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Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.

Nuti E, Cuffaro D, Bernardini E, Camodeca C, Panelli L, Chaves S, Ciccone L, Tepshi L, Vera L, Orlandini E, Nencetti S, Stura EA, Santos MA, Dive V, Rossello A
J Med Chem 61 4421-4435 (2018)
Related entries: 6ela, 6enm, 6eox, 6esm

Cited: 8 times
EuropePMC logo PMID: 29727184

Abstract

Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results.

Reviews citing this publication (4)

  1. Digestive Inflammation: Role of Proteolytic Dysregulation. Mariaule V, Kriaa A, Soussou S, Rhimi S, Boudaya H, Hernandez J, Maguin E, Lesner A, Rhimi M. Int J Mol Sci 22 2817 (2021)
  2. Developments in Carbohydrate-Based Metzincin Inhibitors. Cuffaro D, Nuti E, D'Andrea F, Rossello A. Pharmaceuticals (Basel) 13 E376 (2020)
  3. Triflamides and Triflimides: Synthesis and Applications. Moskalik MY, Astakhova VV. Molecules 27 5201 (2022)
  4. Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives. Di Leo R, Cuffaro D, Rossello A, Nuti E. Molecules 28 4378 (2023)

Articles citing this publication (4)

  1. Generation of highly selective monoclonal antibodies inhibiting a recalcitrant protease using decoy designs. Lee KB, Dunn ZS, Lopez T, Mustafa Z, Ge X. Biotechnol Bioeng 117 3664-3676 (2020)
  2. Network Pharmacology Research Indicates that Wu-Mei-Wan Treats Obesity by Inhibiting Th17 Cell Differentiation and Alleviating Metabolic Inflammation. Cheng Z, Xiong X, Wu F, Zhao Y, Dong R, Jiang S, Fang K, Huang P, Chen G. Comb Chem High Throughput Screen 26 30-48 (2023)
  3. Identification of N-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization. Cuffaro D, Gimeno A, Bernardoni BL, Di Leo R, Pujadas G, Garcia-Vallvé S, Nencetti S, Rossello A, Nuti E. Int J Mol Sci 24 11098 (2023)
  4. New isoxazolidinyl-based N-alkylethanolamines as new activators of human brain carbonic anhydrases. Cuffaro D, Di Leo R, Ciccone L, Nocentini A, Supuran CT, Nuti E, Rossello A. J Enzyme Inhib Med Chem 38 2164574 (2023)


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