Carboranyl Analogues of Mefenamic Acid and Their Biological Evaluation

Abstract

Mefenamic acid represents a widely used nonsteroidal anti-inflammatory drug (NSAID) to treat the pain of postoperative surgery and heavy menstrual bleeding. Like other NSAIDs, mefenamic acid inhibits the synthesis of prostaglandins by nonselectively blocking cyclooxygenase (COX) isoforms COX-1 and COX-2. For the improved selectivity of the drug and, therefore, reduced related side effects, the carborane analogues of mefenamic acid were evaluated. The ortho -, meta -, and para -carborane derivatives were synthesized in three steps: halogenation of the respective cluster, followed by a Pd-catalyzed B–N coupling and hydrolysis of the nitrile derivatives under acidic conditions. The COX inhibitory activity and cytotoxicity for different cancer cell lines revealed that the carborane analogues have stronger antitumor potential compared to their parent organic compound.

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors

“…As lead compounds of this study, indometacin happens to be unselective, whereas celecoxib represents a selective inhibitor for the isoenzyme. The ability to inhibit both isoforms, ovine COX-1 and human COX-2, was determined using the “COX Fluorescent Inhibitor Screening Assay Kit” (Cayman Chemical, Ann Arbor, MI, USA) in a concentration range up to 100 µM [ 40 , 41 ]; the results are shown in Table 2 . In general, modification of indometacin ( A ) and celecoxib derivatives ( B and C ) with linker and zinc binding motifs was tolerated by COX-2 leading to inhibitory potencies in the low micromolar range of IC 50 between 1–10 µM with exception of compound B1 (IC 50 = 43.0 µM).…”

“…The COX inhibition potency against ovine COX-1 and human COX-2 was determined using the fluorescence-based COX assay “COX Fluorescent Inhibitor Screening Assay Kit” (catalog number 700100; Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer’s instructions as previously reported by us [ 40 , 41 ]. All compounds were assayed in a concentration range of 10 nM to 100 μM in a 10-fold dilutions series, and every inhibitor concentration was assayed in duplicate.…”

New Apoptosis Inducers Containing Anti-inflammatory Drugs and Pnictogen Derivatives: A New Strategy in the Development of Mitochondrial Targeting Chemotherapeutics

“…), modifies the permeability of the inner mitochondrial membrane, leading cells to death either by necrosis or by apoptosis . Moreover, MefH was found to promote cytostatic activity against various cancer types such as human liver cancer cells (CHANG and HuH-7) through apoptosis . The anticancer properties upon MefH administration to human breast cancer (MCF-7), human bladder (T24), human lung carcinoma (A-549), and mouse fibroblast-like (L-929) cells have also been reported .…”

Carborane Analogues of Fenoprofen Exhibit Improved Antitumor Activity

“…Aiming for improvement of COX‐2 selectivity, metabolic stability, anticancer potential and prolongation of the plasma half‐life of the drugs, one promising way is the incorporation of carboranes as phenyl mimetics for structural modification of a conventional drug [5,15,16–22] …”

“…Following this strategy, our group has reported the structural modification of numerous commercial NSAIDs using carboranes as phenyl mimetics [5,16–22] . One of the first carborane modified NSAID to be published was asborin, the carborane analogue of aspirin, [21] and more recently we reported the structural modification of mefenamic acid using the three carborane isomers (Scheme 1).…”