Abstract
Considering the promising antitumor effects of compounds with dual anti-inflammatory and antiproliferative activities, thus benzophenones analogs (2-7) were evaluated on in vivo antiinflammatory assay and molecular docking analysis. Those with the best molecular docking results were in vitro evaluated on cyclooxygenase (COX) enzymes and tested regarding antiproliferative activity. All derivatives displayed in vivo anti-inflammatory activity. Among them, the substances 2’-hydroxy-4’-benzoylphenyl-β-D-glucopyranoside (4), 4-hydroxy-4’-methoxybenzophenone (5) and 4’-(4’’-methoxybenzoyl)phenyl-β-D-glucopyranoside (7) showed the best values of Glide Score in COX-2 docking evaluation and 4 and 5 selectively inhibited COX-2 and COX-1 in vitro enzymatic assay, respectively. Thus, 4 and 5 were tested against breast cancer (MCF-7, MDA‑MB-231, Hs578T) and non-small-cell-lung cancer (A549) cell lines. The estrogen-positive MCF-7 cell line was more responsive compared to other tested cell lines. They induced cell cycle arrest at G1/S transition in MCF-7 cell line once there was an increase in G0/G1 population with concomitant reduction of S population. The antiproliferative activity of these substances on MCF-7 was associated with their ability to inhibit cyclin E expression, a critical regulator of G1/S transition. Taken together, the data indicate that 4 and 5 have dual anti-inflammatory and antiproliferative activities and support further studies to evaluate their antitumor potential.
Highlights
Chronic inflammation is associated with different pathological processes including cancer development and cancer progression.[1,2] The constant exposure to inflammatory mediators such as arachidonic acid metabolites, cytokines, chemokines, and free radicals can contribute to uncontrolled cell proliferation, mutagenesis, angiogenesis, and activation of oncogenic pathways.[3,4] Nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated potential in the prevention and treatment of cancer[2] and maybe incorporated in chemotherapy and radiotherapy regimens.[5]
There are different described glycosylation methods involving the reaction of a glucosyl donor that generates an electrophilic compound, which interacts with a nucleophilic reagent to form a glycosidic linkage with the first chemical entity.[44]
All acetylated glucosides of benzophenones were deacetylated by stirring them in a potassium hydroxide/ methanol solution for 30 min, affording yields around 85% to the unprotected glucosides 4 and 7.29 The IR spectra of these compounds did not show the ester bands registered for acetylated glucosides but, concomitantly, contained large bands close to 3300 cm-1 which correspond to the hydroxyl groups of deacetylated derivatives (Figures S5 and S13, SI section)
Summary
Chronic inflammation is associated with different pathological processes including cancer development and cancer progression.[1,2] The constant exposure to inflammatory mediators such as arachidonic acid metabolites, cytokines, chemokines, and free radicals can contribute to uncontrolled cell proliferation, mutagenesis, angiogenesis, and activation of oncogenic pathways.[3,4] Nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated potential in the prevention and treatment of cancer[2] and maybe incorporated in chemotherapy and radiotherapy regimens.[5]. Benzophenone glucosides can be synthesized using a classical method of reaction between the phenol and the base on the per-acetylglucosyl bromide, or by glucosylation of phenols through phase transfer, as an option possible with high yield.[24,25,26] In the present work, innovative glucosides benzophenones were synthesized by these two methods (Figure 1) aiming to identify substances with dual anti-inflammatory and antiproliferative activities.
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