2. Academic Validation
  3. Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability

Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability

  • Eur J Med Chem. 2019 Feb 15;164:59-76. doi: 10.1016/j.ejmech.2018.12.029.
Maria Laura Pati 1,  Paola Vitale 1,  Savina Ferorelli 1,  Mariaclara Iaselli 1,  Morena Miciaccia 1,  Angelina Boccarelli 2,  Giuseppe Davide Di Mauro 3,  Cosimo G Fortuna 3,  Thaisa Francielle Souza Domingos 4,  Luiz Cláudio Rodrigues Pereira da Silva 4,  Marcelo de Pádula 4,  Lucio Mendes Cabral 4,  Plínio Cunha Sathler 4,  Angelo Vacca 5,  Antonio Scilimati 6,  Maria Grazia Perrone 7
Affiliations

Affiliations

  • 1 Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy.
  • 2 Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy.
  • 3 Department of Chemical Science, University of Catania, Viale Andrea Doria 6, 95125, Catania, Italy.
  • 4 Faculty of Pharmacy, Federal University of Rio de Janeiro, Center of Health Sciences, Carlos Chagas Filho Avenue, 373, 21941599, Rio de Janeiro, Brazil.
  • 5 Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy.
  • 6 Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy. Electronic address: antonio.scilimati@uniba.it.
  • 7 Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy. Electronic address: mariagrazia.perrone@uniba.it.
PMID: 30590258 DOI: 10.1016/j.ejmech.2018.12.029
Abstract

A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 Inhibitor [COX-1 IC50 = 0.0079 μM and COX-2 IC50 > 50 μM, with a selectivity index (SI) in favor of COX-1 higher than 6300]. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. SIs ranged between 1 and higher than 1190.3,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 μM and COX-2 IC50 > 50 μM. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 μM, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and Apoptosis when co-administered with the Proteasome Inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22.

Keywords

Bortezomib; Cyclooxygenase; Mofezolac; Multiple myeloma; Selective COX-1 inhibition; Structure-inhibitory activity relationships in silico investigation.

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