Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myelo...

ID: ALA4422618

Journal: Eur J Med Chem

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

Authors: Pati ML, Vitale P, Ferorelli S, Iaselli M, Miciaccia M, Boccarelli A, Di Mauro GD, Fortuna CG, Souza Domingos TF, Rodrigues Pereira da Silva LC, de Pádula M, Cabral LM, Sathler PC, Vacca A, Scilimati A, Perrone MG.

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.

CiteXplore: 30590258

DOI: 10.1016/j.ejmech.2018.12.029

Patent ID: ┄