- Synthesis and cytotoxic evaluation of monocarbonyl curcuminoids and their pyrazoline derivatives
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Abstract: A small set of structurally different monocarbonyl curcuminoids was prepared and screened for cytotoxic activity. In particular, bis-3-methoxy-4-hydroxy- and bis-4-methoxyphenyl-substituted monocarbonyls were synthesized and transformed into the corresponding three-dimensional N-acetylpyrazoline derivatives. In addition, a non-symmetrical indole-based monocarbonyl curcumin was prepared as well. Preliminary cytotoxic evaluation revealed significant effects for 4-hydroxy (pyrazoline) monocarbonyl curcuminoids, whereas the non-phenolic variants displayed rather poor activity. Graphic abstract: [Figure not available: see fulltext.].
- Van de Walle, Tim,Theppawong, Atiruj,Grootaert, Charlotte,De Jonghe, Steven,Persoons, Leentje,Daelemans, Dirk,Van Hecke, Kristof,Van Camp, John,D’hooghe, Matthias
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- Anti-tumor agents 255: Novel glycyrrhetinic acid-dehydrozingerone conjugates as cytotoxic agents
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Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anti-cancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED50 values of 0.6, 0.8, and 0.9 μM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anti-cancer drug discovery and development.
- Tatsuzaki, Jin,Taniguchi, Masahiko,Bastow, Kenneth F.,Nakagawa-Goto, Kyoko,Morris-Natschke, Susan L.,Itokawa, Hideji,Baba, Kimiye,Lee, Kuo-Hsiung
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- Small molecules interacting with α-synuclein: Antiaggregating and cytoprotective properties
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Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O 2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.
- Marchiani, Anna,Mammi, Stefano,Siligardi, Giuliano,Hussain, Rohanah,Tessari, Isabella,Bubacco, Luigi,Delogu, Giovanna,Fabbri, Davide,Dettori, Maria A.,Sanna, Daniele,Dedola, Sonia,Serra, Pier A.,Ruzza, Paolo
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- Retro-curcuminoids as mimics of dehydrozingerone and curcumin: Synthesis, NMR, X-ray, and cytotoxic activity
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Curcumin and its derivatives have been extensively studied for their remarkable medicinal properties, and their chemical synthesis has been an important step in the optimization of well-controlled laboratory production. A family of new compounds that mimic the structure of curcumin and curcuminoids, here named retro-curcuminoids (7-14), was synthesized and characterized using 1D 1H- and 13C-NMR, IR, and mass spectrometry; the X-ray structure of 7, 8, 9, 10, 12, 13, and 14 are reported here for the first time. The main structural feature of these compounds is the reverse linkage of the two aromatic moieties, where the acid chloride moiety is linked to the phenolic group while preserving α,β-unsaturated ketone functionality. The cytotoxic screening of 7, 8, 9, and 10 at 50 and 10 μg/mL was carried out with human cancer cell lines K562, MCF-7, and SKLU-1. Lipid peroxidation on rat brain was also tested for compounds 7 and 10. Compounds 7, 8, and 10 showed relevant cytotoxic activity against these cancer cell lines, and 10 showed a protective effect against lipid peroxidation. The molecular resemblance to curcuminoids and analogs with ortho substituents suggests a potential source of useful bioactive compounds.
- Obregón-Mendoza, Marco A.,Estévez-Carmona, María Mirian,Hernández-Ortega, Simón,Soriano-García, Manuel,Ramírez-Apan, María Teresa,Orea, Laura,Pilotzi, Hugo,Gnecco, Dino,Cassani, Julia,Enríquez, Raúl G.
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- The synthesis and evaluation of vanillin derivatives as the fruit fly attractant
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The present study was conducted to synthesize 4-(4-hydroxyphenyl-3-methoxy)-4-hydroxy-2-butanone, a compound with similar structure to cue lure [4-(4-Acetyoxyphenyl)-2-butanone], using vanillin as a started material. The synthesis process was completed in two steps. The first step was the condensation reaction of Claisen Smidth between vanillin and acetone on alkaline conditions to produce 4-(4-hydroxyphenyl-3-methoxy)-3-buten-2-one, and the second step was the hydration reaction using zeolite catalysts activated by HCl, to produce 4-(4-hydroxyphenyl-3-methoxy)-4-hydroxy-2-butanone. Characterization of the compounds was performed using IR and 1H-NMR spectroscopy. The evaluation of 4-(4-hydroxyphenyl-3-methoxy)-4-hydroxy-2-butanone as fruit flies’ attractant was carried out in yard areas planted with guava and start fruit, in the Klidon village, Sukoharjo, Sleman Yogyakarta, with methyl eugenol as a standard. The observations were made for 24 hours. The synthesis product was obtained in the form of a white-orange solid with a melting point of 79-81oC and 60% yield.The field test showed that 4-(4-hydroxyphenyl-3-methoxy)-4-hydroxy-2-butanone was potential as fruit flies’ attractant, indicated by the presence of lured fruit flies around the test location.
- Prabawati, Susy Yunita,Iskandar, Damayanti,Suci, Liimroati Purwo
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- Synthesis and studies of the inhibitory effect of hydroxylated phenylpropanoids and biphenols derivatives on tyrosinase and laccase enzymes
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The impaired activity of tyrosinase and laccase can provoke serious concerns in the life cycles of mammals, insects and microorganisms. Investigation of inhibitors of these two enzymes may lead to the discovery of whitening agents, medicinal products, anti-browning substances and compounds for controlling harmful insects and bacteria. A small collection of novel reversible tyrosinase and laccase inhibitors with a phenylpropanoid and hydroxylated biphenyl core was prepared using naturally occurring compounds and their activity was measured by spectrophotometric and electrochemical assays. Biosensors based on tyrosinase and laccase enzymes were constructed and used to detect the type of protein-ligand interaction and half maximal inhibitory concentration (IC50). Most of the inhibitors showed an IC50 in a range of 20–423 nM for tyrosinase and 23–2619 nM for laccase. Due to the safety concerns of conventional tyrosinase and laccase inhibitors, the viability of the new compounds was assayed on PC12 cells, four of which showed a viability of roughly 80% at 40 μM. In silico studies on the crystal structure of laccase enzyme identified a hydroxylated biphenyl bearing a prenylated chain as the lead structure, which activated strong and effective interactions at the active site of the enzyme. These data were confirmed by in vivo experiments performed on the insect model Tenebrio molitur.
- Dettori, Maria Antonietta,Fabbri, Davide,Dessì, Alessandro,Dallocchio, Roberto,Carta, Paola,Honisch, Claudia,Ruzza, Paolo,Farina, Donatella,Migheli, Rossana,Serra, Pier Andrea,Pantaleoni, Roberto A.,Fois, Xenia,Rocchitta, Gaia,Delogu, Giovanna
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- Applying an Electrophilicity-Based Strategy to Develop a Novel Nrf2 Activator Inspired from Dietary [6]-Shogaol
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Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial cellular defense mechanisms against oxidative stress and also an effective means to decrease the risk of oxidative stress-related diseases including cancer. Thus, identifying novel Nrf2 activators is highly anticipated. Inspired from [6]-shogaol (6S), an active component of ginger, herein we developed a novel potent Nrf2 activator, (1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-7-methylocta-1,4,6-trien-3-one (SA) by an electrophilicity-based strategy. Compared with the parent 6S, SA bearing a short but entirely conjugated unsaturated ketone chain manifested the improved electrophilicity and cytoprotection (cell viability for the 10 μM 6S- and SA-treated group being 48.9 ± 5.3% and 76.1 ± 3.2%, respectively) against tert-butylhydroperoxide (t-BHP)-induced cell death (cell viability for the t-BHP-stimulated group being 42.4 ± 0.4%) of HepG2. Mechanistic study uncovers that SA works as a potent Nrf2 activator by inducing Keap1 modification, inhibiting Nrf2 ubiquitylation and phosphorylating ERK in a Michael acceptor-dependent fashion. Taking 6S as an example, this works illustrates the feasibility and importance of applying an electrophilicity-based strategy to develop Nrf2 activators with dietary molecules as an inspiration due to their low toxicity and extraordinarily diverse chemical scaffolds.
- Du, Yu-Ting,Zheng, Ya-Long,Ji, Yuan,Dai, Fang,Hu, Yong-Jing,Zhou, Bo
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- Prenylated Curcumin Analogues as Multipotent Tools to Tackle Alzheimer's Disease
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Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of Aβ peptides into oligomers and fibrils, neuroinflammation, and oxidative stress. To date, no effective treatments are available, and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic Aβ oligomers, by shifting the equilibrium toward smaller nontoxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind Aβ structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and antioxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worthy to be further investigated and exploited in the Alzheimer's disease multitarget context.
- Bisceglia, Federica,Seghetti, Francesca,Serra, Massimo,Zusso, Morena,Gervasoni, Silvia,Verga, Laura,Vistoli, Giulio,Lanni, Cristina,Catanzaro, Michele,De Lorenzi, Ersilia,Belluti, Federica
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- Synthesis of 1,4-Thiazepane-Based Curcuminoids with Promising Anticancer Activity
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Curcumin, the main component of turmeric (Curcuma longa) is known to display an interesting bioactivity profile, including pronounced anticancer properties. However, its low bioavailability, metabolic instability and nonspecific activity are concerns that have to be addressed before curcuminoids can be considered for therapeutic applications. Within that framework, intensive research has been carried out in the last decades to develop new curcumin derivatives, generally centered on standard modifications of the sp2 curcumin framework, with the aim to augment its bioavailability while maintaining or improving its anticancer properties. To find potential hit molecules by moving away from the classical flat curcumin framework, we investigated an unexplored modification to produce novel, out-of-plane 1,4-thiazepane-based curcuminoids and assessed the impact of this modification on the biological activity. In this way, 21 new, structurally diverse thiazepane scaffolds (4-aryl-1-(7-aryl-1,4-thiazepan-5-ylidene)but-3-en-2-ones) were synthesized, as well as some biologically interesting unexpected reaction products (such as 5-aryl-6-arylmethylene-3-ethoxycyclohex-2-en-1-ones and 4-acetyl-5-aryl-2-(3-arylacryloyl)-3-methylcyclohex-2-en-1-ones). All these analogues were subsequently tested on their antioxidant capacity, their cytotoxicity properties and their ROS (reactive oxygen species) production. Many compounds demonstrated interesting activities, with ten curcuminoids, whereof eight 1,4-thiazepane-based, showing better antiproliferative properties compared to their mother compounds, as well as an increased ROS production. This unprecedented 3D curcumin modification has thus delivered promising new hit compounds with good activity profiles eligible for further exploration.
- Theppawong, Atiruj,Van de Walle, Tim,Van Hecke, Kristof,Grootaert, Charlotte,Van Camp, John,D'hooghe, Matthias
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- Synthesis of new ferrocenyl dehydrozingerone derivatives and their effects on viability of PC12 cells
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A series of novel compounds deriving from the conjugation of ferrocene with curcumin-related bioactive molecules as dehydrozingerone, zingerone and their biphenyl dimers was prepared by Claisen-Schmidt condensation of the suitable aromatic aldehydes and acetylferrocene in different conditions according to the starting material. The obtained compounds were fully characterized by NMR spectroscopy and cyclic voltammetry and reversible electrochemical behavior was recorded for monomer derivatives. The cell viability of PC12 cells after exposure to the organometallic compounds was also evaluated and a reduced toxicity with respect to the ferrocene was detected. In comparison with biphenyl 4, a compound that manifested antiproliferative and apoptotic activities and was quite toxic on PC12 cells, the exposure to the ferrocenyl analogue 14 resulted in roughly fourfold increase in the cell viability. Ferrocenyl chalcones 14 and 16-18 significantly increased the oxidative stress generated by hydrogen peroxide, a molecule generally accumulated in cancer cells and, recently, studied as prodrug.
- Pedotti, Sonia,Patti, Angela,Dedola, Sonia,Barberis, Antonio,Fabbri, Davide,Dettori, Maria Antonietta,Serra, Pier Andrea,Delogu, Giovanna
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- Organophosphorus chemistry 32. 1 The reaction of vanillin, ortho-vanillin and piperonal with stabilized methylenetriphenylphosphoranes (wittig reagents)
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Vanillin (1) and piperonal (3) reacted with ylidenetriphenylphosphoranes 4a-f in boiling toluene following the Wittig mechanism to give the ethylenes 5a-f and 7a-f. Similarly, ethylenes 8c-f were produced when ortho-vanillin (2) was allowed to react with 4c-f. The reaction of aldehyde (2) with the P-ylides 4a,b yielded the Wittig products 8a,b and 8-methoxycoumarin (10). Triphenylphosphine oxide (TPPO, 6) was isolated and identified in all cases. The mechanism for formation of 10 was discussed. Structural reasonings for all new compounds were based upon compatible elementary as well as spectroscopic (IR, 1H-NMR and MS) measurements.
- Hafez, Taghrid S.,Henary, Maged M.,Mahran, Mohamed Refat H.
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- Heterogeneous Catalytic Synthesis of Zingerone and Dehydrozingerone
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Abstract: Results of a single-stage heterogeneous catalytic synthesis of zingerone and dehydrozingerone have been described. The prospects of the proposed approach have been shown; the main kinetic laws governing the reaction have been revealed. Optimum conditions for zingerone and dehydrozingerone synthesis providing a yield of the target products of 45.8 and 76.2%, respectively, have been found.
- Chistyakov, A. V.,Chistyakova, P. A.,Tsodikov, M. V.
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- Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies
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Background: Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo. Method: The?binding affinity of DHZ?with MAO-A (PDB ID: 2Z5Y) was assessed?using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the?standard?antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following?the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry. Results: DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide?in silico. Immobility in TST and FST were significantly (p??0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1?h?post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential. Conclusion: DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.
- Moorkoth, Sudheer,Prathyusha, N. Sai,Manandhar, Suman,Xue, Yuanxin,Sankhe, Runali,Pai,Kumar, Nitesh
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- Biocatalytic Properties and Structural Analysis of Eugenol Oxidase from Rhodococcus jostii RHA1: A Versatile Oxidative Biocatalyst
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Eugenol oxidase (EUGO) from Rhodococcus jostii RHA1 had previously been shown to convert only a limited set of phenolic compounds. In this study, we have explored the biocatalytic potential of this flavoprotein oxidase, resulting in a broadened substrate scope and a deeper insight into its structural properties. In addition to the oxidation of vanillyl alcohol and the hydroxylation of eugenol, EUGO can efficiently catalyze the dehydrogenation of various phenolic ketones and the selective oxidation of a racemic secondary alcohol—4-(1-hydroxyethyl)-2-methoxyphenol. EUGO was also found to perform the kinetic resolution of a racemic secondary alcohol. Crystal structures of the enzyme in complexes with isoeugenol, coniferyl alcohol, vanillin, and benzoate have been determined. The catalytic center is a remarkable solvent-inaccessible cavity on the si side of the flavin cofactor. Structural comparison with vanillyl alcohol oxidase from Penicillium simplicissimum highlights a few localized changes that correlate with the selectivity of EUGO for phenolic substrates bearing relatively small p-substituents while tolerating o-methoxy substituents.
- Nguyen, Quoc-Thai,de Gonzalo, Gonzalo,Binda, Claudia,Rioz-Martínez, Ana,Mattevi, Andrea,Fraaije, Marco W.
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- Design, synthesis, and molecular docking study of novel quinoline-based bis-chalcones as potential antitumor agents
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A novel series of quinoline-based symmetrical and unsymmetrical bis-chalcones was synthesized via a Claisen–Schmidt condensation reaction between 3-formyl-quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by using KOH/MeOH/H2O as a reaction medium. Twelve of the obtained compounds were evaluated for their in vitro cytotoxic activity against 60 different human cancer cell lines according to the National Cancer Institute protocol. Among the screened compounds, the symmetrical N-butyl bis-quinolinyl-chalcone 14g and the unsymmetrical quinolinyl-bis-chalcone 17o bearing a 7-chloro-substitution on the N-benzylquinoline moiety and 4-hydroxy-3-methoxy substituent on the phenyl ring, respectively, exhibited the highest overall cytotoxicity against the evaluated cell lines with a GI50 range of 0.16–5.45 μM, with HCT-116 (GI50 = 0.16) and HT29 (GI50 = 0.42 μM) (colon cancer) representing best-case scenarios. Notably, several GI50 values for these compounds were lower than those of the reference drugs doxorubicin and 5-FU. Docking studies performed on selected derivatives yielded very good binding energies in the active site of proteins that participate in key carcinogenic pathways.
- Insuasty, Daniel,García, Stephanie,Abonia, Rodrigo,Insuasty, Braulio,Quiroga, Jairo,Nogueras, Manuel,Cobo, Justo,Borosky, Gabriela L.,Laali, Kenneth K.
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- Microwave induced rate enhancement in aldol condensation
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The rate of formation of aldol condensed products using microwave of various aromatic aldehydes and ketones in aqueous medium dramatically enhanced with respect to conventional methods in high yield (50-95.2%).
- Kad,Kaur, Kanwal Preet,Singh, Vasundhara,Singh, Jasvinder
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- Synthesis of Enones and Enals via Dehydrogenation of Saturated Ketones and Aldehydes
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A general, efficient and economic palladium-catalyzed dehydrogenation to form enones or enals has been developed. The approach possesses extremely broad substrate scope including various linear or cyclic saturated ketones and aldehydes. The protocol is ligand-free, and molecular oxygen is used as the sole clean oxidant in the reaction. Due to mild reaction conditions, good functional group compatibility, and versatile utilities of enones and enals, the method can be applied in the late-stage synthesis of natural products, pharmaceuticals and fine chemicals. (Figure presented.).
- Pan, Gao-Fei,Zhu, Xue-Qing,Guo, Rui-Li,Gao, Ya-Ru,Wang, Yong-Qiang
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- Stability of curcumin in different solvent and solution media: UV–visible and steady-state fluorescence spectral study
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In aqueous solution, curcumin is photodegradable (light sensitive), it is also self-degradable in the dark. In basic medium, the second process is enhanced. The dark process has been studied in water and also in a number of protic and aprotic solvents, and aqueous solutions of ionic liquids, pluronics, reverse micelles and salt. The kinetics of the process followed the first order rate law; a comparative as well as individual assessment of which has been made. The kinetics of curcumin self-degradation has been found to be fairly dependent on salt (NaCl) concentration. Curcumin molecules in solution may remain in the enol or keto–enol form. From the visible spectral analysis, an estimate of the proportions of these forms in aqueous ethanol medium has been made. The temperature effect on the visible and fluorescence spectra of curcumin has been also studied. The steady state fluorescence anisotropy of the photoactive curcumin has been evaluated in different solvent and solution media. The reversibility of the steady state fluorescence anisotropy of curcumin on heating and cooling conditions has been examined. The results herein presented are new and ought to be useful as the study of physicochemistry of curcumin has been gaining importance in the light of its biological importance.
- Mondal, Satyajit,Ghosh, Soumen,Moulik, Satya P.
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- Resolving Binding Events on the Multifunctional Human Serum Albumin
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Physiological processes rely on initial recognition events between cellular components and other molecules or modalities. Biomolecules can have multiple sites or mode of interaction with other molecular entities, so that a resolution of the individual binding events in terms of spatial localization as well as association and dissociation kinetics is required for a meaningful description. Here we describe a trichromatic fluorescent binding- and displacement assay for simultaneous monitoring of three individual binding sites in the important transporter and binding protein human serum albumin. Independent investigations of binding events by X-ray crystallography and time-resolved dynamics measurements (switchSENSE technology) confirm the validity of the assay, the localization of binding sites and furthermore reveal conformational changes associated with ligand binding. The described assay system allows for the detailed characterization of albumin-binding drugs and is therefore well-suited for prediction of drug-drug and drug-food interactions. Moreover, conformational changes, usually associated with binding events, can also be analyzed.
- Wenskowsky, Lea,Wagner, Michael,Reusch, Johannes,Schreuder, Herman,Matter, Hans,Opatz, Till,Petry, Stefan Matthias
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- Synthesis and anticancer activity of chalcone analogues with sulfonyl groups
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Three series of sulfonyl esters were synthesized in reactions of sulfonyl chlorides with three different phenolic chalcone analogues (dehydrozingerone (4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one), (E)-1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one, and (E)-1-(4-hydroxy-3-methoxyphenyl)-5-methylhex-1-en-3-one). The structures of the new compounds were determined by IR, MS, and NMR methods. Screening of the new sulfonyl esters’ in vitro cytotoxic activities against human epithelial cervical carcinoma (HeLa) and normal human fibroblast (MRC-5) cell lines by the MTT method was performed. The five most active were selected and further tested on HeLa, MRC-5, and MCF-7 (breast carcinoma) cell lines. The examined compounds exhibit strong in vitro anticancer activities with moderate-to-high selectivity, inducing apoptotic cell death and cell cycle arrest in both HeLa and MCF-7 cell lines, but have little to no effect on the non-cancerous MRC-5 cell line.
- Mu?kinja, Jovana M.,Burmud?ija, Adrijana Z.,Baski?, Dejan D.,Popovi?, Suzana L.,Todorovi?, Danijela V.,Zari?, Milan M.,Ratkovi?, Zoran R.
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- Triazole tethered C5-curcuminoid-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies
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Keeping in view the confines allied with presently accessible antitumor agents and success of C5-curcuminoid based bifunctional hybrids as novel antitubulin agnets, molecular hybrids of C5-curcuminoid and coumarin tethered by triazole ring have been synthesized and investigated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and PC-3 human tumor cell lines. The results revealed that the compounds A-2 to A-9, B-2, B-3, B-7 showed significant cytotoxic potential against THP-1, COLO-205 and HCT-116 cell lines, while the PC-3 cell line among these was found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and the length of carbon-bridge (n) connecting triazole ring with coumarin moiety considerably influence the activity. Methoxy substituted phenyl ring as Ring X and two carbon-bridges were found to be the ideal structural features. The most potent compounds (A-2, A-3 and A-7) were further tested for tubulin polymerization inhibition. Compound A-2 was found to significantly inhibit the tubulin polymerization (IC50 = 0.82 μM in THP-1 tumor cells). The significant cytotoxicity and tubulin polymerization inhibition by A-2 was further rationalized by docking studies where it was docked at the curcumin binding site of tubulin.
- Singh, Harbinder,Kumar, Mandeep,Nepali, Kunal,Gupta, Manish K.,Saxena, Ajit K.,Sharma, Sahil,Bedi, Preet Mohinder S.
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- A simple and efficient method for selective single aldol condensation between arylaldehydes and acetone
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A simple and efficient method has been developed for selective single aldol condensation between acetone and various aromatic/heterocyclic aldehydes using aqueous sodium hydroxide at 5-10°C.
- Paul, Satya,Gupta, Monika
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- Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies
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Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB-3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO-205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50 = 1.2 μM against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling studies where it was docked at the curcumin binding site of tubulin.
- Sharma, Sahil,Gupta, Manish K.,Saxena, Ajit K.,Bedi, Preet Mohinder S.
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- Structure and synthesis of [n]-dehydroshogaols from Zingiber officinale
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Three new dehydroshogaols have been isolated from the rhizomes of Zingiber officinale. Their structures were established by spectroscopic analysis and synthesis.
- Wu, Tian-Shung,Wu, You-Cheng,Wu, Pei-Lin,Chern, Ching-Yuh,Leu, Yann-Lii,Chan, Yu-Yi
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- Synthesis and antioxidant activity of caffeic acid derivatives
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A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon–carbon bonds. All reactions were performed in water medium at 90?C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12, 13, and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12, 13, and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry.
- Sidoryk, Katarzyna,Jaromin, Anna,Filipczak, Nina,Cmoch, Piotr,Cybulski, Marcin
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- Insect growth inhibition, antifeedant and antifungal activity of compounds isolated/ derived from Zingiber officinale Roscoe (ginger) rhizomes
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Fresh rhizomes of Zingiber officinale (ginger), when subjected to steam distillation, yielded ginger oil in which curcumene was found to be the major constituent. The thermally labile zingiberene-rich fraction was obtained from its diethyl ether extract. Column chromatography of ginger oleoresin furnished a fraction from which [6]-gingerol was obtained by preparative TLC. Naturally occurring [6]-dehydroshogaol was synthesised following condensation of dehydrozingerone with hexanal, whereas zingerone and 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)butane were obtained by hydrogenation of dehydrozingerone with 10% Pd/C. The structures of the compounds were established by 1H NMR, 13C NMR and mass (EI-MS and ES-MS) spectral analysis. The test compounds exhibited moderate insect growth regulatory (IGR) and antifeedant activity against Spilosoma obliqua, and significant antifungal activity against Rhizoctonia solani. Among the various compounds, [6]-dehydroshogaol exhibited maximum IGR activity (EC50 3.55mg ml-1) while dehydrozingerone imparted maximum antifungal activity (EC50 86.49mg litre-1).
- Agarwal, Manjree,Walia, Suresh,Dhingra, Swaran,Khambay, Bhupinder P. S.
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Read Online
- Synthesis, in vitro and molecular docking studies of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one as new potential anti-inflammatory
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Synthesis of new asymmetrical curcumin analogue of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one via condensation reaction between vanillinacetone and veratraldehyde in ethanol has been performed. The in vitro anti-inflammatory activities of the synthesized compounds showed excellent anti-inflammatory activity. In vitro anti-inammatory activity by using inhibition of albumin denaturation technique compared to standard dichlorofenac. Molecular docking studies were performed, where docking of the compound into 6COX active site suggested that it could exert its anti-inflammatory potential by cyclooxygenase inhibition.
- Sohilait, Mario Rowan,Pranowo, Harno Dwi,Haryadi, Winarto
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- Dehydrozingerone, a structural analogue of curcumin, induces cell-cycle arrest at the G2/M phase and accumulates intracellular ROS in HT-29 human colon cancer cells
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Dehydrozingerone (1) is a pungent constituent present in the rhizomes of ginger (Zingiber officinale) and belongs structurally to the vanillyl ketone class. It is a representative of half the chemical structure of curcumin (2), which is an antioxidative yellow pigment obtained from the rhizomes of turmeric (Curcuma longa). Numerous studies have suggested that 2 is a promising phytochemical for the inhibition of malignant tumors, including colon cancer. On the other hand, there have been few studies on the potential antineoplastic properties of 1, and its mode of action based on a molecular mechanism is little known. Therefore, the antiproliferative effects of 1 were evaluated against HT-29 human colon cancer cells, and it was found that 1 dose-dependently inhibited growth at the G2/M phase with up-regulation of p21. Dehydrozingerone additionally led to the accumulation of intracellular ROS, although most radical scavengers could not clearly repress the cell-cycle arrest at the G2/M phase. Furthermore, two synthetic isomers of 1 (iso-dehydrozingerone, 3, and ortho-dehydrozingerone, 4) were also examined. On comparing of their activities, accumulation of intracellular ROS was found to be interrelated with growth-inhibitory effects. These results suggest that analogues of 1 may be potential chemotherapeutic agents for colon cancer.
- Yogosawa, Shingo,Yamada, Yasumasa,Yasuda, Shusuke,Sun, Qi,Takizawa, Kaori,Sakai, Toshiyuki
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- Identification of a new curcumin synthase from ginger and construction of a curcuminoid-producing unnatural fusion protein diketide-CoA synthase::curcumin synthase
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The biosynthesis and metabolic engineering of curcuminoids received considerable attention for their important pharmaceutical properties. In the present study, a new curcumin synthase (ZoCURS) was identified from ginger (Zingiber officinale). Notably, ZoCURS efficiently accepts 3-(4-hydroxyphenyl)propionyl-CoA to produce tetrahydrobisdemethoxycurcumin, which would be meaningful to further understand the biosynthesis of curcuminoids in ginger. In addition, a curcuminoid-producing unnatural fusion protein diketide-CoA synthase::curcumin synthase (DCS::CURS) was constructed. Comparing to ZoCURS, DCS::CURS indicated similar substrate specificities and catalytic potentials to catalyze the formation of various curcuminoids, however, the yield of curcuminoids produced by DCS::CURS was obviously increased, which would be useful for metabolic engineering of pharmaceutically important curcuminoid analogs, particularly including asymmetric dihydrocurcuminoids such as 3-(4-hydroxyphenyl)propionyl-feruloylmethane, 3-(4-hydroxyphenyl)propionyl-p-coumaroylmethane, and 3-(4-hydroxyphenyl)propionyl-cinnamoylmethane.
- Zhang, Le,Gao, Bowen,Wang, Xiaohui,Zhang, Zhongxiu,Liu, Xiao,Wang, Juan,Mo, Ting,Liu, Yuyu,Shi, Shepo,Tu, Pengfei
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- A Thorough Study on the Photoisomerization of Ferulic Acid Derivatives
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A thorough study on the (E) to (Z) photoisomerization of ferulic acid derivatives (esters, amides of all types, and ketones) was carried out. At the photostationary state, only aliphatic or benzylic tertiary amides reach a nearly complete conversion of (E) isomers into the (Z) ones, whereas for esters, primary and secondary amides or aromatic tertiary amides mixtures of (Z)/(E) ranging from 7 : 93 to 72 : 28 are observed. Ketones show rather limited photoisomerization. However, (Z) ketones may be obtained by the reaction of organometal compounds with an isomerized (Z) Weinreb amide.
- Moni, Lisa,Banfi, Luca,Basso, Andrea,Mori, Alessia,Risso, Federica,Riva, Renata,Lambruschini, Chiara
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p. 1737 - 1749
(2021/03/23)
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- Vanillin enones as selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII. The out of the active site pocket for the design of selective inhibitors?
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New C-glycosides and α,β-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.
- Bua, Silvia,Colinas, Pedro A.,Lavecchia, Martín J.,Le Pors, Macarena S.,Riafrecha, Leonardo E.,Supuran, Claudiu T.
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p. 2118 - 2127
(2021/10/08)
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- Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs
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Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure–activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.
- He, Wenfei,Wang, Jingsong,Jin, Qiling,Zhang, Jiafeng,Liu, Yugang,Jin, Zewu,Wang, Hua,Hu, Linya,Zhu, Lu,Shen, Mengya,Huang, Lili,Huang, Shengwei,Li, Wulan,Zhuge, Qichuan,Wu, Jianzhang
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- Discovery, Biocatalytic Exploration and Structural Analysis of a 4-Ethylphenol Oxidase from Gulosibacter chungangensis
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The vanillyl-alcohol oxidase (VAO) family is a rich source of biocatalysts for the oxidative bioconversion of phenolic compounds. Through genome mining and sequence comparisons, we found that several family members lack a generally conserved catalytic aspartate. This finding led us to study a VAO-homolog featuring a glutamate residue in place of the common aspartate. This 4-ethylphenol oxidase from Gulosibacter chungangensis (Gc4EO) shares 42 % sequence identity with VAO from Penicillium simplicissimum, contains the same 8α-N3-histidyl-bound FAD and uses oxygen as electron acceptor. However, Gc4EO features a distinct substrate scope and product specificity as it is primarily effective in the dehydrogenation of para-substituted phenols with little generation of hydroxylated products. The three-dimensional structure shows that the characteristic glutamate side chain creates a closely packed environment that may limit water accessibility and thereby protect from hydroxylation. With its high thermal stability, well defined structural properties and high expression yields, Gc4EO may become a catalyst of choice for the specific dehydrogenation of phenolic compounds bearing small substituents.
- Alvigini, Laura,Fraaije, Marco W.,Gran-Scheuch, Alejandro,Guo, Yiming,Mattevi, Andrea,Saifuddin, Mohammad,Trajkovic, Milos
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p. 3225 - 3233
(2021/10/04)
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- Aminium cation-radical catalysed selective hydration of (E)-aryl enynes
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The hydration of carbon-carbon triple bonds is an important and atom economic synthetic transformation. Herein, we report a mild and selective method for the catalytic Markovnikov hydration of (E)-aryl enynes to the corresponding enones, mediated through the bench-stable aminium salt, tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA). The chemoselective and diastereoselective method proceeds under neutral metal-free conditions, delivering excellent product yields from terminal and internal alkyne units. The synthesis of biologically important (E)-3-styrylisocoumarins, including a formal synthesis of the natural product achlisocoumarin III, demonstrates the utility of this novel transformation.
- Giel, Marie-Claire,Barrow, Andrew S.,Smedley, Christopher J.,Lewis, William,Moses, John E.
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p. 6991 - 6994
(2021/07/21)
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- Synthesis and biological evaluations of monocarbonyl curcumin inspired pyrazole analogues as potential anti-colon cancer agent
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Purpose: The monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities. Methods: Fifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis. Results: The IC50 value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC50 = 9.36 μM), adriamysin (IC50 = 3.28 μM) and oxaliplatin (IC50 = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells. Conclusion: A new MCACs 7h was synthesized and found to exhibit excellent anti-proliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.
- Hong, Xing,Hu, Xiamin,Min, Zhenli,Ye, Min,Yu, Zhijun,Yuan, Qiong,Zhu, Yue
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p. 2517 - 2534
(2020/07/04)
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- NOVEL SMALL MOLECULES THAT BIND AND/OR MODULATE DIFFERENTFORMS OF TAU OLIGOMERS
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The present invention relates to novel small molecules of Formulas I, II, III, Ilia, Illb, and IV and pharmaceutically acceptable salts thereof, as well as the preparation and the use thereof.
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Page/Page column 34; 35
(2020/11/03)
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- Discovery and Characterization of Pure RhlR Antagonists against Pseudomonas aeruginosa Infections
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Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic human pathogen that forms biofilms and produces virulence factors via quorum sensing (QS). Blocking the QS system in P. aeruginosa is an excellent strategy to reduce biofilm formation and the production of virulence factors. RhlR plays an essential role in the QS system of P. aeruginosa. We synthesized 55 analogues based on the chemical structure of 4-gingerol and evaluated their RhlR inhibitory activities using the cell-based reporter strain assay. Comprehensive structure-activity relationship studies identified the alkynyl ketone 30 as the most potent RhlR antagonist. This compound displayed selective RhlR antagonism over LasR and PqsR, strong inhibition of biofilm formation, and reduced production of virulence factors in P. aeruginosa. Furthermore, the survival rate of Tenebrio molitor larvae treated with 30 in vivo greatly improved. Therefore, compound 30, a pure RhlR antagonist, can be utilized for developing QS-modulating molecules in the control of P. aeruginosa infections.
- Nam, SangJin,Ham, So-Young,Kwon, Hongmok,Kim, Han-Shin,Moon, Suhyun,Lee, Jeong-Hoon,Lim, Taehyeong,Son, Sang-Hyun,Park, Hee-Deung,Byun, Youngjoo
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supporting information
p. 8388 - 8407
(2020/09/21)
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- Chemoselective and metal-free reduction of α,β-unsaturated ketones by: In situ produced benzeneselenol from O -(tert -butyl) Se-phenyl selenocarbonate
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The carbon-carbon double bond of arylidene acetones and chalcones can be selectively reduced with benzeneselenol generated in situ by reacting O-(tert-butyl) Se-phenyl selenocarbonate with hydrochloric acid in ethanol. This mild, metal-free and experimentally simple reduction procedure displays considerable functional-group compatibility, products are obtained in good to excellent yields, and the use of toxic Se/CO mixture and NaSeH, or the smelly and air-sensitive benzeneselenol, is avoided. This journal is
- Ballarotto, Marco,Siciliano, Carlo,Temperini, Andrea
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p. 33706 - 33717
(2020/10/22)
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- GINGEROL DERIVATIVE HAVING INHIBITORY ACTIVITY AGAINST BIOFILM FORMATION AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS EFFECTIVE INGREDIENT FOR PREVENTING OR TREATING BIOFILM-CAUSED INFECTION SYMPTOM
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The present invention relates to a gingerol derivative having inhibitory activity against biofilm formation and a pharmaceutical composition for preventing or treating infections caused by biofilms including the gingerol derivative as an active ingredient. The gingerol derivative of the present invention exhibits significantly improved binding affinity for LasR and inhibitory activity against biofilm formation. Therefore, the gingerol derivative of the present invention can act on various membrane surfaces where biofilms tend to form and can effectively inhibit the formation of the corresponding biofilms. In addition, the use of the pharmaceutical composition according to the present invention can fundamentally prevent or treat a variety of infections caused by biofilms due to the presence of the gingerol derivative in the pharmaceutical composition.
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Paragraph 0032; 0049
(2020/09/22)
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- Synthesis, characterization, and antioxidant activity of some 2-methoxyphenols derivatives
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Oxidative stress is a causative factor in the pathophysiology of numerous diseases, such as diabetes, atherosclerosis, cancer, and neurodegenerative and cardiovascular diseases. Therapeutic antioxidants are promising candidates for preventing and treating conditions in which oxidative stress is a contributing factor. In this study, we report the design, synthesis and antioxidant activity of six compounds containing the 2-methoxyphenol moiety core structure. The synthesized derivatives were characterized using 1H NMR, 13C NMR, Fourier-transform infrared (FT-IR), and elemental analysis spectroscopy. The antioxidant properties of the compounds were evaluated using the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and oxygen radical absorbance capacity (ORAC) assay. New phenolic acid-derived compounds with antioxidant activity were identified.
- Al Ajeil, Ruba,AlNeyadi, Shaikha S.,Amer, Naheed,Breitener, Priya,Munawar, N.,Thomas, Tony G.
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p. 112 - 122
(2020/10/23)
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- Dehydrozingerone derivative and preparation method and application thereof
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The invention provides a dehydrozingerone derivative as shown in the description. R-R are each independently selected from hydrogen or halogen or a nitro group or an alkyl group or a substitutedalkoxy group or an alkoxy group or a hydroxyl group; the substituent in the substituted alkoxy group is selected from one or multiple of halogen, a nitro group and a hydroxyl group; R and R areeach independently selected from hydrogen or halogen or nitrogen-containing heterocycle; R is selected from an alkyl group or an alkoxy group or a substituted alkoxy group; the substituent in thesubstituted alkyl group is selected from one or multiple of halogen, a nitro group and a hydroxyl group; X is selected from a hetero atom or a hydroxylamine group. The dehydrozingerone derivative hasbroad-spectrum activity against plant pathogenic fungi and bacteria, and has certain nematicidal activity, and is a lead compound with the broad biological activity.
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Paragraph 0120-0121
(2019/11/20)
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- A carboxyl group-containing single-carbonyl curcumin derivative and its preparation method and application (by machine translation)
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The invention discloses a carboxyl group-containing single-carbonyl curcumin derivative and its preparation method and application, the carboxyl group-containing single-carbonyl curcumin derivatives having a structure of formula (I) shown, the carboxyl group-containing single-carbonyl curcumin derivatives high stability, high solubility, inhibit β - secretase, acetylcholine esterase and oxidation resistance, the role for protecting nerve cells, can be used for preparing the treatment of senile dementia drug. (by machine translation)
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Paragraph 0037; 0038; 0044; 0045
(2019/05/10)
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- Dehydrozingerone Inspired Discovery of Potential Broad-Spectrum Fungicidal Agents as Ergosterol Biosynthesis Inhibitors
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A series of dehydrozingerone derivatives were synthesized, and their fungicidal activities and action mechanism against Colletotrichum musae were evaluated. The bioassay result showed that most compounds exhibited excellent fungicidal activity in vitro at 50 μg mL-1. Compounds 13, 16, 18, 19, and 27 exhibited broad-spectrum fungicidal activity; especially, compounds 19 and 27 were found to have more potent fungicidal activity than azoxystrobin. The EC50 values of compounds 19 and 27 against Rhizoctonia solani were 0.943 and 0.161 μg mL-1 respectively. Moreover, compound 27 exhibited significant in vitro bactericidal activity against Xanthomonas oryzae pv. oryzae, with an EC50 value of 11.386 μg mL-1, and its curative effect (49.64%) and protection effect (51.74%) on rice bacterial blight disease was equivalent to that of zhongshengmycin (42.90%, 40.80% respectively). Compound 27 could also effectively control gray mold (87.10%, 200 μg mL-1) and rice sheath blight (100%, 200 μg mL-1 82.89%, 100 μg mL-1) in vivo. Preliminary action mechanism study showed that compound 27 mainly acted on the cell membrane and significantly inhibited ergosterol biosynthesis in Colletotrichum musae.
- Song, Xiangmin,Zhu, Xinyue,Li, Ting,Liang, Cai,Zhang, Meng,Shao, Yu,Tao, Jun,Sun, Ranfeng
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p. 11354 - 11363
(2019/10/16)
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- Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship
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(E)-3,4-Dihydroxybenzylideneacetone (compound 1) inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with IC50 of 7.8 μM (IC50 of alendronate, 3.7 μM) while stimulating the differentiation of MC3T3-E1 osteoblastic cells, accompanied by the induction of Runt-related transcription factor 2, alkaline phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with IC50 of 0.11 μM while sustaining osteoblast-stimulatory activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one (compound 2g) stimulated alkaline phosphatase production 2-fold at 50 μM without changing osteoclast-inhibitory activity, compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity of a few benzylideneacetone derivatives to inhibit osteoclastogenesis supported by independent osteoblastogenesis activation was convincingly reflected in in vivo management of osteoporosis, suggesting a potential novel therapeutics for osteopenic diseases.
- Pativada, Triveni,Kim, Myung Hwan,Lee, Jung-Hun,Hong, Seong Su,Choi, Chun Whan,Choi, Yun-Hyeok,Kim, Woo Jung,Song, Da-Woon,Park, Serk In,Lee, Eun Jung,Seo, Bo-Yeon,Kim, Hankyeom,Kim, Hong Kyu,Lee, Kee Ho,Ahn, Sung K.,Ku, Jin-Mo,Park, Gil Hong
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p. 6063 - 6082
(2019/08/02)
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- Ferulic acid derivative and application thereof
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The invention discloses a ferulic acid derivative and application thereof, and belongs to the field of structural modification of microorganism secondary metabolites being applied to agricultural plant protection. The ferulic acid derivative is prepared from 4-(4-hydroxy-3-methoxyphenyl)-3-butene-2-ketone, 4-hydroxy-3-methoxyl cinnamic acid vinyl ester, 3-(4-hydroxy-3-methoxyphenyl)-N-(4-methoxyphenyl)acrylamide and N-(4-fluorophenyl) -3-(4-hydroxy-3-methoxyphenyl) acrylamide. The ferulic acid derivative has the very high activity of inhibiting growing of weeds and killing and removing the weeds, has certain inhibition effects on amaranthus retroflexus, barnyard grass, crab grass, green bristlegrass, oilseed rape and the like, can be widely applied to agricultural production, is a novel active ingredient of weed killers, and has the advantages that the preparation method is simple, the synthetic raw materials are easy to obtain, and the ferulic acid derivative is safe and environmentally friendly, does not make any harm to non-target crops and the like.
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Paragraph 0014-0016
(2018/07/30)
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- Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives
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In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents.
- Lino, Cleudiomar Inácio,Gon?alves de Souza, Igor,Santos Teixeira, Iasmin Natália,Maltarollo, Vinícius Gon?alves,de Oliveira, Renata Barbosa,Borelli, Beatriz Martins,Silvério Matos, Thelma Tirone,Johann, Susana,Ramos, Jonas Pereira,Maria de Souza Fagundes, Elaine,de Oliveira Fernandes, Philipe
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p. 248 - 260
(2019/03/12)
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- Comparative study on the reaction of organophosphorus reagents with moringa oleifera vanillin. Synthesis of phosphoranylidenepyranone, dioxaphospholane and butenethione derivatives as antitumor agents
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VANILLIN organophosphorusfrom Moringa reagents.oleifera Treatmentplant ofwas 4-hydroxy-3-methoxybenzaldehydeallowed to react with differentnucleophilic (vanillin) with the active
- Abd-El-Maksoud,Saleh,Abdallah,Soliman
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p. 469 - 478
(2018/08/16)
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- Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin
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Inflammation and oxidative stress are common in many chronic diseases. Targeting signaling pathways that contribute to these conditions may have therapeutic potential. The transcription factor Nrf2 is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. Nrf2 is widespread in the CNS and is recognized as an important regulator of brain inflammation. The natural product curcumin exhibits numerous biological activities including ability to induce the expression of Nrf2-dependent phase II and anti-oxidant enzymes. Curcumin has been examined in a number of clinical studies with limited success, mainly owing to limited bioavailability and rapid metabolism. Enone analogues of curcumin were examined with an Nrf2 reporter assay to identify Nrf2 activators. Analogues were separated into groups with a 7-carbon dienone spacer, as found in curcumin; a 5-carbon enone spacer with and without a ring; and a 3-carbon enone spacer. Activators of Nrf2 were found in all three groups, many of which were more active than curcumin. Dose-response studies demonstrated that a range of substituents on the aromatic rings of these enones influenced not only the sensitivity to activation, reflected in EC50 values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2 by these analogues.
- Deck, Lorraine M.,Hunsaker, Lucy A.,Vander Jagt, Thomas A.,Whalen, Lisa J.,Royer, Robert E.,Vander Jagt, David L.
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supporting information
p. 854 - 865
(2017/12/13)
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- Preparation method of (E)-1-(4-hydroxy-3-methoxyphenyl)-4-ene-3-decalone
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The invention discloses a preparation method of (E)-1-(4-hydroxy-3-methoxyphenyl)-4-ene-3-decalone and relates to the field of medicinal chemistry. The method comprises the steps as follows: 1) 4-(4-hydroxy-3-methoxyphenyl)-2-butanone is dissolved in a halogenated hydrocarbon solvent, pyrrolidine or piperidine is added at the room temperature, and the mixture reacts for 15-120 min; 2) a halogenated hydrocarbon solution of n-hexaldehyde is added, and the mixture reacts for 2-24 h; 3) an inorganic base solution is added, the mixture reacts for 1-24 h, aftertreatment is performed, and a compoundshown in formula (1) is prepared. Reactions at the room temperature are conducted with inorganic base and other weak bases, and the total yield is 78% or above. The method has mild reaction conditionsand is convenient to operate and suitable for industrial production.
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Paragraph 0029; 0030; 0032
(2018/07/15)
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- Structure-Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents
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Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.
- Choi, Hyunsuk,Ham, So-Young,Cha, Eunji,Shin, Yujin,Kim, Han-Shin,Bang, Jeong Kyu,Son, Sang-Hyun,Park, Hee-Deung,Byun, Youngjoo
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p. 9821 - 9837
(2017/12/26)
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- Discovery of New Monocarbonyl Ligustrazine-Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer
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The elevation of oxidative stress preferentially in cancer cells by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive oxygen species (ROS) production has emerged as an effective strategy for selectively targeting cancer cells. In this study, we designed and synthesized 21 ligustrazine-curcumin hybrids (10a-u). Biological evaluation indicated that the most active compound 10d significantly inhibited the proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant (A549/DDP) lung cancer cells but had little effect on nontumor lung epithelial-like cells (HBE). Furthermore, 10d suppressed the TrxR/Trx system and promoted intracellular ROS accumulation and cancer cell apoptosis. Additionally, 10d inhibited the NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine 123, P-gp ATPase activity, and P-gp expression in A549/DDP cells. Finally, 10d repressed the growth of implanted human drug-resistant lung cancer in mice. Together, 10d acts a novel TrxR inhibitor and may be a promising candidate for intervention of lung cancer.
- Ai, Yong,Zhu, Bin,Ren, Caiping,Kang, Fenghua,Li, Jinlong,Huang, Zhangjian,Lai, Yisheng,Peng, Sixun,Ding, Ke,Tian, Jide,Zhang, Yihua
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p. 1747 - 1760
(2016/03/25)
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- Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents
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Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = 0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.
- Hampannavar, Girish A.,Karpoormath, Rajshekhar,Palkar, Mahesh B.,Shaikh, Mahamadhanif S.,Chandrasekaran, Balakumar
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supporting information
p. 686 - 691
(2016/07/26)
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- Traceless OH-Directed Wacker Oxidation-Elimination, an Alternative to Wittig Olefination/Aldol Condensation: One-Pot Synthesis of α,β-Unsaturated and Nonconjugated Ketones from Homoallyl Alcohols
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A new method for one-pot synthesis of β-substituted and β,β-disubstituted α,β-unsaturated methyl ketones from homoallyl alcohols by sequential PdCl2/CrO3-promoted Wacker process followed by an acid-mediated dehydration reaction has been developed. Remarkably, internal homoallyl alcohols delivered regioselectively nonconjugated unsaturated carbonyl compounds under the same protocol. A new starting material-based synthesis of α,β-unsaturated and nonconjugated methyl ketones is demonstrated.
- Bethi, Venkati,Fernandes, Rodney A.
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p. 8577 - 8584
(2016/09/28)
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- Palladium-Catalyzed Directed para C?H Functionalization of Phenols
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Various practical methods for the selective C?H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C?H functionalization of toluene derivatives, we herein report the first remote para C?H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.
- Patra, Tuhin,Bag, Sukdev,Kancherla, Rajesh,Mondal, Anirban,Dey, Aniruddha,Pimparkar, Sandeep,Agasti, Soumitra,Modak, Atanu,Maiti, Debabrata
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supporting information
p. 7751 - 7755
(2016/07/07)
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- Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α,β-unsaturated aromatic side chain
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A new series of vinca-alkaloids derivatives containing various α,β-unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 μM, thus comparable with vinblastine.
- Ngo, Quoc Anh,Nguyen, Le Anh,Vo, Ngoc Binh,Nguyen, Thuy Hang,Roussi, Fanny,Nguyen, The Hung,Nguyen, Van Tuyen
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p. 5597 - 5600
(2015/11/17)
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- Synthesis of natural and non-natural curcuminoids and their neuroprotective activity against glutamate-induced oxidative stress in HT-22 cells
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A strategy for the synthesis of natural and non-natural 5-deoxy-6,7-dihydrocurcuminoids (diarylheptanoids) was developed for the preparation of 14 compounds with varying aromatic substituent patterns and a different functionality in the aliphatic seven-carbon chain. The in vitro protective activity against glutamate-induced neuronal cell death was examined in the murine hippocampal cell line HT-22 to find structural motifs responsible for neuroprotective effects in vitro. Among the tested compounds the ferulic acid-like unit, present in the structures of (E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hept-1-en-3-one (5) and (E)-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hept-1-en-3-one (7), appeared to be an important feature for protection against glutamate-induced neurotoxicity. Both compounds demonstrated significant neuroprotective activity in a concentration range between 1 and 25 ～M without showing toxic effects in a cytotoxicity assay with HT-22 cells. Furthermore, (E)-1,7-bis(3,4-dihydroxyphenyl)hept-1-en-3-one (9), exhibiting a caffeic acid-like structural motif, displayed a neuroprotective activity at a nontoxic concentration of 25 ～M. In contrast, (1E,6E)-1,7-bis(3,4-dihydroxyphenyl)hepta-1,6-diene-3,5-dione (4, di-O-demethylcurcumin) showed mainly cytotoxic effects. A corresponding single-ring analogue that contains the ferulic acid-like unit as an enone was not active.
- Jirsek, Petr,Amslinger, Sabine,Heilmann, J?rg
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p. 2206 - 2217
(2014/12/11)
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- Synthesis, cytotoxicity against human oral cancer KB cells and structure-activity relationship studies of trienone analogues of curcuminoids
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A general method for the synthesis of substituted (1E,4E,6E)-1,7- diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9-20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure-activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study.
- Chuprajob, Thipphawan,Changtam, Chatchawan,Chokchaisiri, Ratchanaporn,Chunglok, Warangkana,Sornkaew, Nilubon,Suksamrarn, Apichart
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supporting information
p. 2839 - 2844
(2014/06/10)
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- Influence of side chain structure changes on antioxidant potency of the [6]-gingerol related compounds
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[6]-Gingerol and [6]-shogaol are the major pungent components in ginger with a variety of biological activities including antioxidant activity. To explore their structure determinants for antioxidant activity, we synthesized eight compounds differentiated by their side chains which are characteristic of the C1-C2 double bond, the C4-C5 double bond or the 5-OH, and the six- or twelve-carbon unbranched alkyl chain. Our results show that their antioxidant activity depends significantly on the side chain structure, the reaction mediums and substrates. Noticeably, existence of the 5-OH decreases their formal hydrogen-transfer and electron-donating abilities, but increases their DNA damage- and lipid peroxidation-protecting abilities. Additionally, despite significantly reducing their DNA strand breakage-inhibiting activity, extension of the chain length from six to twelve carbons enhances their anti-haemolysis activity.
- Lu, Dong-Liang,Li, Xiu-Zhuang,Dai, Fang,Kang, Yan-Fei,Li, Yan,Ma, Meng-Meng,Ren, Xiao-Rong,Du, Gao-Wei,Jin, Xiao-Ling,Zhou, Bo
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p. 191 - 197
(2014/06/24)
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