. This strategy was applied to nonfunctionalized amino acids and to functionalized amino acids such as serine and aspartic acid. Additionally, acidic hydrolysis of cis or trans imidazolidinones to the corresponding chiral 4-aminopyrrolidones is described.
- Cam, Thuy Hoang,Bouillere, Francelin,Johannesen, Sine,Zulauf, Anais,Panel, Cecilia,Pouilhes, Annie,Gori, Didier,Alezra, Valerie,Kouklovsky, Cyrille
-
experimental part
p. 4177 - 4187
(2009/09/08)
-
- N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides
-
(Chemical Equation Presented) Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, isolated as stable solids, and completely characterized. The procedure has been extended to the synthesis of amino alkyl isothiocyanates from Boc- and Z-protected amino acids as well. The utility of these isothiocyanates for peptidomimetics synthesis has been demonstrated by employing them in the preparation of a series of dithioureidopeptide esters. Boc-Gly-OH and Boc-Phe-OH derived isothiocyanates 9a and 9c have been obtained as single crystals and their structures solved through X-ray diffraction. They belong to the orthorhombic crystal system, and have a single molecule in the asymmetric unit (Z′ = 1). 9a crystallizes in the centrosymmetric space group Pbca, while 9c crystallizes in the noncentrosymmetric space group P212121.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Hemantha,Narendra,Das, Ushati,Guru Row, Tayur N.
-
supporting information; experimental part
p. 5260 - 5266
(2009/12/06)
-
- A Stereoselective entry into functionalized 1,2-diamines by zinc-mediated homologation of α-aminoacids
-
A general, stereoselective synthsis of 4,5-disubstituted imidazolidines-2-ones from α-aminoacids has been developed: the key steps are a Biaise reaction of bromoacetate on α-aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture of cis and trans isomers 6a-e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a-e with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to β,γ-diaminoacids or 3-aminopyrrolidines.
- Hoang, Cam Thuy,Alezra, Valerie,Guillot, Regis,Kouklovsky, Cyrille
-
p. 2521 - 2524
(2008/02/05)
-
- Protease inhibitors
-
The present invention provides compounds of formula (I) which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy; and metabolic bone disease therewith.
- -
-
-
- Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
-
The present invention relates to compounds and pharmaceutical compositions which inhibit proteases, such as cysteine proteases. In particular, the present invention relates to compounds and pharmaceutical compositions which inhibit cysteine proteases of the papain superfamily. The compounds and pharmaceutical compositions of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by such proteases. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.
- -
-
-
- PROTEASE INHIBITORS
-
Disclosed herein is a compound of the formula STR1 known as 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl) benzyloxy]carbonyl-L-leucinyl]carbohydrazide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
- -
-
-
- Protein backbone modification by novel C(α)-C side-chain scission
-
α-Ketoamide (-NH-CO-CO-) units in intact peptides are generated from Ser/Thr residues via Ru(VIII)-catalyzed C(α)-C side-chain scission. Facets associated with this novel α-carbon modification have been probed with 75 peptides chosen to represent every possible peptide environment. The reactions were carried out at room temperature with in situ generated Ru(VIII) in biphasic (CH3CN/CCl4/pH 3 phosphate buffer, 1:1:2 v/v) medium. Whereas Ser/Thr residues placed at the C-terminal end in peptides undergo N-C bond scission leading to des-Ser/Thr peptide amides - thus acting as Gly equivalents in simulating the α-amidating action of pituitary enzymes - those located at the N-terminal or nonterminal or even at the C-terminal position (protected as amide) were found to undergo oxidative C-C bond scission (involving C(α) and C side-chain bond), resulting in the generation of α-ketoamide (-NH-CO-CO-) units in the intact peptide backbone. The difference in the products arising from C(α)-C side-chain scission of Ser/Thr esters and amides is rationalized on the basis of a common mechanism involving either oxaloesters [PeP-NH-CO-COX; X = OMe] or oxalamides [X = NH2 or NH-Pep] arising from the oxidation of initially formed carbinolamide intermediates [Pep-NH-CH(OH)-COX], wherein, while the former are shown to undergo hydrolysis to terminal amides [Pep-NH2], the oxalamides are found to be stable to hydrolysis. Ancillary noteworthy findings are those of peptide bond scission when contiguous Ser-Ser/Thr-Thr residues are present and the oxidative cleavage at C-terminal Tyr/Trp sites generating des amides. The oxidative methodology presented here is mild, simple, and practical and proceeds with chiral retention. The insensitivity of a large number of amino acid residues, such as Gly, Ala, Leu, Asn, Gln, Asp, Glu, Pro, Arg, Phe, Lys, Val, and Aib, and N-protecting groups, such as Boc, Z, and Bz, toward Ru(VIII) under the experimental conditions should make this methodology practical and useful. Sulfur-containing amino acids Cys and Met get oxidized to sulfones in the products.
- Ranganathan,Vaish,Shah
-
p. 6545 - 6557
(2007/10/02)
-
- 3,3,3-TRIFLUORO-2-MERCAPTOMETHYL-N-TETRAZOLYL SUBSTITUTED PROPANAMIDES AND METHOD OF USING SAME
-
Compounds of the formula STR1 wherein Y can be tetrazolyl are disclosed. These compounds are useful as cardiovascular agents.
- -
-
-
- Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N,O-acetals: Preparation of Oligopeptides with Amide or Phosphonate C-Terminus
-
Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and di-, tri- and tetrapeptides are electrolyzed in MeOH or AcOH, with formation of N-acyl-N,O-acetals (1b - 15b, 20b), in an anodic oxidative substitution of the COOH by an OR group.The amine ends of the oligopeptides may be benzyloxycarbonyl(Z)- or (tert-butoxy)carbonyl(Boc)-protected.With unprotected dipeptides, an electrolytic decarboxylative cyclization to imidazolidinones (18c, 19c) may also occur (in H2O/NH4OAc).The electrolyses are carried out in simple flasks with cooling jackets ('undivided cell'), using constant current conditions and anodes of Pt or glassy C.The electrolyte is generated in situ by adding 10 - 20 mol-percent of a tertiary amine.Mild acidic hydrolysis of electrolysis products thus obtained may lead to amino-acid amides or peptide amides (10c, 11c, 12c, 17c) with one amino acid less than the starting material.The N,O-acetals from L-threonine and the oligopeptides also react with organometallic nucleophiles such as Grignard compounds (->21 - 26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity).By treatment of the peptide-derived (open-chain) N,O-acetals with trialkyl or triaryl phosphites/TiCl4, the RO group is replaced by a phosphodiester group in a (non-diastereoselective) Michaelis-Arbuzov-type reaction (1d, 1e, 2d - 9d, 5e).Thus, the two-step sequence of electrolysis and phosphonation converts an oligopeptide derivative to an analogue with a phosphonic-acid end group.The diastereoisomeric N-protected dimethyl and diethyl dipeptidephosphonates (also prepared from the corresponding diaryl esters by Ti(OR)4-mediated transesterification) could be separated by preparative HPLC (SiO2, Lichrosorb Si 60, 10 μm); the dextrorotatory isomers of 1d - 3d were assigned L,D-, the laevorotatory ones L,L-configuration by hydrolysis to and identification of the known amino and aminophosphonic acids.The results described demonstrate a new simple route leading, from a give oligopeptide, to pure peptide analogues of known configuration.
- Seebach, Dieter,Charczuk, Roland,Gerber, Christian,Renaud, Philippe,Berner, Heinz,Schneider, Helmut
-
p. 401 - 425
(2007/10/02)
-
- Interactions between Terminally Substituted Amino Acids in an Aqueous and a Non-Aqueous Environment. Enthalpic Interaction Coefficients in Water and in N,N-Dimethylformamide at 25 deg C
-
Enthalpies of dilution of the N-acetyl amides of glycine, L-alanine, L-valine, L-leucine, and L-phenylalanine, dissolved in N,N-dimethylformamide (DMF) as a solvent have been measured at 25 deg C.The results obtained have been analyzed to give the enthalpic interaction (or virial) coefficients of the solutes and these are compared with information previously obtained in aqueous systems.There are marked differences in the interaction properties in the two solvents and, while the additivity approache of Savage and Wood is applicable to the solutes in water it is suitable for representing the interactions in DMF.A correlation is presented between the enthalpic second virial coefficients in DMF and the propensity of side-chains to be in proximity in globular proteins.
- Kent, Hilary E.,Lilley, Terence H.,Milburn, Peter J.,Bloemendal, Michael,Somsen, Gus
-
p. 101 - 116
(2007/10/02)
-
- Dichlorotris(dimethylamino)phosphorane as a Dehydratisation Reagent for the Preparation of N-Protected Amino Acid Amides
-
Besides for the synthesis of peptides and activated esters dichlorotris(dimethylamino)phosphorane (2) now proved to be an excellent reagent for the preparation of N-protected amino acid amides.
- Appel, Rolf,Hiester, Ernst
-
p. 2037 - 2040
(2007/10/02)
-