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

被引：12

作者：

Pati, Maria Laura ^{[1
]}

Vitale, Paola ^{[1
]}

Ferorelli, Savina ^{[1
]}

Iaselli, Mariaclara ^{[1
]}

Miciaccia, Morena ^{[1
]}

Boccarelli, Angelina ^{[2
]}

Di Mauro, Giuseppe Davide ^{[3
]}

Fortuna, Cosimo G. ^{[3
]}

Domingos, Thaisa Francielle Souza ^{[4
]}

Rodrigues Pereira da Silva, Luiz Claudio ^{[4
]}

de Padula, Marcelo ^{[4
]}

Cabral, Lucio Mendes ^{[4
]}

Sathler, Plinio Cunha ^{[4
]}

Vacca, Angelo ^{[5
]}

Scilimati, Antonio ^{[1
]}

Perrone, Maria Grazia ^{[1
]}

机构：

[1] Univ Bari Aldo Moro, Dept Pharm Pharmaceut Sci, Via E Orabona 4, I-70125 Bari, Italy

[2] Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol, Piazza Giulio Cesare 11, I-70124 Bari, Italy

[3] Univ Catania, Dept Chem Sci, Viale Andrea Doria 6, I-95125 Catania, Italy

[4] Univ Fed Rio de Janeiro, Fac Pharm, Ctr Hlth Sci, Carlos Chagas Filho Ave,373, BR-21941599 Rio De Janeiro, Brazil

[5] Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol, Internal Med Unit G Baccelli, Med Sch, Bari, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 164卷

关键词：

Cyclooxygenase; Selective COX-1 inhibition; Mofezolac; Structure-inhibitory activity relationships in silico investigation; Bortezomib; Multiple myeloma; IN-VITRO CYTOTOXICITY; ARYL NITRILE OXIDES; CYCLOOXYGENASE-1; COX-1; GROWTH-FACTOR; 3-ARYLISOXAZOLES; ANTIPLATELET; DIARYLISOXAZOLES; DIMERIZATION; SUPPRESSION; DERIVATIVES;

D O I：

10.1016/j.ejmech.2018.12.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M and COX-2 IC50 > 50 mu M, 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. Sls ranged between 1 and higher than 11903,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 mu M and COX-2 IC50 > 50 mu M. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 mu M, 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. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：59 / 76

页数：18