- Synthesis of four isotopically labeled forms of a proteasome inhibitor, bortezomib
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[D2](1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]-amino]butyl] boronic acid ([D2]bortezomib), a proteasome inhibitor, was synthesized in 11 steps from isobutyryl chloride. Key steps in the synthesis inclu
- Li, Yuexian,Plesescu, Mihaela,Sheehan, Patrick,Daniels, J. Scott,Prakash, Shimoga R.
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- Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i)
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Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.
- Klein, Markus,Busch, Michael,Friese-Hamim, Manja,Crosignani, Stefano,Fuchss, Thomas,Musil, Djordje,Rohdich, Felix,Sanderson, Michael P.,Seenisamy, Jeyaprakashnarayanan,Walter-Bausch, Gina,Zanelli, Ugo,Hewitt, Philip,Esdar, Christina,Schadt, Oliver
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supporting information
p. 10230 - 10245
(2021/07/26)
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- SUBSTITUTED BORIC ACID COMPOUND, PHARMACEUTICAL COMPOSITION COMPRISING SAME, AND APPLICATION THEREOF
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A substituted boric acid compound, a pharmaceutical composition comprising same, and an application thereof. The substituted boric acid compound is a compound represented by formula (I), or a crystal form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, a hydrate, or a solvent compound thereof. The boric acid compound has proteasome inhibitory activity, good pharmacodynamic/pharmacokinetic performance, good applicability, and high safety, and can be used for preparing drugs for treating diseases related to proteasomes.
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Paragraph 0038; 0041
(2019/05/10)
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- Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids
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Boronic acids are an increasingly important compound class for many applications, including C-C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and its diol esters. The method is performed under mild conditions, provides high yields, and eliminates cumbersome and problematic purification steps.
- Hinkes, Stefan P.A.,Klein, Christian D.P.
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supporting information
p. 3048 - 3052
(2019/05/10)
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- De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX
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Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.
- Tan, Joanne,Grouleff, Julie J.,Jitkova, Yulia,Diaz, Diego B.,Griffith, Elizabeth C.,Shao, Wenjie,Bogdanchikova, Anastasia F.,Poda, Gennady,Schimmer, Aaron D.,Lee, Richard E.,Yudin, Andrei K.
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p. 6377 - 6390
(2019/08/02)
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- Structure-based development of (1-(3′-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- And Serine-β-lactamases
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The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2′S)-(1-(3′-mercapto-2′-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.
- Wang, Yao-Ling,Liu, Sha,Yu, Zhu-Jun,Lei, Yuan,Huang, Meng-Yi,Yan, Yu-Hang,Ma, Qiang,Zheng, Yang,Deng, Hui,Sun, Ying,Wu, Chengyong,Yu, Yamei,Chen, Qiang,Wang, Zhenling,Wu, Yong,Li, Guo-Bo
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p. 7160 - 7184
(2019/08/28)
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- Preparation of (1R)-(S)-pinane diol-1-amino-3-methyl-butane-1-borate and a salt thereof
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The invention discloses a method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester and a salt thereof. The method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester comprises step A and step B in the following synthetic route, wherein in the formula, X represents a halogen atom and M represents an alkali metal. (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester is subjected to a salt forming reaction with an organic acid or an inorganic aid, and an acidic salt of (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester is obtained. The method of the invention can help to synthesize high-purity bortezomib or other boropeptide compounds in low cost, is accord with industrial production requirements and has practical value.
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Paragraph 0047-0050
(2016/10/08)
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- Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids
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A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids were designed and synthesized. Their structures were elucidated by 1H NMR, 13C NMR, LC-MS and HRMS. These compounds were evaluated for their β5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of αα-amino acids were as active as bortezomib. Interestingly, the activities of those derived from αβ-amino acids lost completely. Of all the inhibitors, compound 22 (IC50 = 4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the β5 subunit active pocket of proteasome.
- Shi, Jingmiao,Lei, Meng,Wu, Wenkui,Feng, Huayun,Wang, Jia,Chen, Shanshan,Zhu, Yongqiang,Hu, Shihe,Liu, Zhaogang,Jiang, Cheng
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supporting information
p. 1958 - 1962
(2016/04/05)
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- Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
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The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.
- Peuchmaur, Marine,Lacour, Marie-Agnes,Sevalle, Jean,Lisowski, Vincent,Touati-Jallabe, Youness,Rodier, Fabien,Martinez, Jean,Checler, Frederic,Hernandez, Jean-Francois
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supporting information
p. 1018 - 1029
(2013/03/14)
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- Observations on the deprotection of pinanediol and pinacol boronate esters via fluorinated intermediates
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(Chemical Equation Presented) Methods for the deprotection of pinanediol and pinacol esters of various boronic acids via fluoroborane intermediates were evaluated. Treatment of the boronate esters with potassium hydrogen difluoride normally gives trifluor
- Inglis, Steven R.,Woon, Esther C. Y.,Thompson, Amber L.,Schofield, Christopher J.
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supporting information; experimental part
p. 468 - 471
(2010/03/25)
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- Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors
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A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (β5) activity (IC50 = 0.28 and 0.51 μM, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at >1 μM concentrations of compound.
- Nakamura, Hiroyuki,Watanabe, Mizuyoshi,Ban, Hyun Seung,Nabeyama, Wataru,Asai, Akira
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scheme or table
p. 3220 - 3224
(2010/04/05)
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- Stability of boronic esters to hydrolysis: A comparative study
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Boronic esters are key intermediates in the synthesis of biologically active compounds such as thrombin and proteasome inhibitors. However, they have low hydrolytic stability both during synthetic reactions and in biological media. We report the preparati
- Bernardini, Raffaella,Oliva, Ambrogio,Paganelli, Alessandro,Menta, Ernesto,Grugni, Mario,De Munari, Sergio,Goldoni, Luca
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supporting information; experimental part
p. 750 - 751
(2011/04/21)
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- NITRIC OXIDE DONATING PROSTAMIDES
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Nitroderivatives of prostaglandins having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 33
(2009/04/25)
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- METHODS FOR PREPARING BORTEZOMIB AND INTERMEDIATES USED IN ITS MANUFACTURE
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Provided herein are methods for preparing bortezomib and intermediates useful in the preparation of bortezomib. The present methods unexpectedly provide superior yields and purities, including optical purities, of bortezomib and the intermediates for the preparation of bortezomib.
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Page/Page column 9
(2009/03/07)
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- Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer
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The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl] amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
- Dorsey, Bruce D.,Iqbal, Mohamed,Chatterjee, Sankar,Menta, Ernesto,Bernardini, Raffaella,Bernareggi, Alberto,Cassarà, Paolo G.,D'Arasmo, Germano,Ferretti, Edmondo,De Munari, Sergio,Oliva, Ambrogio,Pezzoni, Gabriella,Allievi, Cecilia,Strepponi, Ivan,Ruggeri, Bruce,Ator, Mark A.,Williams, Michael,Mallamo, John P.
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p. 1068 - 1072
(2008/12/22)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- Proteasome inhibitors and methods of using the same
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.
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Page/Page column 30
(2008/06/13)
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- PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
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Page/Page column 55-56
(2008/06/13)
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- P1 Phenethyl peptide boronic acid inhibitors of HCV NS3 protease
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A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.
- Priestley,De Lucca, Indawati,Ghavimi, Bahman,Erickson-Viitanen, Susan,Decicco, Carl P.
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p. 3199 - 3202
(2007/10/03)
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- (Chloromethyl)lithium: Efficient generation and capture by boronic esters and a simple preparation of diisopropyl (chloromethyl)boronate
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(Chloromethyl)lithium is efficiently generated and captured at -78°C by adding n -butyllithium to a mixture of iodochloromethane and a boronic ester in tetrahydrofuran, resulting in conversion of boronic esters, RB(OR′)2, to their homologues, RCH2B(OR′)2, with retention of the configuration of the R group. With triisopropyl borate in place of the boronic ester, a high yield of diisopropyl (chloromethyl)boronate is obtained.
- Sadhu, Kizhakethil Mathew,Matteson, Donald S.
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p. 1687 - 1689
(2008/10/08)
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- Pinanediol [α-(trimethylsilyl)allyl]boronate and related boronic esters
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Homologation of (+)-pinanediol phenylboronate with [chloro(trimethylsilyl)methyl]lithium yielded (αS)-and (αR)-[α-(trimethylsilyl)benzyl]boronic esters in a 73:27 ratio, as shown by peroxidic deboronation to the known α-(trimethylsilyl)benzyl alcohol. Similar homologations of pinanediol vinyl, (Z)-1-propenyl, and isobutyl boronates were carried out, but the diastereoisomeric ratios were not determined. Reaction of the allylic α-trimethylsilyl boronic esters with aldehydes was studied. Pinanediol or pinacol 3-(trimethylsilyl)-1-propene-3-boronates yielded mainly (Z)-1-(trimethylsilyl)-1-alken-4-ols with aldehydes. Pinanediol (Z)-1-(trimethylsilyl)-2-butene-1-boronate with benzaldehyde yielded (E)-1-(trimethylsilyl)-3-methyl-4-phenylbut-1-en-4-ol with only 4% Z isomer. The stereochemical implications and utility of these reactions in synthesis are discussed. A brief investigation indicated that pinanediol α-trimethylsilyl boronic esters can be desilylated to boronic esters by tetrabutylammonium fluoride in moist THF.
- Tsai, David J. S.,Matteson, Donald S.
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p. 236 - 241
(2008/10/08)
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