Benzophenone Derivatives Showed Dual Anti-Inflammatory and Antiproliferative Activities by Inhibiting COX Enzymes and Promote Cyclin E Downregulation

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.

Naturally occurring benzophenones and xanthones from Garcinia smeathmannii (Planch. & Triana) Oliv. displayed anti-inflammatory effects by modulating the activities of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages

“…1,3,5,6-tetrahydroxyxanthone (3) and guttiferone E (7) were reported as potential inhibitors of NO production and 15-LOX activity ( Dzoyem et al, 2015 ). In the study of Folquitto et al (2022) , some benzophenones analogs including 2′-hydroxy-4′-benzoylphenyl-β-D-glucopyranoside, 4-hydroxy-4′-methoxybenzophenone and 4′-(4″-methoxybenzoyl) phenyl-β-D-glucopyranoside showed interestig values of Glide Score in COX-2 docking evaluation and selectively inhibited COX-2 and COX-1 in an vitro enzymatic assay ( Folquitto et al, 2022 ). Malik et al (2022) showed the ability of some benzophenone derivatives to inhibit pro-inflammatory mediators including IFN-γ, TNF-α, IL-1β, IL-6, GM-CSF, IL-2and nitric oxide (NO) ( Dzoyem et al, 2015 ; Folquitto et al, 2022 ; Malik et al, 2022 ; Saikia et al, 2023 ).…”

“…In the study of Folquitto et al (2022) , some benzophenones analogs including 2′-hydroxy-4′-benzoylphenyl-β-D-glucopyranoside, 4-hydroxy-4′-methoxybenzophenone and 4′-(4″-methoxybenzoyl) phenyl-β-D-glucopyranoside showed interestig values of Glide Score in COX-2 docking evaluation and selectively inhibited COX-2 and COX-1 in an vitro enzymatic assay ( Folquitto et al, 2022 ). Malik et al (2022) showed the ability of some benzophenone derivatives to inhibit pro-inflammatory mediators including IFN-γ, TNF-α, IL-1β, IL-6, GM-CSF, IL-2and nitric oxide (NO) ( Dzoyem et al, 2015 ; Folquitto et al, 2022 ; Malik et al, 2022 ; Saikia et al, 2023 ). Another study reported the potential of hydroxyxanthone derivatives to inibit COX-2 enzyme ( Dzoyem et al, 2015 ; Folquitto et al, 2022 ; Malik et al, 2022 ; Saikia et al, 2023 ).…”

“… Malik et al (2022) showed the ability of some benzophenone derivatives to inhibit pro-inflammatory mediators including IFN-γ, TNF-α, IL-1β, IL-6, GM-CSF, IL-2and nitric oxide (NO) ( Dzoyem et al, 2015 ; Folquitto et al, 2022 ; Malik et al, 2022 ; Saikia et al, 2023 ). Another study reported the potential of hydroxyxanthone derivatives to inibit COX-2 enzyme ( Dzoyem et al, 2015 ; Folquitto et al, 2022 ; Malik et al, 2022 ; Saikia et al, 2023 ). Despite these previous work, the full anti-inflammatory potential of the great diversity of benzophenones and xanthones has not yet been fully investigated, exploring additional targets such as enzymes and cytokines, involved in their inflammatory response could provide more comprehensive understanding of the compounds’ anti-inflammatory effects.…”