- Optimization and anti-cancer properties of fluoromethylketones as covalent inhibitors for ubiquitin C-terminal hydrolase L1
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The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 μM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.
- Chen, Hao,Das, Chittaranjan,Flaherty, Daniel P.,Galardy, Paul J.,Hewitt, Chad S.,Hussain, Sajjad,Imhoff, Ryan D.,Krabill, Aaron D.,Muli, Christine S.,Wendt, Michael K.
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supporting information
(2021/05/31)
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- Legumain Activated Doxorubicin Derivative as well as Preparation Method and Application Thereof
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The present invention discloses doxorubicin derivatives for targeted activation by Legumain, its preparation method and use. The doxorubicin derivatives are obtained by condensation between the amino group of compound A and the carboxyl group of compound B and have the following structure: compounds A and B have the following structures, respectively: wherein R3 in compound B is Leu or absent; R4 is any one amino acid selected from the group consisting of Ala and Thr; R5 is any one amino acid selected from the group consisting of Ala, Thr and Asn; R6 is wherein n=1-20; or wherein R7 is substituted or unsubstituted, linear or branched, saturated or unsaturated C1-C20 fatty hydrocarbon, or substituted or unsubstituted C6-C20 aromatic hydrocarbon. The doxorubicin derivatives of the present invention are specifically tumor-targeted and have a long in vivo metabolic half-life, as compared with doxorubicin. They exhibit an efficient and safe anti-tumor effect and could be used to prepare an anti-tumor drug.
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Paragraph 0041; 0044; 0045
(2019/05/18)
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- Legumain Activated Doxorubicin Derivative as well as Preparation Method and Application Thereof
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The present invention discloses doxorubicin derivatives for targeted activation by Legumain, its preparation method and use. The doxorubicin derivatives are obtained by condensation between the amino group of compound A and the carboxyl group of compound B and have the following structure: compounds A and B have the following structures, respectively: wherein R3 in compound B is Leu or absent; R4 is any one amino acid selected from the group consisting of Ala and Thr; R5 is any one amino acid selected from the group consisting of Ala, Thr and Asn; R6 is wherein n=1-20; or wherein R7 is substituted or unsubstituted, linear or branched, saturated or unsaturated C1-C20 fatty hydrocarbon, or substituted or unsubstituted C6-C20 aromatic hydrocarbon. The doxorubicin derivatives of the present invention are specifically tumor-targeted and have a long in vivo metabolic half-life, as compared with doxorubicin. They exhibit an efficient and safe anti-tumor effect and could be used to prepare an anti-tumor drug.
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Paragraph 0041; 0044; 0045
(2017/05/07)
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- SPECIFICALLY ACTIVATED MICROMOLECULAR TARGET COUPLING BODY IN TUMOR MICROENVIRONMENT AND USE THEREOF
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Provided are an anticancer compound comprising a cleavable linker specifically activated in a tumor microenvironment, and use thereof. The anticancer compound is represented by the following formula, wherein, R1 is a normal functional group or a protection group; R2 is Ala, Thr, Val or Ile; R3 is Ala, Val or Asn; R4 is a drug group linked via a hydroxyl group or an amino group; and the general formula of the drug is R4H. The anticancer compound is only activated at a local portion of a tumor, thus avoiding the defect of immune system damage of a traditional chemotherapeutic drug, and promoting tumor immunization by removing a tumor immunosuppression cell. The anticancer compound or pharmaceutical composition thereof is jointly used with immunotherapy, thus improving the effect of treating the tumor, and effectively inhibiting tumor metastasis and osseous metastasis.
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Paragraph 0080; 0083; 0084; 0227; 0229
(2017/07/14)
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- Carboxypeptidase from Streptomyces bikiniensis: Primary structure, isolation, and properties
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A metallocarboxypeptidase produced by Streptomyces bikiniensis 27 strain (VKPM Ac-1783) (CPSb) was purified and characterized. The enzyme cleaves both basic and hydrophobic C-terminal amino acid residues from synthetic peptides, that is, it possesses specificity of mammalian carboxypeptidases A and B. The enzyme also hydrolyzes peptides bearing glutamic acid at the C-end. CPSb exhibits its maximal activity at pH 7.0-7.6 and 55°C. The nucleotide sequence encoding the mature CPSb in S. bikiniensis 27 (VKPM Ac-1783) genome (Accession No. GU362077) was determined. It is shown that the primary structure of the mature enzyme has a moderate degree of identity with orthologs from Streptomyces griseus (79% identity) and Streptomyces avermitilis (85% identity).
- Serkina,Zalunin,Levitin,Voejkova,Tyaglov,Novikova,Emeljanova,Konstantinova,Chestukhina
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experimental part
p. 1032 - 1038
(2011/11/06)
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- Synthesis of peptide aldehydes via enzymatic acylation of amino aldehyde derivatives
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Two ways for semi-enzymatic preparation of the peptide aldehydes are proposed: (1) enzymatic acylation of amino alcohols with acyl peptide esters and subsequent chemical oxidation of the resulting peptide alcohols with DMSO/acetic anhydride mixture or (2) enzymatic acylation of the preliminarily obtained by a chemical route amino aldehyde semicarbazones. Subtilisin 72, serine proteinase with a broad specificity, distributed over macroporous silica, was used as a catalyst in both cases. Due to the practical absence of water in the reaction mixtures the yields of the products in both enzymatic reactions were nearly quantitative. The second way seems to be more attractive because all chemical stages were carried out with amino acid derivatives, far less valuable compounds than peptide ones. A series of peptide aldehydes of general formula Z-Ala-Ala-Xaa-al (where Xaa-al=leucinal, phenylalaninal, alaninal, valinal) was obtained. The inhibition parameters for these compounds, in the hydrolysis reactions of corresponding chromogenic substrates for subtilisin and α-chymotrypsin, were determined. Copyright (C) 1999 Elsevier Science Ltd.
- Voyushina, Tatiana L.,Potetinova, Joanna V.,Milgotina, Ekaterina I.,Stepanov, Valentin M.
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p. 2953 - 2959
(2007/10/03)
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- Characterization of acyl adenyl anhydrides: Differences in the hydrolytic rates of fatty acyl-AMP and aminoacyl-AMP derivatives
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An improved procedure has been developed to prepare RCOOPO2-Ado (R = C6H13 and C15H31), the intermediate in the enzymatic synthesis of acyl-CoA's. The product has been characterized by spectral methods which, in turn, were used to define the hydrolysis rates of RCO-AMP. When R is a fatty acyl group, the hydrolysis rate is 10-fold slower than when R is aminoacyl. In both cases, the hydrolysis rate is enhanced by Mg2+. We speculate that the rate acceleration is due to intramolecular participation of the second carbonyl group in the aminoacyl residue.
- Schall, Otto F.,Suzuki, Iwao,Murray, Clare L.,Gordon, Jeffrey I.,Gokel, George W.
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p. 8661 - 8667
(2007/10/03)
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- Selective deprotection of phenacyl, benzyl and methyl esters of N-protected amino acids and dipeptides and N-protected amino acids benzyl ester linked to resins with bis(tributyltin) oxide
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Phenacyl, methyl and benzyl esters of various N-α-Boc, N-α-Cbz or N,N-dimethylamino protected amino acids and dipeptides, as well as esters of N-α-protected amino acids linked to Wang and Pam resins have been efficiently and chemoselectively cleaved by bis(tributyltin) oxide in aprotic solvents to give the corresponding carboxylic acids in good yields. Moreover, the absence of racemization during the deprotection has been demonstrated. A limitation of the method is the instability of the N-ε-Fmoc group in the amino acid esters 8 and 10, N-α-Fmoc-L-alanine linked to Wang resin 23 and the Cbz protecting groups in N-α-Boc-N-ε-Cbz-L-lysine benzyl and methyl esters (5 and 7), respectively, and N-α-Cbz-L-alanyl-L-alanine methyl ester 19. In the case of N-α-protected dipeptides, there was no evidence of free amino acid which indicates that the peptide bond is unaffected.
- Salomon, Claudio J.,Mata, Ernesto G.,Mascaretti, Oreste A.
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p. 995 - 999
(2007/10/03)
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- N-BENZHYDRYL-GLYCOLAMIDE ESTERS (OBg ESTERS) AS CARBOXYL PROTECTING GROUPS IN PEPTIDE SYNTHESIS
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N-benzhydryl-glycolamide esters (OBg esters) of various N-protected amino acids have been synthesized.In order to demonstrate their usefulness in peptide chemistry, the syntheses of For-Met-Leu-Phe-OH (chemiotactic peptide) and Pro-Leu-Gly-NH2 (MIF) have been carried out.OBg esters are compatible with commonly used protecting groups and are cleanly and selectively removed in mild alkaline conditions without any side reaction, except for β-benzyl aspartyl containing sequences.
- Amblard, Muriel,Rodriguez, Marc,Martinez, Jean
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p. 5101 - 5108
(2007/10/02)
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- UTILISATION DES HYDROLASES EN CHIMIE ORGANIQUE: SYNTHESE DE LIAISONS ESTER ET AMIDE CATALYSEE PAR LA PAPAINE INDUSTRIELLE
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The use of hydrolases in organic chemistry: synthesis of amide and ester bonds catalyzed by industrial papain.Industrial papain, which is readily available, catalyzed the synthesis of L-Z-alanine ethyl ester (L-ZAEt) in organic medium, under different conditions, with good yields.L-ZAEt was obtained from DL-Z-alanine with 100 percent optical purity.We studied the effects of pH, the solvent/substrate and papain/substrate ratios and the type of organic solvent added, on the L-ZAEt yield.Unreactive D-ZA was also easily isolated from the aqueous phase with good optical purity.This attractive method has been applied to other N-Z-amino acid esters with the same succes.This procedure has been developed for the preparation of peptides using carboxylic or phosphonic substrates.These peptides have anti-bacterial activity. enzymatic catalysis / papain / chymopapain / stereospecific esterification of carboxylic amino acids / dipeptides / phosphonopeptides / anti-bacterial activity
- Moriniere, Jean-Luc,Danree, Bernard,Guy, Alain
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p. 347 - 358
(2007/10/02)
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- Thermitase - A Thermostable Serine Protease. II. Synthesis of Substrate Analogous Peptide Chloromethyl Ketones as Irreversibly Acting Inhibitors
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The preparation of dipeptide to pentapeptide chloromethyl ketones of alanine with variation of the amino acid in the P1 and P2 position of the peptides is described.The synthesis is performed by fragment condensation of N-acylated amino acids or peptides with the unprotected chloromethyl ketone derivatives of amino acids and peptides, respectively.Some examples of enzyme inactivation by peptide chloromethyl ketones are discussed.
- Jahreis, Guenther,Smalla, Kornelia,Fittkau, Siegfried
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- Peptide-bond Formation, Chemoselective Acylation of Amino Acids, and Crosslinking Reaction between Amino Acids Utilizing a Functional Five-membered Heterocycle, 1,3-Thiazolidine-2-thione
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The monitored aminolysis of 3-acyl-1,3-thiazolidine-2-thiones has been extended to the peptide-bond formation, the chemoselective acylation of amino acids having multifunctional groups, and the crosslinking reaction between amino acids.
- Nagao, Yoshimitsu,Miyasaka, Tadayo,Seno, Kaoru,Fujita, Eiichi,Shibata, Daisuke,Doi, Etsushiro
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p. 2439 - 2446
(2007/10/02)
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- A Convenient Synthesis of Peptide Using Oxallates
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The equimolar reactions of N-protected amino acids , amino acids or amino acid esters with oxallates (1a-1e) having active ester groups in the presence of pyridine in acetonitrile afforded the corresponding dipeptides via active esters in good yields.
- Takeda, Kazuyoshi,Sawada, Izumi,Suzuki, Akira,Ogura, Haruo
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p. 4451 - 4454
(2007/10/02)
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