molecules Article
Practical Synthesis of Chalcone Derivatives and Their Biological Activities Jae-Chul Jung 1 , Yongnam Lee 2 , Dongguk Min 2 , Mankil Jung 2, * and Seikwan Oh 1, * 1 2
*
Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07985, Korea;
[email protected] Department of Chemistry, Yonsei University, Seoul 03722, Korea;
[email protected] (Y.L.);
[email protected] (D.M.) Correspondence:
[email protected] (M.J.);
[email protected] (S.O.); Tel.: +82-2-2650-5749 or +82-2-2643-0634 (S.O.)
Received: 30 September 2017; Accepted: 24 October 2017; Published: 1 November 2017
Abstract: Practical synthesis and biological activities of 4-hydroxy-3-methoxy-2-propene derivatives are described. The novel chalcone derivatives were prepared by acid catalysed one-step condensation of 1,3- or 1,4-diacetylbenzene and 1,3,5-triacetylbenzene with 4-hydroxy-3-methoxybenzaldehyde. They were then evaluated for free radical scavenging activity, suppression of lipopolysaccharides (LPS)-induced NO generation, and anti-excitotoxicity in vitro. It was found that all compounds showed good effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, LPS-induced NO generation, and anti-neurotoxicity. Compounds 6 and 7 were potent suppressor of NO generation with the concentration range 10 µM and especially compound 8 showed very potent anti-inflammatory activity with 1 µM. In addition, the di- and tri-acetylbenzyl derivatives 6, 7, and 8 showed enhanced anti-neurotoxicity activity in cultured cortical neurons. Molecular modelling studies to investigate the chemical structural characteristics required for the enhanced biological activities interestingly revealed that compound 8 has the smallest highest occupied molecular orbital-lowest energy unoccupied molecular orbital (HOMO-LUMO) gap, which signifies easy electron and radical transfer between HOMO and LUMO in model studies. Keywords: chalcones; condensation reaction; free radical scavenging; NO generation; neurotoxicity; molecular modelling
1. Introduction Most of the chalcone moieties have evoked a great deal of interest due to their biological properties and characteristic conjugated molecular architecture. Chalcones have been considered derivatives of the 1,3-diaryl-2-propene-1-one parent compound composed of two phenolic rings, referred to as the A and B rings. Many of them possess important pharmacological properties, such as analgesic [1], arthritis [2], anti-inflammatory [3], anti-pyretic [4], anti-bacterial [5], anti-viral [6,7], and anti-cancer [8,9] effects. They were also potentially useful for many industrial products and phytochemical applications, including food sciences. Nowadays, a number of comparative pharmacological investigations of the chalcones have showed good antioxidant activity with low side effects [10–13] (Figure 1). Especially, curcumin and its related enones, such as yakuchinones A and B, inhibited the activation of the prosurvival transcription factor nuclear factor-kβ (NF-kβ) and up-regulation of cyclooxygenase-2 (COX-2). The chemical synthesis, quantitative structural modification, and a wide variety of biological activities of chalcones were reported in many studies [14–16].
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www.mdpi.com/journal/molecules
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OMe 4: Yakuchinone B
Figure Figure 1. 1. Structures Structures of of chalcone chalcone 1, 1, curcumin curcumin 2, 2, JC-3 JC-3 3, 3, and yakuchinone B 4. 4.
Naturally occurring chalcones derived from general foods are phloretin and its glucoside phloridzin Naturally occurring chalcones derived from general foods are phloretin and its glucoside chalconaringenin, and arbutin. Most of the studies to date, regarding the synthetic approaches of phloridzin chalconaringenin, and arbutin. Most of the studies to date, regarding the synthetic chalcone derivatives [17–21],were reported by the organic and medicinal chemists through the approaches of chalcone derivatives [17–21],were reported by the organic and medicinal chemists formation of the 1,4-enones using acid- or base-catalysed condensation reactions of aldehyde and aryl through the formation of the 1,4-enones using acid- or base-catalysed condensation reactions of methyl ketones in alcoholic solvents with variable yields. aldehyde and aryl methyl ketones in alcoholic solvents with variable yields. An interesting biological report of chalcone derivatives described the potential antioxidant An interesting biological report of chalcone derivatives described the potential antioxidant activities of conjugated phenolic enones by the Vander Jagt group [22]. The Oh group described the activities of conjugated phenolic enones by the Vander Jagt group [22]. The Oh group described neuroprotective effects of benzylideneacetophenone derivatives on excitotoxicity and inflammation the neuroprotective effects of benzylideneacetophenone derivatives on excitotoxicity and inflammation via the phosphorylated janus tyrosine kinase 2/phosphorylated signal transducer and activator of via the phosphorylated janus tyrosine kinase 2/phosphorylated signal transducer and activator of transcription 3 and mitogen-activated protein K pathways, and compound 6 was more potent than transcription 3 and mitogen-activated protein K pathways, and compound 6 was more potent than compound 3 in the aspect of proteasome inhibition, which induced apoptosis significantly in the compound 3 in the aspect of proteasome inhibition, which induced apoptosis significantly in the prostate cancer cells [23,24]. The Ryu group demonstrated that the optimal length of linker between prostate cancer cells [23,24]. The Ryu group demonstrated that the optimal length of linker between aryl groups played an important role for the biological activity, and the Di Pietro group showed that aryl groups played an important role for the biological activity, and the Di Pietro group showed that potent bis-chalcone inhibitors were identified, the efficiency depending on both position of the central potent bis-chalcone inhibitors were identified, the efficiency depending on both position of the central ketone groups and the number and positions of lateral methoxy substituents in breast cancer ketone groups and the number and positions of lateral methoxy substituents in breast cancer resistance resistance protein inhibition [25,26]. protein inhibition [25,26]. In our previous study of 1,3-diaryl-2-propenones, we have developed a simple synthesis via the In our previous study of 1,3-diaryl-2-propenones, we have developed a simple synthesis via the Grignard reaction of aldehyde and oxidation of secondary alcohols [27]. We also reported the Grignard reaction of aldehyde and oxidation of secondary alcohols [27]. We also reported the one-step one-step synthesis of benzylideneacetophenones and the evaluation of their biological activities [28]. synthesis of benzylideneacetophenones and the evaluation of their biological activities [28]. We are We are continuously interested in the chemistry of chalcone derivatives, in part for their potential continuously interested in the chemistry of chalcone derivatives, in part for their potential use as use as scaffolds in medicinal chemistry. We wish to report herein the simple synthesis and biological scaffolds in medicinal chemistry. We wish to report herein the simple synthesis and biological activities activities of dimer or trimer of 4-hydroxy-3-methoxy-2-propene derivatives 6–8 for free radical of dimer or trimer of 4-hydroxy-3-methoxy-2-propene derivatives 6–8 for free radical scavenging, scavenging, suppression of lipopolycahharide (LPS)-induced NO generation in vitro, and suppression of lipopolycahharide (LPS)-induced NO generation in vitro, and anti-excitotoxicity, anti-excitotoxicity, which were prepared by 4-hydroxy-3-methoxybenzaldehyde and diacetophenone which were prepared by 4-hydroxy-3-methoxybenzaldehyde and diacetophenone or triacetophenone or triacetophenone via acid catalysed one-pot condensation reaction in good yields. Biological via acid catalysed one-pot condensation reaction in good yields. Biological activities of their activities of their derivatives for suppression of LPS-induced NO generation in vitro suggests that derivatives for suppression of LPS-induced NO generation in vitro suggests that they can be possible they can be possible anti-inflammatory lead compounds. Furthermore, molecular modelling studies anti-inflammatory lead compounds. Furthermore, molecular modelling studies were reported to were reported to investigate the chemical structural characteristics required for the biological investigate the chemical structural characteristics required for the biological activities and schematizes activities and schematizes a delocalized form of electron density. These efforts might be help to a delocalized form of electron density. These efforts might be help to develop and design more potent develop and design more potent novel chalcones with neuroprotective effects. novel chalcones with neuroprotective effects.
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2. Results and Discussion 2.1. Chemistry Since chalcone synthesis has been achieved by employing the Suzuki reaction, the base-catalysed condensation has been accomplished with good yields [29]. In a model study, we investigated the reactivity of several bases, such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide [Mg(OH)2 ], and barium hydroxide [Ba(OH)2 ]. Isovanillin was treated with 3-fluoro-4-methoxy acetophenone in methanol in the presence of two equivalents of bases to give (E)-1-(3-fluoro-4-methoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)-prop-2-en-1-one. An excellent result of the desired product was obtained using LiOH in methanol at room temperature for 148 h in 90% yield. Practically, most of the other bases showed good yields, while the reaction with Mg(OH)2 failed to afford 1,4-enones. Lithium hydroxide proved to be the superior base and consistently gave higher yields than the other bases. It seems probable that the effectiveness of lithium hydroxide can be explained in part by a lithium chelating effect. Based on these results, we modified to generate our desired dimer or trimer types of chalcone derivatives. Interestingly, the base for catalysing the Claisen-Schmidt condensation of 4-hydroxy-3-methoxybenzaldehyde and 1,3-diacetylbenzene, 1,4-diacetylbenzene or 1,3,5-triacetylbenzene is unsatisfied. To establish generality, the acid-catalysed condensation reaction of aldehyde with 1,3-diacetylbenzene or 1,4-diacetylbenzene and 1,3,5-triacetylbenzene under mild reaction conditions was carried out in the presence of various acids, such as AcOH, c-HCl, c-H2 SO4 , H3 PO4 , BF3 -EtO2 , AlCl3 , and Montmorillonite K 10. The reasonable result was obtained in the case of the use of stoichiometric amounts of c-sulphuric acid in ethanol. The reaction was monitored by thin-layer chromatography (TLC) and gas chromatography- mass spectrometry (GC-MS) and easy to perform without any elaborative work-up. In the continuous of our medicinal program dealing with the development of new 1,3-diaryl-2-propen-1-one derivatives, we have introduced dimer and trimer types of the benzylideneacetophenone backbone in order to develop antioxidant agents and anti-excitotoxic compounds. 4-Hydroxy-3-methoxy-2-propene derivatives 6–8 were prepared from commercially available 4-hydroxy-3-methoxybenzaldehyde 5 and 1,3-diacetylbenzene, 1,4-diacetylbenzene or 1,3,5-triacetylbenzene in the presence of stoichiometric amounts of c-sulphuric acid in ethanol to give 3-(4-hydroxy-3-methoxy-phenyl)-1-{3-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-propenone, 3-(4-hydroxy-3-methoxy-phenyl)-1-{4-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-propenone, and 1-{3,5-bis-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-phenyl}-3-(4-hydroxy-3-methoxy-phenyl)propenone in 23%, 35%, and 73% yields, respectively (Scheme 1). 2.2. Molecular Modeling The main objectives of the molecular modelling studies were to investigate the effects of monomer, dimmer, and trimer on free radical scavenging, cell viability, and LPS-induced nitric oxide generation in chalcone derivatives 3, and 6–8 to investigate their neuroprotective effects. The results of the molecular modelling studies of chalcone derivatives 3 and 6–8 are as shown in Table 1. Although diverse compounds were not used in this modelling study, a significant result was obtained. The highest-occupied molecular orbital (HOMO) and the lowest-unoccupied molecular orbital (LUMO) energies ranged between −5.855 and −5.664 and −2.307 and −1.943 eV, respectively. Especially, compound 8 had the smallest HOMO-LUMO gap (3.507 eV), which signifies rapid electron and radical transfer between HOMO and LUMO (Figure 2). This could be one of the reasons that compound 8 showed good free radical scavenging activity. This finding reveals a close relationship to the electro density of compound 8 based on resonance effect, which is represented in Figure 3. On the basis of these results, we could expect that the HOMO-LUMO gap could be considered to be important parameters for choosing anti-neurotoxic compounds among the evaluated chalcone derivatives.
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Scheme 1. Reagents conditions: (a) 1,3-diacetylbenzene, c-H 2SO 4, 4EtOH, reflux 3 h;3 (b) Scheme 1. Reagents andand conditions: 1,3-diacetylbenzene, c-H 2SO , EtOH, reflux h; (b) Scheme 1. Reagents and conditions: (a)(a)1,3-diacetylbenzene, c-H 2 SO4 , EtOH, reflux 3 h; (b) 1,41,4-diacetylbenzene, c-H 2SO4, EtOH, reflux 3 h; and (c) 1,3,5-triacetylbenzene, c-H2SO4, EtOH, reflux 3 h. 1,4-diacetylbenzene, 2SO4, EtOH, reflux 3 h; and (c) 1,3,5-triacetylbenzene, c-H2SO4, EtOH, reflux 3 h. diacetylbenzene, c-Hc-H 2 SO4 , EtOH, reflux 3 h; and (c) 1,3,5-triacetylbenzene, c-H2 SO4 , EtOH, reflux 3 h. Table 1. Results of the molecular modelling study for benzylideneacetophenone derivatives.
Table derivatives. Table 1. 1. Results Results of of the the molecular molecular modelling modelling study study for for benzylideneacetophenone benzylideneacetophenone derivatives. Energy E. HOMO a E. LUMO b ΔE c a b Compounds Energy E. HOMO E. (eV) LUMO ΔE c (eV)a (eV) ∆E c b CompoundsEnergy (au) E. HOMO E. LUMO Compounds 3 (au) (eV) (eV) (eV) −843.796 −5.845 −1.943 3.901 (au) (eV) (eV) (eV) 3 6 −843.796 −5.845 −1.943 3.690 3.901 −1455.342 −5.664 −1.974 3 − 1.943 3.901 −1455.334 −5.845 −5.855 −2.307 3.548 6 7 −843.796 −1455.342 −5.664 −1.974 3.690 6 − 1455.342 − 5.664 − 1.974 3.690 8 −2066.890 −5.695 −2.189 3.507 7 −1455.334 −5.855 −2.307 3.548 7 − 1455.334 − 5.855 − 2.307 3.548 a Energy of highest-occupied molecular orbital. b Energy of lowest-unoccupied molecular orbital. c ΔE 8 −2066.890 −5.695 −5.695 3.507 8 −2066.890 −−2.189 2.189 3.507 represents the orbital energy difference. HOMO: the highest-occupied molecular orbital; LUMO: the c a Energy b Energy ofhighest-occupied highest-occupied molecular orbital. of lowest-unoccupied molecular orbital. ΔE a Energy of b molecular orbital. Energy of lowest-unoccupied molecular orbital. c ∆E represents lowest-unoccupied molecular orbital. represents the orbital energyHOMO: difference. HOMO: the highest-occupied orbital; LUMO: the the orbital energy difference. the highest-occupied molecular orbital;molecular LUMO: the lowest-unoccupied molecular orbital. -1.5 lowest-unoccupied molecular orbital. -1.5
-2.0 -2.5
-2.0
−1.943(eV)
LUMO
−1.974(eV) −2.307(eV)
−1.943(eV)
−1.974(eV) −2.307(eV)
-3.0
−2.189(eV)
LUMO −2.189(eV)
-2.5 -3.5
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E(eV))
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3.507(eV)
E(eV))
-4.0 -5.0 -4.5 -5.5 -5.0 -6.0
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3
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6
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7
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HOMO
8
-5.5 -6.0
Figure 2. HOMO-LUMO gaps of chalcone derivatives 3 and 6–8. −5.664(eV) −5.695(eV)
3
HOMO
−5.855(eV)
−5.845(eV)
6
7
8
Figure Figure 2. 2. HOMO-LUMO HOMO-LUMO gaps gaps of of chalcone chalcone derivatives derivatives 33 and and 6–8. 6–8.
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Figure 3. LUMO and HOMO maps of chalcones derivatives derivatives 3 and and 6–8. 6–8.
2.3. Biological Evaluation 2.3.1. Radical Scavenging Activity 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals radicals are representative method for the preliminary 2,2-Diphenyl-1-picrylhydrazyl (DPPH) preliminary screening of of compounds compoundscapable capableofof scavenging activated oxygen species are much scavenging activated oxygen species sincesince they they are much more more and easier to handle than oxygen free radicals. The scavenging radical scavenging of stable stable and easier to handle than oxygen free radicals. The radical activity activity of the 1,3the 1,3-diphenyl-2-propen-1-ones, 3 and were evaluated by the known[30,31] method and diphenyl-2-propen-1-ones, 3 and 6–8 were6–8 evaluated by the known method and[30,31] the results the are summarized in All Figure 4. compounds All these compounds exhibited free radical scavenging are results summarized in Figure 4. these exhibited free radical scavenging ability at ability at concentrations of 5µM, µM,5010µM, µM,100 50 µM, µM, and 100 µM, andas 100 µM as compared withmaterial, control concentrations of 5 µM, 10 100 µM compared with control material, respectively. Interestingly prepared compounds showed higher DPPHradical radical scavenging respectively. Interestingly prepared compounds 6–8 6–8 showed higher DPPH activity than that of standard compound, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) [32]. Additionally, compounds compounds 6–8 showed showed good good DPPH DPPH radical radical scavenging scavenging activity activity compared compared with with trolox trolox at at the the concentration concentration of 50 50 and and 100 100 µM. µM. Estimation Estimation of of the the structural structural characteristics characteristics of prepared prepared chalcone chalcone derivatives revealed that the major feature is composed according to monomers, dimers, and trimers based on the 1,4-phenethyldion 1,4-phenethyldion conjugated conjugated skeleton. skeleton. Compound 8 exhibited the most potent radical scavenging scavenging activity activity among among these these analogues. analogues. This finding suggests that the trimer group significantly significantly enhanced enhanced radical scavenging and antioxidant activity due to internal internal electronic electronic effect favourable binding binding to to the the active active sites. sites. effect and/or and/or favourable
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DPPH Scavenging Activity DPPH Scavenging Activity (%)(%)
100 100
comp3 comp6 comp3 comp7 comp6 comp8 comp7 trolox comp8
80 80
trolox
60 60 40 40 20 20 0 0
5 uM 5 uM
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Figure Rateofofscavenging scavenging2,2-diphenyl-1-picrylhydrazyl 2,2-diphenyl-1-picrylhydrazyl (DPPH) 3 and 6–8. Figure 4. 4.Rate (DPPH)radical radicalofofanalogues analogues 3 and 6–8. Figure 4. Rate of scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical of analogues 3 and 6–8.
Nitrite generation (μM) Nitrite generation (μM)
2.3.2. InhibitionofofNO NOGeneration Generation 2.3.2. Inhibition 2.3.2. Inhibition of NO Generation The in vitro suppression of NO production of compounds 3 and 6–8 were evaluated in LPS–treated The in in vitro suppression ofofNO production compounds 33and and6–8 6–8were wereevaluated evaluated inLPS–treated LPS–treated The vitro suppression NOsummarized production of of microglia cells, and the results are incompounds Figure 5. Interestingly, dimer moietyincompound 6 microglia cells, and results summarized inFigure Figure5.5.Interestingly, Interestingly, dimer moiety compound microglia cells, andthe theinhibitory resultsare are summarized dimer moiety compound and 7 showed higher activity of NO in generation than that of the single moiety3 at 5 and6 6 and 77 showed higherinhibitory inhibitoryactivity activity of NO generation than that of single the single moiety 3 at 5 and showed higher of NO generation than the at 5cells, and 10 µM. It was found that all compounds showed suppression of that NO of generation onmoiety3 microglia and1010µM. µM.It It was found that all compounds showed suppression of NO generation on microglia cells, was found all compounds showed suppression NO generation microglia cells, with the most potent that inhibition trimer compound 8, even at aofconcentration of on 1 µM. This result with thethe most potent inhibition trimer compound 8, even at group a concentration of 1 µM. result implied with most potent inhibition trimer compound 8, even at a concentration of ring 1This µM. This result implied that the methoxyl and para-position methoxyl at the benzene enhanced to that the methoxyl and para-position methoxyl group at the benzene ring enhanced to delocalize fortothe implied that the methoxyl and para-position methoxyl group at the benzene ring enhanced delocalize for the electron density based on resonance effect. Compounds with dimer and timer electron density based on groups resonance effect. Compounds with dimer and timer methoxyl delocalize for hydroxyl the electron density basedshowed on resonance effect. Compounds with dimerand andhydroxyl timer methoxyl and generally increased suppression of NO production. methoxyl and hydroxyl generally showed suppression of NO production. groups generally showed groups increased suppression ofincreased NO production. 60 60
1 uM 5 uM 1 uM 10uM 5 uM 10uM
50 50 40 40 30 30 20 20 10 10 0 0
Vehi LPS Vehi LPS
LPS+3 LPS+3
LPS+6 LPS+6
LPS+7 LPS+7
LPS+8 LPS+8
Figure 5. Suppression of NO production in lipopolysaccharide (LPS–treated BV2 cells. The cells were Figure 5. Suppression NOproduction production inlipopolysaccharide lipopolysaccharide (LPS–treated BV2 cells. The cells were treated with 1 µg/mLof ofofNO LPS only or LPSin plus different concentration (1, 5 and 10 µM) of compounds Figure 5. Suppression (LPS–treated BV2 cells. The cells were treated with 1 µg/mL of LPS only or LPS plus different concentration (1, 5 and 10 µM)to ofmeasure compounds 3 and 6–8 at 37 °C for 24 h. At the end of incubation, 50 µL of the medium was taken the treated with 1 µg/mL of LPS only or LPS plus different concentration (1, 5 and 10 µM) of compounds 3 and 6–8 at 37 °C for 24values h. At the end of incubation, µL of the medium wasoftaken to measure the nitrite represent mean 50 ± 50 Standard Error (SE) three-independent 3 and 6–8production. at 37 ◦ C forAll 24 h. At the end of the incubation, µL of the medium was taken to measure nitrite production. All values represent the mean ± Standard Error (SE) of three-independent performedAll in values triplicate. theexperiments nitrite production. represent the mean ± Standard Error (SE) of three-independent experiments performed in triplicate. experiments performed in triplicate.
2.3.3. Neuroprotective Activity: Inhibition of Glutamate-Induced Neurotoxicity 2.3.3. Neuroprotective Activity: Inhibition of Glutamate-Induced Neurotoxicity 2.3.3. Neuroprotective Activity: Inhibition of Glutamate-Induced We have examined the neuroprotective effects of 3 and 6–8Neurotoxicity on the inhibition of glutamateWe neurotoxicity have examined the neuroprotective effectsMost of 3 of and on thecompound inhibition showed of glutamateinduced in cultured cortical neurons. the6–8 chalcone good We have examined the neuroprotective effects of 3Most and of 6–8the onchalcone the inhibition of glutamate-induced induced neurotoxicity in cultured cortical neurons. compound showed good anti–excitotoxicity on the concentration range over 10 µM as shown in Figure 6. Compound 8 neurotoxicity in cultured cortical neurons. Most of µM the aschalcone compound showed good anti–excitotoxicity on the concentration range over 10 shown in Figure 6. Compound exhibited the most potent activity among these analogues. The increasing efficacy of hydroxyl8 anti–excitotoxicity on the concentration range over µM as shown Figure 6. Compound 8 exhibited exhibited the most potent activity among these10analogues. Theinincreasing efficacy of hydroxyl
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the most potent activity among these analogues. The increasing efficacy of hydroxyl moieties 6–8 is presumably due the para-position, which has increased density of the density hydroxyl moieties 6–8 is to presumably due to the para-position, whichthe haselectron increased the electron of group the and loweredgroup the oxygen–hydrogen bonding energy. bonding energy. hydroxyl and lowered the oxygen–hydrogen 1 uM 5 uM 10uM
Cell Viability (%)
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Vehi Glu
Glu+3
Glu+6
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Figure Inhibitionofofglutamate-induced glutamate-induced neurotoxicity neurotoxicity in Glutamate alone Figure 6. 6.Inhibition incultured culturedcortical corticalneurons. neurons. Glutamate alone ◦ with (60µM), µM),compounds compounds33and and 6–8 6–8 were were applied applied for of of neurons or or with (60 for 24 24hhatat37 37°C.C.After Afterincubation incubation neurons with WST-1 andquantified quantifiedspectrophotometrically. spectrophotometrically. All ± SE of of with WST-1 forfor2 2h hand Allvalues valuesrepresent representthe themean mean ± SE three-independent experiments performed in triplicate. three-independent experiments performed in triplicate.
Materials and Methods 3. 3. Materials and Methods Synthesis 3.1.3.1. Synthesis commercialreagents reagentsand andsolvents solvents were were used purification unless AllAll commercial used as asreceived receivedwithout withoutfurther further purification unless specified. The reactions were monitored and the Rf values determined using TLC with Merck silica specified. The reactions were monitored and the Rf values determined using TLC with Merck gel 60, F-254 pre-coated plates (0.25-mm thickness) (Merck, Frankfurt, Germany). Spots on the TLC silica gel 60, F-254 pre-coated plates (0.25-mm thickness) (Merck, Frankfurt, Germany). Spots on plates were visualized using ultraviolet light (254 nm) (Spectroline, New York, USA) and a basic the TLC plates were visualized using ultraviolet light (254 nm) (Spectroline, New York, NY, USA) potassium permanganate solution or cerium sulfate/ammonium dimolybdate/sulfuric acid solution and a basic potassium permanganate solution or cerium sulfate/ammonium dimolybdate/sulfuric in house, followed by heating on a heat-gun, PHG 630 DCE (BOSCH, Gerlingen, Germany). acid solution Magnetic in house,Resonance followed(NMR) by heating onwere a heat-gun, 630 DCE (BOSCH, 1H-Nuclear spectra recorded PHG on Bruker DPX-250 (BrukerGerlingen, Optics, 1 Germany). H-Nuclear Magnetic Proton Resonance (NMR) spectra were in recorded Bruker DPX-250 Billerica, MA, USA) spectrometers. chemical shifts are reported ppm (δ) on relative to internal (Bruker Optics, Billerica, MA, USA) spectrometers. Proton chemical shifts are reported in ppm tetramethylsilane (TMS, δ 0.00) or with the solvent reference relative to TMS as the internal standard (δ)(CDCl relative internal (TMS, δ 0.00) orδ with the solvent reference relative to TMS 3, δto 7.26 ppm; dtetramethylsilane 4-CD3OD, δ 3.31 ppm, d6-DMSO, 2.50 ppm). Data are reported as follows: as chemical the internal (CDCl 7.26doublet ppm; d(d), 3.31 ppm, d6 -DMSO, δ 2.50 Data 3 , δ (s), 4 -CD 3 OD, shiftstandard multiplicity [singlet triplet (t),δ quartet (q), and multiplet (m)],ppm). coupling 13 areconstants reported[Hz], as follows: chemical shift multiplicity [singlet (s), doublet (d), triplet (t), quartet integration. C-NMR spectra were recorded on Bruker DPX-250 (63 MHz)(q), and multiplet (m)], coupling constants [Hz], integration. C-NMR spectra were recorded on Bruker spectrometers with complete proton decoupling. Carbon13chemical shifts are reported in ppm (δ) relative (63 to TMS with the respective with solvent resonance as the decoupling. internal standard (CDClchemical 3, δ 77.0 ppm; d4-are DPX-250 MHz) spectrometers complete proton Carbon shifts CD3OD,inδ ppm 49.0 ppm, d6-DMSO, δ 39.5with ppm). (IR) solvent spectra were recorded on ainternal Nicolet standard Model reported (δ) relative to TMS theInfrared respective resonance as the Impact spectrometer (Thermo MA, USA). Data(IR) are reported in (CDCl 77.0 400 ppm; d4 -CD3 OD, δ 49.0 Fisher ppm, dScientific, δ 39.5 ppm). Infrared spectra were 3 , δFT-IR 6 -DMSO,Waltham, −1 wave numbers (cm ). Model Mass spectra were recorded on a Matrix Assisted Laser Desorption/Ionizationrecorded on a Nicolet Impact FT-IR 400 spectrometer (Thermo Fisher Scientific, Waltham, − 1 Time-of-Flight Mass Spectrometry (MALDI-TOF) Voyager-DE STR (Applied Biosystems MA, USA). Data are reported in wave numbers (cm ). Mass spectra were recorded on a 4700 Matrix proteomics analyser spectrometer, Palo Alto, CA, USA) with a α-cyano-4-hydroxycinnamic acid Assisted Laser Desorption/Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF) Voyager-DE (α-CHCA) matrix. High-Resolution Mass Spectrometry (HRMS) was recorded on a LTQ Orbitrap STR (Applied Biosystems 4700 proteomics analyser spectrometer, Palo Alto, CA, USA) with a Velos Liquid Chromatography Mass Spectrometry (LC-MS) (Thermo Fisher Scientific, Waltham, MA, α-cyano-4-hydroxycinnamic acid (α-CHCA) matrix. High-Resolution Mass Spectrometry (HRMS) was USA). Electrospray ionization (ESI)-LC-MS was recorded on a Waters ZQ 4000 LC-MS spectrometer recorded on a LTQ Orbitrap Velos Liquid Chromatography Mass Spectrometry (LC-MS) (Thermo Fisher (Waters Corporation, Milford, MA, USA). Purified human 20S proteasome was purchased from Enzo Scientific, Waltham, MA, USA). Electrospray ionization (ESI)-LC-MS was recorded on a Waters ZQ Life Sciences (Plymouth Meeting, PA, USA). Fluorogenic peptide substrates Suc-LLVY-AMC was 4000 LC-MS spectrometer (Waters Corporation, Milford, MA, USA). Purified human 20S proteasome obtained from Sigma-Aldrich (St. Louis, MO, USA).
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was purchased from Enzo Life Sciences (Plymouth Meeting, PA, USA). Fluorogenic peptide substrates Suc-LLVY-AMC was obtained from Sigma-Aldrich (St. Louis, MO, USA). (E)-1-{3-[(E)-3-(4-Hydroxy-3-methoxyphenyl)acryloyl]phenyl}-3-(4-hydroxy-3-methoxyphenyl)-2-propenone (6). To a stirred solution of 1,3-diacetylbenzene (0.24 g, 1.48 mmol) and c-H2 SO4 (0.15 g, 1.48 mmol) in ethanol (10 mL) was refluxed for 30 min and then a solution of vanillin (0.45 g, 2.96mmol) in ethanol (10 mL) was added to the reaction mixture. The resulting solution was refluxed for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes) to give pure product 6 as a brown solid (0.3 g, 23%). Rf = 0.28 (dichloromethane/methanol = 50:1, v/v); m.p. 165–168 ◦ C; IR νmax (CHCl3 , KBr) 3394, 1655, 1585, 1512, 1463, 1450, 1429, 1270, 1204, 1178, 1124, 1031, 980, 845, 755 cm−1 ; 1 H-NMR (250 MHz, CDCl3 ) δ 8.62 (s, 1 H), 8.20 (dd, J = 7.58, 1.58 Hz, 2H), 7.80 (d, J = 15.48 Hz, 2H), 7.62 (t, J = 7.74 Hz, 1H), 7.42 (d, J = 15.48 Hz, 2H), 7.23 (d, J = 1.90 Hz, 1H), 7.20 (d, J = 1.90 Hz, 1H), 7.15 (d, J = 1.58 Hz, 2H), 6.96 (d, J = 8.21 Hz, 2H), 3.94 (s, 6H); 13 C-NMR (63 MHz, CDCl3 ) δ190.06, 148.80, 147.04, 146.26, 138.91, 132.31, 129.05, 128.28, 127.31, 123.97, 119.23, 115.09, 110.20, 56.16; MALDI-TOF [M + H] 431.0972; HRMS calcd. for C26 H22 O6 : 430.1416 [M]+ , found: 430.1421. (E)-1-{4-[(E)-3-(4-Hydroxy-3-methoxyphenyl)acryloyl]phenyl}-3-(4-hydroxy-3-methoxyphenyl)-2-propenone (7). To a stirred solution of 1,4-diacetylbenzene (0.053 g, 0.33 mmol) and c-H2 SO4 (0.032 g, 0.33 mmol) in ethanol (5 mL) was refluxed for 30 min and a solution of vanillin (0.1 g, 0.66 mmol) in ethanol (5 mL) was added to the reaction mixture. The resulting mixture was refluxed for 12 h. The reaction mixture was cooled to room temperature. The solid was filtered and washed with ethanol and ether to give pure product 7 as a brown solid (0.05 g, 35%). Rf = 0.6 (dichloromethane/methanol = 9:1, v/v); m.p. 228–230 ◦ C; IR νmax (acetone, KBr) 3423, 2926, 2850, 1728, 1649, 1582, 1514, 1430, 1384, 1272, 1161, 1126, 1092, 1030, 815, cm−1 ; 1 H-NMR (250 MHz, acetone-d6 ) δ 8.22 (s, 4H), 7.74–7.77 (m, 4H), 7.53 (s, 2H), 7.34 (dd, J = 2.0, 8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 3.94 (s, 6H); 13 C-NMR (63 MHz, acetone-d6 ) δ 189.9, 150.8, 149.0, 146.5, 129.5, 128.1, 124.9, 120.2, 116.4, 112.4, 109.8, 56.6; LC-MS (ESI) m/z 453 [M + Na]+ ; MALDI-TOF [M + H] 431.1430; HRMS calcd. for C26 H22 O6 : 430.1416 [M]+ , found: 430.1432. (E)-1-{3,5-Bis[(E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl]phenyl}-3-(4-hydroxy-3-methoxyphenyl)-2-propenone (8). To a stirred solution of 1,3,5-triacetylbenzene (0.045 g, 0.22 mmol) and c-H2 SO4 (0.022 g, 0.22 mmol) in ethanol (5 mL) was refluxed for 30 min and then a solution of vanillin (0.1 g, 0.66 mmol) in ethanol (5 mL) was added to the reaction mixture. The resulting mixture was refluxed for 3 h and cooled to room temperature. The solid was filtered and washed with ethanol and ether to give pure product 8 as a brown solid (0.097 g, 73%). Rf = 0.6 (dichloromethane/methanol = 9:1, v/v); m.p. 255–256 ◦ C; IRmax (acetone, KBr) 3435, 3062, 2933, 1649, 1591, 1514, 1429, 1384, 1269, 1161, 1124, 1029, 810 cm−1 ; 1 H-NMR (250 MHz, acetone-d ) δ8.89 (s, 3H), 7.85–7.88 (m, 6H), 7.58 (s, 3H), 7.29 (d, J = 8.3 Hz, 3H), 6 6.92 (d, J = 8.2 Hz, 3H), 3.94 (s, 9H); 13 C-NMR (100 MHz, acetone-d6 ) δ 189.4, 150.9, 148.9, 147.0, 140.6, 132.1, 128.1, 125.2, 120.0, 116.4, 112.5, 56.6; LC-MS (ESI+) m/z 629 [M + Na]. MALDI-TOF [M + H] 607.1219; HRMS calcd. for C36 H30 O9 : 606.1890 [M]+ , found: 606.1885. 3.2. Molecular Modeling The lower energy conformers for each compound, compounds 3 and 6–8 were searched with the semi-empirical AM1 method [33]. The lower energy conformers were submitted to a geometry optimization and energy calculations by density functional theories (DFT) model calculation at the B3LYP 6-31G** level [34]. The HOMO and LUMO values of the selected conformers were also calculated. All calculations and graphical representations were performed by using the SPARTAN 06 for Windows software package (SPARTAN 06 for Windows, Wavefuction Inc., Irvine, CA, USA) [35]. 3.3. Biology-Measurement of Cell Viability Cortical neuronal cell number and viability were assessed by using the reagent water soluble tetrazolium-1 (WST-1) (Roche, Indianapolis, IN). This colorimetric assay measures the
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metabolic activity of viable cells based on cleavage of the tetrazolium salt WST-1 substrate 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate into formazan by mitochondria dehydrogenase in live cells. This was followed by incubation with WST-1 reagent at a dilution of 1:10 in the original conditioned media at 37 ◦ C for 2 h. After thorough shaking, the formazan produced by the metabolically active cells in each sample was measured at a wavelength of 450 nm and a reference wavelength of 650 nm. Absorbance readings were normalized against control wells with untreated cells. Neuronal death was analysed 24 h later, and the percentage of neurons undergoing actual neuronal death was normalized to the mean value that was found after a 24 h exposure to 300 µM N-methyl-D-aspartate (NMDA) (defined as 0) or a sham control (defined as 100). 4. Conclusions Simple synthesis involving one-step aldol condensation and biological properties of 4-hydroxy-3-methoxyphenyl-2-propenes 6–8 have been described. A simple synthetic strategy was established with an aldol reaction of 4-hydroxy-3-methoxybenzaldehyde and acetophenones in the presence of acidic media to generate novel chalcones 6–8. These analogues have been contributed to form the stable phenoxy radical based on delocalizing electron movement and intramolecular hydrogen bonding. It was found that all compounds showed good effects for DPPH free radical scavenging, LPS-induced NO generation, and anti-neurotoxicity. Compounds 6 and 7 were potent suppressor of NO generation with the concentration range 10 µM and especially compound 8 showed very potent anti-inflammatory activity with 1 µM. The di- and tri-acetylbenzyl derivatives 6, 7, and 8 showed enhanced anti-neurotoxicity activity in cultured cortical neurons. Furthermore, the HOMO-LUMO gap could be considered to be potential explanations for the anti-neurotoxic effects of chalcone derivatives. Acknowledgments: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2010-0027945). Author Contributions: J.-C.J., M.J., and S.O. were responsible for study design and the provision of research funding. J.-C.J., Y.L., and D.M. performed the experimental operation. J.-C.J., M.J., and S.O. wrote the manuscript. All authors have read and approved the final manuscript. Conflicts of Interest: The authors declare no conflict of interest.
References 1. 2. 3. 4.
5. 6.
7.
Viana, G.S.B.; Bandeira, M.A.M.; Matos, F.J.A. Analgesic and antiinflammatory effects of chalcones isolated from Myracrodruon urundeuva Allemão. Phytomedicine 2003, 10, 189–195. [CrossRef] [PubMed] Rojas, J.; Payá, M.; Domínguez, J.N.; Ferrándiz, M.L. ttCH, a selective inhibitor of inducible nitric oxide synthase expression with antiarthritic properties. Eur. J. Pharmcol. 2003, 465, 183–189. [CrossRef] Nowakowska, Z. A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem. 2007, 42, 125–137. [CrossRef] [PubMed] Al Rahim, M.; Nakajima, A.; Misawa, N.; Shindo, K.; Adachi, K.; Shizuri, Y.; Ohizumi, Y.; Yamakuni, T. A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Aβ-inhibition of the cascade in cultured rat CNS neurons. Eur. J. Pharmacol. 2008, 600, 10–17. [CrossRef] [PubMed] Nielsen, S.F.; Larsen, M.; Boesen, T.; Schonning, K.; Kromann, H. Cationic chalcone antibiotics. Design, synthesis, and mechanism of action. J. Med. Chem. 2005, 48, 2667–2677. [CrossRef] [PubMed] Ali, M.A.; Shaharyar, M.; De Clercq, E. Synthesis of 5-(4-hydroxy-3-methylphenyl)-5-(substituted phenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives with anti-viral activity. J. Enzyme Inhib. Med. Chem. 2007, 22, 702–708. [CrossRef] [PubMed] Onyilagha, J.C.; Malhotra, B.; Elder, M.; French, C.J.; Towers, G.H.N. Comparative studies of inhibitory activities of chalcones on tomato ringspot virus (ToRSV). Can. J. Plant Pathol. 1997, 19, 133–137. [CrossRef]
Molecules 2017, 22, 1872
8.
9.
10.
11. 12.
13.
14.
15.
16.
17. 18.
19.
20. 21.
22. 23.
24. 25.
10 of 11
Konieczny, M.T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.; Wakiec, R.; Augustynowicz-Kopec, E.; Zwolska, Z. Synthesis of isomeric, oxathiolone fused chalcones, and comparison of their activity toward various microorganisms and human cancer cells line. Chem. Pharm. Bull. 2007, 55, 817–820. [CrossRef] [PubMed] Gschwendt, M.; Kittstein, W.; Furstenberger, G.; Marks, F. The mouse ear edema: A quantitatively evaluable assay for tumor promoting compounds and for inhibitors of tumor promotion. Cancer Lett. 1984, 25, 177–185. [CrossRef] Bhale, P.S.; Chavan, H.V.; Dongare, S.B.; Shringare, S.N.; Mule, Y.B.; Nagane, S.S.; Bandgar, B.P. Synthesis of extended conjugated indolyl chalcones as potent anti-breast cancer, anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. Lett. 2017, 27, 1502–1507. [CrossRef] [PubMed] Sokmen, M.; Khan, M.A. The antioxidant activity of some curcuminoids and chalcones. Inflammopharmacology 2016, 24, 81–86. Hofmann, E.; Webster, J.; Do, T.; Kline, R.; Snider, L.; Hauser, R.; Higginbottom, G.; Campbell, A.; Ma, L.; Paula, S. Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers. Bioorg. Med. Chem. 2016, 24, 578–587. [CrossRef] [PubMed] Miranda, C.L.; Stevens, J.F.; Ivanov, V.; McCall, M.; Frei, B.; Deinzer, M.L.; Buhler, D.R. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J. Agric. Food. Chem. 2000, 48, 3876–3884. [CrossRef] [PubMed] Nakamura, C.; Kawasaki, N.; Miyataka, H.; Jayachandran, E.; Kim, I.H.; Kirk, K.L.; Taguchi, T.; Takeuchi, Y.; Hori, H.; Satoh, T. Synthesis and biological activities of fluorinated chalcone derivatives. Bioorg. Med. Chem. 2002, 10, 699–706. [CrossRef] Park, P.H.; Kim, H.S.; Hur, J.; Jin, X.Y.; Jin, Y.L.; Sohn, D.H. YL-I-108, a synthetic chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 murine macrophages: Involvement of heme oxygenase-1 induction and blockade of activator protein-1. Arch. Pharm. Res. 2009, 32, 79–89. [CrossRef] [PubMed] Ansari, F.L.; Umbreen, S.; Hussain, L.; Makhmoor, T.; Nawaz, S.A.; Lodhi, M.A.; Khan, S.N.; Shaheen, F.; Choudhary, M.I.; Atta-ur-Rahman. Syntheses and biological activities of chalcone and 1,5-benzothiazepine derivatives: Promising new free-radical scavengers, and esterase, urease, and α-glucosidase inhibitors. Chem. Biodivers. 2005, 2, 487–496. [CrossRef] [PubMed] Burnham, W.S.; Sidwell, R.W.; Tolman, R.L.; Stout, M.G. Synthesis and antiviral activity of 40 -hydroxy-5,6,7,8-tetramethoxyflavone. J. Med. Chem. 1972, 15, 1075–1076. [CrossRef] [PubMed] Boeck, P.; Falcao, C.A.B.; Leal, P.C.; Yunes, R.A.; Cechinel, V.; Torres-Santos, E.C.; Rossi-Bergmann, B. Synthesis of chalcone analogues with increased antileishmanial activity. Bioorg. Med. Chem. 2006, 14, 1538–1545. [CrossRef] [PubMed] Dominguez, J.N.; Leon, C.; Rodrigues, J.; de Dominguez, N.G.; Gut, J.; Rosenthal, P.J. Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives. J. Med. Chem. 2005, 48, 3654–3658. [CrossRef] [PubMed] Quintin, J.; Desrivot, J.; Thoret, S.; Le Menez, P.; Cresteil, T.; Lewin, G. Synthesis and biological evaluation of a series of tangeretin-derived chalcones. Bioorg. Med. Chem. Lett. 2009, 19, 167–169. [CrossRef] [PubMed] Prakash, O.; Kumar, A.; Sadana, A.; Prakash, R.; Singh, S.P.; Claramunt, R.M.; Sanz, D.; Alkorta, I.; Elguero, J. Study of the reaction of chalcone analogs of dehydroacetic acid and o-aminothiophenol: Synthesis and structure of 1,5-benzothiazepines and 1,4-benzothiazines. Tetrahedron 2005, 61, 6642–6651. [CrossRef] Weber, W.M.; Hunsaker, L.A.; Abcouwer, S.F.; Deck, L.M.; Vander Jagt, D.L. Anti-oxidant activities of curcumin and related enones. Bioorg. Med. Chem. 2005, 13, 3811–3820. [CrossRef] [PubMed] Jang, S.; Jung, J.C.; Kim, D.H.; Ryu, J.H.; Lee, Y.; Jung, M.; Oh, S. The neuroprotective effects of benzylideneacetophenone derivatives on excitotoxicity and inflammation via phosphorylated janus tyrosine kinase 2/phosphorylated signal transducer and activator of transcription 3 and mitogen-activated protein K pathways. J. Pharmacol. Exp. Ther. 2009, 328, 435–447. [CrossRef] [PubMed] Lee, Y.H.; Yun, J.; Jung, J.C.; Oh, S.; Jung, Y.S. Anti-tumor activity of benzylideneacetophenone derivatives via proteasomal inhibition in prostate cancer cells. Pharmazie 2016, 71, 274–279. [PubMed] Lee, H.J.; Kim, J.S.; Yoon, J.W.; Kim, H.-D.; Ryu, J.-H. Suppression of inducible nitric oxide synthase expression by yakuchinones and their analogues. Chem. Pharm. Bull. 2006, 54, 377–379. [CrossRef] [PubMed]
Molecules 2017, 22, 1872
26.
27. 28.
29. 30. 31. 32.
33. 34. 35.
11 of 11
Winter, E.; Devantier, N.P.; Chiaradia-Delatorre, L.D.; Gauthier, C.; Yunes, R.A.; Nunes, R.J.; Creczynski-Pasa, T.B.; Di Pietro, A. Symmetric bis-chalcones as a new type of breast cancer resistance protein inhibitors with a mechanism different from that of chromones. J. Med. Chem. 2014, 57, 2930–2941. [CrossRef] [PubMed] Jang, S.; Jung, J.C.; Oh, S. Synthesis of 1,3-diphenyl-2-propen-1-one derivatives and evaluation of their biological activities. Bioorg. Med. Chem. 2007, 15, 4098–4105. [CrossRef] [PubMed] Jung, J.-C.; Jang, S.; Lee, Y.; Min, D.; Lim, E.; Jung, H.; Oh, M.; Oh, S.; Jung, M. Efficient synthesis and neuroprotective effect of substituted 1,3-diphenyl-2-propen-1-ones. J. Med. Chem. 2008, 51, 4054–4058. [CrossRef] [PubMed] Eddarir, S.; Cotelle, N.; Bakkour, Y.; Rolando, C. An efficient synthesis of chalcones based on the Suzuki reaction. Tetrahedron Lett. 2003, 44, 5359–5363. [CrossRef] Lawinski, M.; Sledzinski, Z.; Kubasik-Juraniec, J.; Spodnik, J.H.; Wozniak, M.; Boguslawski, W. Does resveratrol prevent free radical-induced acute pancreatitis? Pancreas 2005, 31, 43–47. [PubMed] Kimura, Y.; Okuda, H.; Arichi, S. Effects of stilbenes on arachidonate metabolism in leukocytes. Biochim. Biophys. Acta Lipids Lipid Metab. 1985, 834, 275–278. Theodosis-Nobelos, P.; Athanasekou, C.; Rekka, E.A. Dual antioxidant structures with potent anti-inflammatory, hypolipidemic and cytoprotective properties. Bioorg. Med. Chem. Lett. 2017, 27, 4800–4804. [CrossRef] [PubMed] Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. AM1: A new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 1985, 107, 3902–3909. [CrossRef] Kohn, W.; Becks, A.D.; Parr, R.G. Density functional theory of electronic structure. J. Phys. Chem. 1996, 100, 12974–12980. [CrossRef] Spartan’06; Wavefunction Inc.: Irvine, CA, USA, 2006.
Sample Availability: Samples of the compounds 6,7,8 are available from the authors. © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
