Development of Novel Selective Peptidomimetics Containing a Boronic Acid Moiety, Targeting the 20S Proteasome as Anticancer Agents

ChemMedChem ◽  
2014 ◽  
pp. n/a-n/a ◽  
Author(s):  
Kety Scarbaci ◽  
Valeria Troiano ◽  
Roberta Ettari ◽  
Andrea Pinto ◽  
Nicola Micale ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Boronic Acid ◽  
20S Proteasome ◽  
Acid Moiety

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

scholarly journals Synthesis and evaluation of antimicrobial properties of some azole derivatives

2020 ◽  
Vol 19 (2) ◽  
pp. 377-382
Author(s):  
Mohd Imran ◽  
Abdulhakim Bawadekji ◽  
Nawaf Alotaibi
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Boronic Acid ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
Penicillium Citrinum ◽  
Proton Nuclear Magnetic Resonance ◽  
Acid Moiety ◽  
Mic Value ◽  
Nuclear Magnetic

Purpose: To synthesize new azole derivatives and determine their antimicrobial properties. Methods: The reaction of the intermediates (2a-2c) with 3a-3c in acetone/potassium carbonate solution yielded 4a-4i, which were characterized using Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR)) and mass spectrometry (MS). Compounds 4a-4i were assessed for their antibacterial and antifungal effects using the sequential dilution technique, relative to ofloxacin and ketoconazole. Results: The spectral data for 4a-4i were consistent with the assigned structures. The MIC of compound 4h (10 μg/ml) was similar to that of ketoconazole against Aspergillus flavus, Penicillium citrinum, and Aspergillus niger. The MIC value of compound 4b (10 μg/ml) for Penicillium citrinum was comparable to that of ketoconazole while the MIC value of compound 4d against Staphylococcus aureus and Escherichia coli (20 μg/ml) was equivalent to the corresponding MIC value for ofloxacin. Conclusion: The synthesized compounds bearing boronic acid moiety are good antimicrobial agents. Accordingly, further investigation into the thiazole-imidazole or thiazole-triazole derivatives bearing boronic acid moiety is suggested. Keywords: Synthesis, Imidazole, Thiazole, Triazole, Antimicrobials

scholarly journals Selecting Aptamers for a Glycoprotein through the Incorporation of the Boronic Acid Moiety

2008 ◽  
Vol 130 (38) ◽  
pp. 12636-12638 ◽  
Author(s):  
Minyong Li ◽  
Na Lin ◽  
Zhen Huang ◽  
Lupei Du ◽  
Craig Altier ◽  
...  
Keyword(s):  
Boronic Acid ◽  
Acid Moiety

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

Probe molecule equipped with boronic acid moiety as a reversible cross-linking group improves its binding affinity

2010 ◽  
Vol 20 (14) ◽  
pp. 4152-4155 ◽  
Author(s):  
Naoyuki Kotoku ◽  
Xiu-Han Guo ◽  
Masayoshi Arai ◽  
Motomasa Kobayashi
Keyword(s):  
Binding Affinity ◽  
Boronic Acid ◽  
Probe Molecule ◽  
Cross Linking ◽  
Acid Moiety

Preclinical evaluation of TQB3602, a small molecule proteasome inhibitor clinical candidate.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20546-e20546
Author(s):  
Xiquan Zhang ◽  
Ling Yang ◽  
Xin Tian ◽  
Lihua He ◽  
Jian Xiong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
Small Molecule ◽  
Boronic Acid ◽  
Proteasome Inhibitor ◽  
Antitumor Efficacy ◽  
20S Proteasome ◽  
Orally Bioavailable ◽  
Clinical Candidate

e20546 Background: Proteasome inhibitors, selectively inhibit the activity of proteasome in ubiquitin proteasome system, together with immunomodulatory drugs formed the basis of many treatment regimens for multiple myeloma in first-line therapy as well as for the treatment of relapsed disease. Bortezomib (Velcade), the first approved therapeutic proteasome inhibitor with a unique boronic acid as warhead, limited by its requirement for parenteral administration (intravenous or subcutaneous). The 2nd generation boronic acid – orally bioavailable Ixazomib (Ninlaro) was approved in 2015 by FDA greatly improved patient’s compliance. However, its adverse effect remained an issue in clinical application. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of TQB3602, a novel orally bioavailable small molecule proteasome inhibitor, in preclinical models of multiple myeloma. Methods: The enzyme inhibition and anti-proliferative activity of TQB3602 was evaluated in 20S proteasome and MM.1S cell line. Oral administration of TQB3602 at 3 doses was used to evaluate the in vivo anti-tumor activity in MM.1S multiple myeloma xenograft (CDX) models. Results: TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. TQB3602 inhibited cell proliferation in MM.1S multiple myeloma cell line with IC50 10.1 nM. In the MM.1S multiple myeloma CB-17 CDX model, TQB3602 showed antitumor efficacy with TGI > 100% @7 mpk, BIW (tumor can’t be measured from day 17). Conclusions: We have identified a novel potent proteasome inhibitor TQB3602. Preclinical studies showed antitumor efficacy of TQB3602 in MM.1S multiple myeloma model. TQB3602 represents a promising clinical candidate for treating multiple myeloma and the First-in-human trial is expected in the middle of 2020.

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