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Design and synthesis of water-soluble and potent MMP-13 inhibitors with activity in human osteosarcoma cells
(2021) Acosta, L. (Lourdes); Pascual-Teresa, B. (Beatriz) de; Pastor, M. (Miryam); Pineda-Lucena, A. (Antonio); Coderch, C. (Claire); Nicolau-Sanus, M. (Maria); Ramos, A. (Ana); Ramos, P. (Pilar); Ortin, I. (Irene); Puchades-Carrasco, L. (Leonor); Zapico, J.M. (José María); Rangasamy, L. (Loganathan); Martínez, A. (Alejandro); Márquez-Cantudo, L. (Laura)
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.