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This research was funded by RTI2018-093539-B-I00 (MICIU/FEDER, UE). Laura Marquez-Cantudo thanks Universidad San Pablo CEU and Banco Santander for a Young Researcher contract. Part of the equipment used in this work was co-funded by the Generalitat Valenciana and European Regional Development Fund (FEDER) funds (PO FEDER of Comunitat Valenciana 2014-2020) and Community of Madrid (S2017/BMD-3864). This project received funding from the European Union's Horizon 2020 research and innovation program under the Marie-Sklodowska-Curie grant agreement number DUALITY 746225.

Analysis of institutional authors

Nicolau-Sanus, MaríaAuthor

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Article

Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells

Publicated to:International Journal Of Molecular Sciences. 22 (18): 9976- - 2021-09-01 22(18), DOI: 10.3390/ijms22189976

Authors: Zapico, Jose Maria; Acosta, Lourdes; Pastor, Miryam; Rangasamy, Loganathan; Marquez-Cantudo, Laura; Coderch, Claire; Ortin, Irene; Nicolau-Sanus, Maria; Puchades-Carrasco, Leonor; Pineda-Lucena, Antonio; Majali-Martinez, Alejandro; Ramos, Pilar; de Pascual-Teresa, Beatriz; Ramos, Ana

Affiliations

CEU Univ, Univ San Pablo CEU, Fac Farm, Dept Quim & Bioquim, Alcorcon 28925, Spain - Author
Inst Invest Sanitaria La Fe, Drug Discovery Unit, Valencia 46026, Spain - Author
Med Univ Graz, Dept Obstet & Gynecol, A-8036 Graz, Austria - Author
Univ Navarra, Mol Therapeut Program, Ctr Invest Med Aplicada, Pamplona 31008, Spain - Author
Vellore Inst Technol VIT, Ctr Biomat Cellular & Mol Theranost CBCMT, Vellore 632014, Tamil Nadu, India - Author
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Abstract

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1 ' heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

Keywords

metalloproteinasesmmp-13 inhibitorsmolecular modelingorganic synthesisrmn2 [4 [4 [2 (2h benzo[d][1-3]triazol 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenylsulfonamido] 3 phenylpropanoic acid2 [4 [4 [2 (2h benzo[d][1-3]triazol 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenylsulfonamido] n hydroxy 3 phenylpropanamide2 [4 [4 [2 (perbromo 2h benzo[d][1-3]triazol 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenylsulfonamido] 3 phenylpropanoic acid2 [[4 [4 [2 (1,3 dioxoisoindolin 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonamido] n hydroxy 3 phenylpropanamide2 [[4 [4 [2 (5 bromo 1,3 dioxoisoindolin 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonamido] n hydroxy 3 phenylpropanamide2 [[4 [4 [2 (5,6 dibromo 1,3 dioxoisoindolin 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonamido] n hydroxy 3 phenylpropanamide4 [[4 [4 [2 (2h benzo[d][1-3]triazol 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonyl] n hydroxytetrahydro 2h pyran 4 carboxamideAccurate dockingAgedArticleBenzotriazole derivativeBromineCell line, tumorChemistryClick chemistryCollagenase 3Collagenase inhibitorCollagenase-3Controlled studyDiscoveryDrug designDrug selectivityDrug solubilityDrug synthesisDrug targetingEnzyme activityEnzyme inhibitionGelatinase aGelatinase bGlideHighly potentHumanHuman cellHumansIc50Inhibitory concentration 50Interstitial collagenaseMacrophage elastaseMagnetic resonance spectroscopyMatrilysinMatrix metalloproteinase 13Matrix metalloproteinase 14Matrix metalloproteinase inhibitorMatrix metalloproteinase inhibitorsMatrix metalloproteinase-13MetabolismMetalloproteinasesMg-63 cell lineMmp-13 inhibitorsModels, molecularMolecular modelMolecular modelingN hydroxy 2 [[4 [4 [2 (5 methyl 1,3 dioxoisoindolin 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonamido] 3 phenylpropanamideN hydroxy 3 phenyl 2 [[4 [4 [2 (4,5,6,7 tetrabromo 1,3 dioxoisoindolin 2 yl)ethyl] 1h 1,2,3 triazol 1 yl]phenyl]sulfonamido]propenamideNeutrophil collagenaseNuclear magnetic resonanceNuclear magnetic resonance spectroscopyOr-ganic synthesisOrganic synthesisOsteoarthritisOsteosarcomaPathologyPhthalimide derivativeRelevanceRheumatoid-arthritisRmnSelectivitySolubilityStromelysinStromelysin 2SynthesisTumor cell lineUnclassified drugWaterWater solubility

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal International Journal Of Molecular Sciences due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 69/297, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 1.25, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-30, the following number of citations:

  • WoS: 8
  • Scopus: 10
  • Europe PMC: 4
  • Google Scholar: 9

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-30:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 31.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 31 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 4.95.
  • The number of mentions on the social network X (formerly Twitter): 8 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Austria; India.