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
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“…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).…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.
“…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).…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.
“…), 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 .…”
{[Ag8(Mef)8(μ2-S,O-DMSO)2(μ2-O-DMSO)2(O-DMSO)8]·2(H2O)} (1), [Ag(Mef)(tpP)2] (2),
[Ag(Mef)(tpAs)3] (3), and {2 [Ag(Mef)(tpSb)3] (DMSO)} (4) were obtained by the conjugation
of mefenamic acid (MefH), a nonsteroidal anti-inflammatory drug (NSAID),
with a mitochondriotropic derivative of pnictogen tpE (tp = triphenyl
group; E = P, As, and Sb) through silver(I). Their hydrophilicity
was adjusted by their dispersion into sodium lauryl sulfate (SLS),
forming SLS@1–4. 1–4 and SLS@1–4 were characterized
by their spectral data and X-ray crystallography. They inhibit the
proliferation of human breast adenocarcinoma cells MCF-7 (hormone-dependent
(HD)) and MDA-MB-231 (hormone-independent (HI)). X-ray fluorescence
reveals the Ag cellular uptake. The in vitro and in vivo nongenotoxicity was confirmed with micronucleus
(MN), Artemia salina, and Allium cepa assays. Their mechanism of action was studied by cell morphology,
DNA fragmentation, acridine orange/ethidium bromide (AO/EB) staining,
cell cycle arrest, mitochondrial membrane permeabilization tests,
DNA binding affinity, and LOX inhibitory activity and was rationalized
by regression analysis.
“…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] …”
Section: Introductionmentioning
confidence: 99%
“…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).…”
Fenoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) against rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Like other NSAIDs, fenoprofen inhibits the synthesis of prostaglandins by blocking both cyclooxygenase (COX) isoforms, COX-1 the "house-keeping" enzyme and COX-2 the induced isoform from pathological stimuli. Unselective inhibition of both COX isoforms results in many side effects, but off-target effects have also been reported. The steric modifications of the drugs could afford the desired COX-2 selectivity. Furthermore, NSAIDs have shown promising cytotoxic properties. The structural modification of fenoprofen using bulky dicarba-closo-dodecaborane(12) (carborane) clusters and the biological evaluation of the carborane analogues for COX inhibition and antitumor potential showed that the carborane analogues exhibit stronger antitumor potential compared to their respective aryl-based compounds.
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