- Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer
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A series of novel dipeptidyl boronic acid compounds were designed, synthesized and biologically investigated for the inhibition of the β5 subunit of 20S proteasome and several compounds showed high activities with IC50 values of less than 10 nM. Some of these compounds potently inhibited the multiple myeloma (MM) cancer cell lines with IC50 values of less than 10 nM. It was reported that the inhibition of both β2 and β5 subunits strongly increased the cytotoxicity of proteasome inhibitors in solid tumor cells, so some of the compounds were evaluated for the inhibition of the β2 subunit and the solid tumor triple-negative breast cancer cell line MDA-MB-231. The results showed that three compounds were active for both the β2 subunit and the triple-negative breast cancer cell line MDA-MB-231. The in vivo pharmacokinetic results showed that compound 8t had good biological parameters for both ig and iv administrations. An in vivo pharmacodynamic experiment showed that compound 8t inhibited the β5 subunit in whole blood more greatly than the marketed MLN9708 with the same dose at different time periods. A pathological analysis indicated that the injection of compound 8t in the tumor of a triple-negative breast cancer xenograft mice model led to tumor cell necrosis, nucleus condensation, deep staining, cell fragmentation, dissolution and neutrophil infiltration compared with the control group. The data in hand showed that compound 8t might be an effective candidate for the treatment of both MM and triple-negative breast cancer.
- Lei, Meng,Feng, Huayun,Bai, Enhe,Zhou, Hui,Wang, Jia,Qin, Yanru,Zhang, Haoyang,Wang, Xueyuan,Liu, Zhaogang,Hai, Ou,Liu, Jia,Zhu, Yongqiang
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p. 683 - 691
(2019/01/24)
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- Synthesis and application of peptide borate compounds
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The invention belongs to the field of drug synthesis, and specifically relates to a series of novel peptide borate compounds or pharmaceutical salts thereof, and a preparation method and pharmaceutical application thereof. The structure of the peptide borate compounds or the pharmaceutical salts thereof is as shown in a formula I which is described in the specification. The compounds of the invention can be used for preparing proteasome inhibitors, and thus can be further used for treating solid tumors and blood tumors.
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Paragraph 0142; 0157-0158; 0161-0162
(2019/12/25)
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- Non-classical N-metallated Pd(II) pincer complexes featuring amino acid pendant arms: Synthesis and biological activity
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A series of non-classical pincer ligands with the secondary amide central unit and amino acid pendant arms was obtained from 2-diphenylphosphanyl- and 2-methylsulfanylbenzoic acids and a range of amino acid derivatives (S-methyl-L-cysteine, L-methionine, and L-histidine methyl esters). In addition, the reactions of amino acid-functionalized chloroacetamides with in situ generated Ph2PSK afforded their counterparts with an aliphatic ligand backbone. All the compounds obtained smoothly underwent direct cyclopalladation upon interaction with PdCl2(NCPh)2 under mild reaction conditions, resulting in N-metallated pincer complexes with 5,6- and 6,6-membered fused metallocycles. The realization of κ3-S,N,S-, S,N,N- and S,N,P-coordination was unambiguously confirmed based on the IR and NMR spectroscopic data. In the case of the methionine-based thiophosphorylacetamide derivative, the unexpected selectivity in the formation of one complex diastereomer was observed in solution. The solid-state structures of some of the complexes obtained were also elucidated by X-ray crystallography. The preliminary investigations on cytotoxicity of the resulting palladocycles against HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 normal cells gave some insight into the structure–activity relationships for this relatively new type of potential anticancer agents. Some of the complexes demonstrated promising cytotoxic effects.
- Churusova, Svetlana G.,Aleksanyan, Diana V.,Rybalkina, Ekaterina Yu.,Nelyubina, Yulia V.,Peregudov, Alexander S.,Klemenkova, Zinaida S.,Kozlov, Vladimir A.
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- Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof
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The invention belongs to the field of drug synthesis and in particular relates to a series of novel peptide boric acids as well as an ester compound or pharmaceutical salt thereof, and a preparation method and application of the peptide boric acids as well as the ester compound or pharmaceutical salt thereof in pharmacodynamics. A structure of the peptide boric acid and the ester compound or pharmaceutical salt thereof is shown in a formula I (described in the specification). The compound provided by the invention can be used for preparing a proteasome inhibitor and can further be used for treating solid tumours and blood tumours, wherein the solid tumours are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, nasopharynx cancer and leukemia; and the blood tumours are selected from multiple myeloma, mantle cell lymphoma and histiocytic lymphoma.
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Paragraph 0137; 0138; 0141; 0142
(2016/12/01)
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- Bio-inspired nitrile hydration by peptidic ligands based on L-cysteine, L-methionine or L-penicillamine and pyridine-2,6-dicarboxylic acid
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Nitrile hydratase (NHase, EC 4.2.1.84) is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III)- and iron(III)-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate). Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L- S-methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III) and iron(III) and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III), converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers.
- Byrne, Cillian,Houlihan, Kate M.,Devi, Prarthana,Jensen, Paul,Rutledge, Peter J.
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p. 20751 - 20767
(2015/02/19)
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS FOR THE TREATMENT OF VARIOUS DISEASES
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The present invention relates to compounds capable of inhibiting and/or decreasing the activity of one or more cathepsins, thereby treating and/or preventing various disease states associated with one or more cysteine proteases including, but not limited
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Page/Page column 26
(2011/01/12)
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- Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue
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Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-dehydro-(S)-proline (Δ3Pro), azetidine-3-carboxylic acid (3Aze) and de
- Torino, Domenica,Mollica, Adriano,Pinnen, Francesco,Lucente, Gino,Feliciani, Federica,Davis, Peg,Lai, Josephine,Ma, Shou-Wu,Porreca, Frank,Hruby, Victor J.
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scheme or table
p. 4115 - 4118
(2010/04/26)
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- PRODRUGS OF INHIBITORS OF CATHEPSIN S
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The present invention provides compounds of formula (I) which are prodrugs of inhibitors of cathepsin S and as such are useful in the prevention and treatment of cathepsin S dependent diseases and conditions including, but not limited to, chronic obstruct
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Page/Page column 19
(2008/06/13)
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- Mild and highly chemoselective oxidation of thioethers mediated by Sc(OTf)3
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(Matrix presented) Catalytic Sc(OTf)3 greatly increases the efficiency of hydrogen peroxide mediated monooxidation of alkyl-aryl sulfides and methyl cysteine containing peptides. The method is high yielding, compatible with many widely used protecting groups, suitable for solid-phase applications and proceeds with minimum over-oxidation.
- Matteucci, Mizio,Bhalay, Gurdip,Bradley, Mark
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p. 235 - 237
(2007/10/03)
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- Copper(II) in Organic Synthesis. XI. Evaluation of the Ligand Architecture on the Efficiency of a Copper(II) Catalyst for Enantioselective Michael Reactions.
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Several bis-copper(II) complexes with chiral ligands derived from 2-substituted 2-(salicylideneamino)ethanols have been tested as catalysts of enantioselective Michael reactions.The degree of enantioselection is strongly affected by the architecture of the ligand.The best result (75percent e.e.) was obtained for a ligand having a substituent potentially suitable to induce the formation of a bis-tetradentate copper(II) complex with a square pyramidal coordination.
- Desimoni, Giovanni,Dusi, Guglielmo,Faita, Giuseppe,Quadrelli, Paolo,Righetti, PierPaolo
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p. 4131 - 4144
(2007/10/02)
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- A simple, high-yielding synthesis of N-t-butoxycarbonyl α-amino esters: Precursors for α-amino aldehydes
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A general one-pot, two-stage procedure is described for the preparation of the title compounds from the free amino acids in near quantitative yields.
- McNulty,Still
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p. 979 - 985
(2007/10/02)
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- Catalysis of the Methoxyaminolysis of Phenyl Acetate by a Preassociation Mechanism with a Solvent Isotope Effect Maximum
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General-acid catalysis of the reaction of methoxyamine with phenyl acetate by the proton, carboxylic acids, and ammonium ions follows a nonlinear Broensted curve.This curve agress quantitavely with the behavior expected for the enforced preassociation mechanism of catalysis that was predicted for this reaction.The stronger acids, including the proton, follow a Broensted slope of α=0.16 that represents rate-limiting amine attack assisted by hydrogen bonding, weaker acids react with partially rate-limiting proton transfer to the addition intermediate T+/-, and the weakest acids follow a steeper Broensted slope approaching α=1.0 that represents rate-limiting separation of the protonated intermediate T+.There is no decrease in the rate constant for catalysis by chloroacetic acid with increasing viscosity in water-glycerol mixtures; a decrease is observed for the reaction of methylamine with p-tolyl acetate catalyzed by acetate buffers, which is believed to proceed by a diffusion-controlled trapping mechanism.A sharp maximum in the solvent isotope effect at pKHA = 6.8 confirms the kinetically significant proton-transfer step in the intermediate region near ΔpK = 0.The decrease with stronger acids represents a decrease in the isotope effect for this proton-transfer step, which is largely rate limiting for acids of pKa = 4-7, but the decrease with weaker acids can be explained by the change to rate-limiting diffusional separation of T+ and A-.Two explanations are offered for the decreased isotope effect with increasing acid strengh. (1) There is a sharp change to an asymmetric structure of the transition state for the very rapid proton-transfer step, as suggested by Melander and Westheimer. (2) There is a shift to a rate-limiting change in solvation that occurs immediately either before or after the proton-transfer step with stronger acids.It is possible to fit the observed Broensted curve and isotope effect maximum with calculated rate constants that are based on a rate law and estimated rate constants for the steps of the latter mechanism.
- Cox, Michael M.,Jencks, William P.
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p. 572 - 580
(2007/10/02)
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