RESUMO
In this work, due to the biological activity evaluation, a series of hydroxy methoxy benzoins (1-8), benzils (10-16) and methoxy benzoin/benzil-O-ß-d-glucosides (17-28) were synthesized. Antioxidant (FRAP, CUPRAC, DPPH), antimicrobial (16 microorganisms, and two yeast), enzyme inhibition (α-amylase, α-glucosidase, AChE, BChE, and tyrosinase) of all synthesized benzoin/benzil analogs were investigated. Benzoins (1-8) showed the most effective antioxidant properties compared to all three methods. Compound 28 against α-amylase, compound 9 against α-glucosidase, compound 11 against AChE, compound 2 against BChE, and compound 13 against tyrosinase showed the best activities with the better or similar IC50 values as used standards. Hydroxy methoxy benzoin compounds (1-8) among all four groups were seen as the most effective against the tested microorganism. Molecular docking analysis showed that all tested compounds 1-28 (0.01-2.22 µM) had the best binding affinity against AChE enzyme. Cytotoxic effects of the many of compounds (1-16, 21, and 24) also investigated and it was found that they caused different effects in different cells. The LDH tests of compounds 1a + b, 4, 7, 8, 9, 11, 12, 21, and 24, seemed to be effective compared to the positive control cisplatin. The cytotoxicity of compounds 6 (9.24%) for MCF7 cancer cells, 8 (5.16%) and 4 (8.26%) for HT29 cancer cells, 24 (9.84%) for Hep3B cells and 8 (8.52%), 7 (5.70%), 4 (6.94) and 9 (7.22%) for C6 cells were at normal values. And also cytotoxic activity of four compounds (5, 9, 21, and 24) among the all synthetic groups, were evaluated to the HeLa and RPE. Compound 5 showed anticancer activity on HeLa and RPE cancer cells as much as or better than cisplatin which was used as standard.
Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Antioxidantes/química , Benzoína/análogos & derivados , Inibidores Enzimáticos/química , Fenilglioxal/análogos & derivados , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Benzoína/síntese química , Benzoína/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fenilglioxal/síntese química , Fenilglioxal/química , Fenilglioxal/farmacologiaRESUMO
BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. OBJECTIVES: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. METHODS: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. RESULTS: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. CONCLUSION: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoína/síntese química , Benzoína/farmacologia , Desenho de Fármacos , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzoína/química , Benzoína/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-AtividadeRESUMO
We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5⯵g/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50â¯=â¯3.5⯵M; Kiâ¯=â¯4.8⯵M) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50â¯=â¯2.3⯵M; Kiâ¯=â¯0.7⯵M) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.
Assuntos
Antibacterianos/farmacologia , Benzoína/análogos & derivados , Benzoína/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Benzoína/síntese química , Domínio Catalítico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Meticilina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacosRESUMO
The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.
Assuntos
Antineoplásicos/síntese química , Benzoína/análogos & derivados , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoína/síntese química , Benzoína/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de ProteínaRESUMO
Deoxybenzoins are potent antioxidants and tyrosinase inhibitors with potential to be developed as food preservatives and cosmetic ingredients. To explore the potential in cardiovascular protection, 25 polyphenolic deoxybenzoins were synthesized and evaluated for inhibitory effects on KCl-induced porcine coronary arterial contraction. The results revealed deoxybenzoins are significant inhibitors of KCl-induced arterial contraction. Among those synthesized, two-thirds of the deoxybenzoins exhibited moderate to good efficacy on relaxing contracted artery including 2,4-dihydroxydeoxybenzoin with EC50=3.30 µM (Emax=100%, n=7) and 2,4-dihydroxy-4'-methoxydeoxybenzoin EC50=3.70 µM (Emax=100%, n=5). Deoxybenzoins displayed an endothelium-dependent relaxing manner on the contracted artery; the contractile responses of neither endothelium denuded nor L-NAME deactivated rings were inhibited. The structure-activity relationships of deoxybenzoin on arterial relaxing effects concluded that the 2,4-dihydroxylated deoxybenzoins presented a potential vascular relaxing pharmacophore, with favoring substitution on ring B in the order of H≥p-OMe>p-OH>o-OMe>m,p-diOMe≥m-OMe.
Assuntos
Benzoína/análogos & derivados , Vasos Coronários/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Animais , Benzoína/síntese química , Benzoína/química , Benzoína/farmacologia , Vasos Coronários/fisiologia , Flavonoides/síntese química , Flavonoides/química , Flavonoides/farmacologia , Técnicas In Vitro , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Polifenóis , Relação Estrutura-Atividade , Sus scrofa , Vasodilatadores/químicaRESUMO
Deoxybenzoins (DOBs) are one-pot synthetic precursors of isoflavones with feature analogous to those beneficial polyphenols such as resveratrol (stilbene) and phloretin (dihydrochalcone). In this study, seventeen polyphenolic DOBs were synthesized and evaluated by various antioxidant assays and tyrosinase inhibitory effect in vitro. Results displayed that these DOBs are powerful antioxidants; for example, 2,3,4-trihydroxy-3',4'-dimethoxydeoxybenzoin possesses an excellent anti-lipid peroxidation activity (IC(50)=0.72+/-0.16 microM), whilst 2,4,4',5-tetrahydroxydeoxybenzoin showed good DPPH radical scavenging activity (IC(50)=0.69+/-0.04 microM), which were better than Trolox and vitamin C. Besides exhibiting a weak metal chelating effect, these DOBs were effective in scavenging ABTS(+) and superoxide anion (O2-) radicals. DOBs also exhibited potent mushroom tyrosinase inhibitory activity; for example 2,3,4'-trihydroxy-4-methoxydeoxybenzoin displayed stable and significant inhibitory effect on tyrosinase activity, with IC(50) values 43.37, 43.10 and 46.10 microM at incubation intervals of 0.5, 1.5, and 2.5h, respectively. These results suggest that, with the advantage of being readily synthesizable small molecules, DOBs can be potentially developed into clinical and industrial antioxidants.
Assuntos
Agaricales/enzimologia , Antioxidantes/farmacologia , Benzoína/análogos & derivados , Flavonoides/farmacologia , Monofenol Mono-Oxigenase/metabolismo , Peptídeos/farmacologia , Fenóis/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Benzoína/síntese química , Benzoína/química , Benzoína/farmacologia , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Flavonoides/síntese química , Flavonoides/química , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Metais/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oxirredução , Peptídeos/síntese química , Peptídeos/química , Fenóis/síntese química , Fenóis/química , PolifenóisRESUMO
Deoxybenzoins are plant compounds with similar structure to isoflavones. In this study, we evaluated the ability of two synthesized deoxybenzoins (compound 1 and compound 2) (a) to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells co-transfected with an estrogen response element-driven luciferase reporter gene and ERalpha- or ERbeta-expression vectors, (b) to modulate the IGFBP-3 and pS2 protein in MCF-7 breast cancer cells, (c) to induce mineralization of KS483 osteoblasts and (d) to affect the cell viability of endometrial (Ishikawa) and breast (MCF-7, MDA-MB-231) cancer cells. Docking and binding energy calculations were performed using the mixed Monte Carlo/Low Mode search method (Macromodel 6.5). Compound 1 displayed significant estrogenic activity via ERbeta but no activity via ERalpha. Compound 2 was an estrogen-agonist via ERalpha and antagonist via ERbeta. Both compounds increased, like the pure antiestrogen ICI182780, the IGFBP-3 levels. Compound 2 induced, like 17beta-estradiol, significant mineralization in osteoblasts. The cell viability of Ishikawa cells was unchanged in the presence of either compound. Compound 1 increased MCF-7 cell viability consistently with an increase in pS2 levels, whereas compound 2 inhibited the cell viability. Molecular modeling confirmed the agonistic or antagonistic behaviour of compound 2 via ER subtypes. Compound 2, being an agonist in osteoblasts, an antagonist in breast cancer cells, with no estrogenic effects in endometrial cancer cells, makes it a potential selective estrogen receptor modulator and a choice for hormone replacement therapy.
Assuntos
Benzoína/análogos & derivados , Calcificação Fisiológica/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Benzoína/síntese química , Benzoína/química , Benzoína/metabolismo , Benzoína/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estradiol/farmacologia , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Estrogênios/agonistas , Feminino , Inibidores do Crescimento/metabolismo , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Método de Monte Carlo , Osteoblastos/metabolismo , Fitoestrógenos/metabolismo , Fitoestrógenos/farmacologia , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Fator Trefoil-1 , Proteínas Supressoras de Tumor/metabolismoRESUMO
Although deoxybenzoins are intermediates in the synthesis of isoflavones, their estrogenic activity has not been investigated. Eleven deoxybenzoins were synthesized and their estrogenicity was evaluated. While their affinities for estrogen receptors (ER) ERalpha and ERbeta were found grossly comparable to those of daidzein, some exhibited considerable selectivity and transcriptional bias toward ERbeta, which appeared to allow for enhancement of ER-mediated transcription via deoxybenzoin binding of ERbeta. Their activity to stimulate the proliferation of ER-positive breast cancer cells and regulate the expression of endogenous and stably transfected reporter genes differed considerably, with some inhibiting cell proliferation while effectively inducing gene expression at the same time. Molecular modeling confirmed that deoxybenzoins fit well in the ligand binding pocket of ERbeta, albeit with different orientations. Our data support the view that deoxybenzoins constitute a promising new class of ERbeta-biased phytoestrogens.