- Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo
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Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.
- Ju, Yuan,He, Lihui,Zhou, Yuanzheng,Yang, Tao,Sun, Ke,Song, Rao,Yang, Yang,Li, Chengwei,Sang, Zitai,Bao, Rui,Luo, Youfu
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supporting information
p. 3104 - 3119
(2020/03/04)
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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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- AN IMPROVED PROCESS FOR THE PREPARATION OF BORONIC ACID ESTERS
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The present invention relates to an improved process for the preparation of a compound of formula (I), wherein PG1 may be independently selected from tert-butyloxycarbonyl (Boc), phthaloyl, 9-fluorenylmethyloxycarbonyl (Fmoc), triphenylmethyl (Trityl), carboxybenzyl (Cbz), trifluoroacetyl, benzyl (Bn), benzylidene, methanesulfonyl (Mesyl), toluene sulfonyl (Tosyl) or acyl; its isolation as solid and use for the preparation of the compound of formula (IV), in particular the compound of formula (IV) i.e. [(1R)-3-methyl-1[[(2S)-1-oxo-3-phenyl-2- [(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid with more than 99.95% chiral purity, as measured by HPLC.
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- Proteasome inhibitor delanzomib for use in the treatment of lupus
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The present invention provides a method for treating lupus in a subject, comprising the step of administering to the subject Compound A.
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Page/Page column 20; 21
(2016/06/06)
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- PROCESS FOR PREPARING OF BORTEZAMIB
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The present invention provides improved processes for the preparation of Bortezomib, tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) and N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6- methano-1,3,2-benzodioxaborol-2-yl]butyl} phenylalanine of formula (V). Compound (IV) is prepared by coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethyl- hexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine of formula (II) or its salt with N-(tert-butoxycarbonyl)-L-phenylalanine of formula (III) in a first solvent in the presence of a first coupling agent and a first base, wherein the coupling process does not comprise solvent exchange. Compound (V) is prepared by deprotecting compound (IV) using an alcoholic solution of an inorganic acid.
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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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- PROCESS FOR MAKING BORTEZOMIB AND INTERMEDIATES FOR THE PROCESS
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The invention relates to processes of making bortezomib of formula (1) enantiomers thereof and/or intermediates thereof, comprising at least one step of coupling a carboxylic acid with an amine, wherein the coupling step is performed in a presence of the compound of formula (8), wherein A is C1-C6 alkyl group, preferably wherein A is n-propyl group.
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- Chemical and biological evaluation of dipeptidyl boronic acid proteasome inhibitors for use in prodrugs and pro-soft drugs targeting solid tumors
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Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from "on target" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.
- Milo, Lawrence J.,Lai, Jack H.,Wu, Wengen,Liu, Yuxin,Maw, Hlaing,Li, Youhua,Jin, Zhiping,Shu, Ying,Poplawski, Sarah E.,Wu, Yong,Sanford, David G.,Sudmeier, James L.,Bachovchin, William W.
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p. 4365 - 4377
(2011/09/15)
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- Design, synthesis, biological evaluation, and Structure-Activity Relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of α-amino acid boronates
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New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC50 values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC50 value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
- Zhu, Yongqiang,Zhao, Xin,Zhu, Xinrong,Wu, Gang,Li, Yuejie,Ma, Yuheng,Yuan, Yunxia,Yang, Jie,Hu, Yang,Ai, Li,Gao, Qingzhi
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experimental part
p. 4192 - 4199
(2010/01/16)
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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 13; 14; title page; sheet 1
(2009/03/07)
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- A convergent approach to synthesis of bortezomib: the use of TBTU suppresses racemization in the fragment condensation
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Bortezomib is a first-in-class therapeutic antineoplastic agent used for treating patients with multiple myeloma and mantle cell lymphoma. In this paper we report an improved method for synthesis of the title compound using a convergent approach. TBTU was
- Ivanov, Andrey S.,Zhalnina, Anna A.,Shishkov, Sergey V.
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experimental part
p. 7105 - 7108
(2009/12/09)
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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 39-40
(2009/04/25)
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- SYNTHESIS OF BORONIC ESTER AND ACID COMPOUNDS
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The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.
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Page/Page column 46-48
(2010/02/14)
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