Cinnamaldehyde Analogues Research Articles

Evaluation of cinnamaldehyde derivatives as potential protective agents against oxidative-stress induced myotube atrophy using chemical, biological and computational analysis

Skeletal muscle atrophy, associated with increased morbidity, mortality and poor quality of life, is a metabolic disorder with no FDA approved drug. Oxidative stress is one of the key mediators of atrophy that influences various cell signaling molecules. The goal of this study is to identify potential antioxidant agents that could be used to treat atrophy. In this study in vitro and in situ screening of different cinnamaldehyde (CNA) derivatives for their antioxidant effects was done along with computational analysis to understand the relationship between their chemical structure and biological activity.Data show that 2-hydroxycinnamaldehyde (2HCNA) worked better than other CNA analogues at physiological pH, while 4-Fluoro-2-methoxycinnamaldehyde (4FoCNA) showed the maximum antioxidant activity under acidic conditions. However, these derivatives (2HCNA and 4FoCNA) were found to be toxic to the cultured myotubes (mature myofiber) under both physiological and pathophysiological conditions. Immunofluorescence, bright-field microscopic and biochemical studies conducted using live C2C12 cells showed that pre-incubation with other CNA analogues i.e. 2-methoxycinnamaldehyde (2MeCNA) and 2-benzyloxycinnamaldehyde (2BzCNA) not only maintained the normal morphology of myotubes but also protected them from H2O2-induced atrophy. These compounds (2MeCNA and 2BzCNA) showed higher stability and antioxidant potential, as indicated by computer simulation data analyzed by Density Functional Theory (DFT) based molecular modeling. Overall, the chemical, biological, and computational studies reveal the therapeutic potential of CNA analogues (BzCNA and MeCNA) against oxidative-stress induced muscle atrophy in C2C12 cells.

Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division.

Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii. Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii. In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii, with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 μg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro, as well as adverse activity in a Caenorhabditis elegans nematode model in vivo. Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii. This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain.

Antibiofilm Activities of Cinnamaldehyde Analogs against Uropathogenic Escherichia coli and Staphylococcus aureus.

Bacterial biofilm formation is a major cause of drug resistance and bacterial persistence; thus, controlling pathogenic biofilms is an important component of strategies targeting infectious bacterial diseases. Cinnamaldehyde (CNMA) has broad-spectrum antimicrobial and antibiofilm activities. In this study, we investigated the antibiofilm effects of ten CNMA derivatives and trans-CNMA against Gram-negative uropathogenic Escherichia coli (UPEC) and Gram-positive Staphylococcus aureus. Among the CNMA analogs tested, 4-nitrocinnamaldehyde (4-nitroCNMA) showed antibacterial and antibiofilm activities against UPEC and S. aureus with minimum inhibitory concentrations (MICs) for cell growth of 100 µg/mL, which were much more active than those of trans-CNMA. 4-NitroCNMA inhibited UPEC swimming motility, and both trans-CNMA and 4-nitroCNMA reduced extracellular polymeric substance production by UPEC. Furthermore, 4-nitroCNMA inhibited the formation of mixed UPEC/S. aureus biofilms. Collectively, our observations indicate that trans-CNMA and 4-nitroCNMA potently inhibit biofilm formation by UPEC and S. aureus. We suggest efforts be made to determine the therapeutic scope of CNMA analogs, as our results suggest CNMA derivatives have potential therapeutic use for biofilm-associated diseases.

Appraisal of Cinnamaldehyde Analogs as Dual-Acting Antibiofilm and Anthelmintic Agents.

Cinnamaldehyde has a broad range of biological activities, which include antibiofilm and anthelmintic activities. The ever-growing problem of drug resistance and limited treatment options have created an urgent demand for natural molecules with antibiofilm and anthelmintic properties. Hence, we hypothesized that molecules with a scaffold structurally similar to that of cinnamaldehyde might act as dual inhibitors against fungal biofilms and helminths. In this regard, eleven cinnamaldehyde analogs were tested to determine their effects on fungal Candida albicans biofilm and nematode Caenorhabditis elegans. α-Methyl and trans-4-methyl cinnamaldehydes efficiently inhibited C. albicans biofilm formation (>90% inhibition at 50 μg/mL) with minimum inhibitory concentrations (MICs) of ≥ 200 μg/mL and 4-bromo and 4-chloro cinnamaldehydes exhibited anthelmintic property at 20 μg/mL against C. elegans. α-Methyl and trans-4-methyl cinnamaldehydes inhibited hyphal growth and cell aggregation. Scanning electron microscopy was employed to determine the surface architecture of C. albicans biofilm and cuticle of C. elegans, and confocal laser scanning microscopy was used to determine biofilm characteristics. The perturbation in gene expression of C. albicans was investigated using qRT-PCR analysis and α-methyl and trans-4-methyl cinnamaldehydes exhibited down-regulation of ECE1, IFD6, RBT5, UCF1, and UME6 and up-regulation of CHT4 and YWP1. Additionally, molecular interaction of these two molecules with UCF1 and YWP1 were revealed by molecular docking simulation. Our observations collectively suggest α-methyl and trans-4-methyl cinnamaldehydes are potent biofilm inhibitors and that 4-bromo and 4-chloro cinnamaldehydes are anthelmintic agents. Efforts are required to determine the range of potential therapeutic applications of cinnamaldehyde analogs.

Inhibitory Effects of Cinnamaldehyde Derivatives on Biofilm Formation and Virulence Factors in Vibrio Species.

Vibrio parahaemolyticus is considered one of the most relevant pathogenic marine bacteria with a range of virulence factors to establish food-related gastrointestinal infections in humans. Cinnamaldehyde (CNMA) and some of its derivatives have antimicrobial and antivirulence activities against several bacterial pathogens. This study examined the inhibitory effects of CNMA and its derivatives on biofilm formation and the virulence factors in Vibrio species, particularly V. parahaemolyticus. CNMA and ten of its derivatives were initially screened against V. parahaemolyticus biofilm formation, and their effects on the production of virulence factors and gene expression were studied. Among the CNMA derivatives tested, 4-nitrocinnamaldehyde, 4-chlorocinnamaldehyde, and 4-bromocinnamaldehyde displayed antibacterial and antivirulence activities, while the backbone CNMA had weak effects. The derivatives could prevent the adhesion of V. parahaemolyticus to surfaces by the dose-dependent inhibition of cell surface hydrophobicity, fimbriae production, and flagella-mediated swimming and swarming phenotypes. They also decreased the protease secretion required for virulence and indole production, which could act as an important signal molecule. The expression of QS and biofilm-related genes (aphA, cpsA, luxS, and opaR), virulence genes (fliA, tdh, and vopS), and membrane integrity genes (fadL, and nusA) were downregulated in V. parahaemolyticus by these three CNMA analogs. Interestingly, they eliminated V. parahaemolyticus and reduced the background flora from the squid surface. In addition, they exhibited similar antimicrobial and antibiofilm activities against Vibrio harveyi. This study identified CNMA derivatives as potential broad-spectrum antimicrobial agents to treat biofilm-mediated Vibrio infections and for surface disinfection in food processing facilities.

Cinnamaldehyde Analogs: Docking Based Optimization, COX-2 Inhibitory In Vivo and In Vitro Studies.

In the past decade CADD has emerged as a rational approach in drug development so with the help molecular docking approach we planned to perform virtual screening of the designed data set of Schiff bases of cinnamaldehyde. The research work will be helpful to put some light on the drug receptor interactions required for anti-inflammatory activity. For carrying out virtual screening of the developed cinnamaldehyde Schiff base data set, AutoDock 4.0 was used. The active hits identified through in silico screening were synthesized. Anti-inflammatory evaluation was carried out using Carrageenan-induced paw oedema method. Compounds V2A44, V2A55, V2A76, V2A82, V2A119, V2A141 and V2A142 has shown highest binding energy (-4.84, -4.76, -4.59, -4.78, -4.74, -4.85 and -4.72 kcal/mol, respectively) and the binding interactions with amino acids namely, Phe478, Glu479, Lys492, Ala493, Asp497 and Ile498. Some of the analogs have shown significant activity and were comparable to Indomethacin (standard drug). Five new compounds have shown significant activity and the results obtained from in silico studies are parallel to those of in vivo studies.

Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases

BackgroundOxidative stress contributes to the pathogenesis of many human diseases. Cinnamon is a worldwide used spice, dietary supplement and traditional medicine, and is used for the therapy of oxidative stress related diseases. A well-established concept is that the functions of cinnamon preventing oxidative stress-induced diseases are attributed to the occurrence of cinnamaldehyde and its analogues. HypothesisIn our continuous searching of natural molecules with antioxidant capacity, we have found that cinnamaldehyde and its analogues in cinnamon are weak inhibitors of oxidative stress, and thus we speculate that there are novel and/or potent molecules inhibiting oxidative stress in cinnamon. Study design and methodsA systemic phytochemical investigation of cinnamon using column chromatography was performed to identify the chemical constituents of cinnamon, and then their capacity of inhibiting oxidative stress and action of mechanism targeting Nrf2 pathway were investigated using diverse bioassay, including NAD(P)H: quinone reductase (QR) assay, immunoblot analysis, luciferase reporter gene assay, immunofluorescence and flow cytometry. ResultsCinnamon improved the intracellular antioxidant capacity. A systemic phytochemical investigation of cinnamon gave the isolation of twenty-two chemical ingredients. The purified constituents were tested for their potential inhibitory effects against oxidative stress. Besides cinnamaldehyde analogues, a lignan pinoresinol (PRO) and a flavonol (-)-(2R,3R)-5,7-dimethoxy-3′, 4′-methylenedioxy-flavan-3-ol (MFO) were firstly identified to be inhibitors of oxidative stress. Further study indicated that PRO and MFO activated Nrf2-mediated antioxidant response, and protected human lung epithelial cells against sodium arsenite [As(III)]-induced oxidative insults. ConclusionThe lignan PRO and the flavonoid MFO are two novel Nrf2 activators protecting tissues against oxidative insults, and these two constituents support the application of cinnamon as an agent against oxidative stress related diseases.

Cinnamaldehyde and related phenylpropanoids, natural repellents, and insecticides against Sitophilus zeamais (Motsch.). A chemical structure-bioactivity relationship.

The insecticidal and repellent effects on adult Sitophilus zeamais of 12 cinnamaldehyde-related compounds was evaluated by contact toxicity bioassays and a two-choice olfactometer. To determine non-toxicity in mammals, body weight, serum biochemical profiles, liver weight, physiological parameters, sperm motility, and histopathological data were obtained as complementary information in C57BL/6 mice treated with the best natural compound. Based on 24 h LC95 and LC50 values, α-methyl-cinnamaldehyde and cinnamaldehyde exhibited better insecticidal action than the other compounds. The best repellent effect was observed with α-bromo-cinnamaldehyde, which even repelled at the lowest concentration studied (0.28 µmol L-1 ). The evaluation of a quantitative structure-activity relationship found a linear relationship between the LC50 values for adult weevil toxicity and dipolo with Q values (giving the difference between orbital electronegativity carbon 1 and orbital electronegativity carbon 3 of the molecule) in cinnamaldehyde-related compounds. The polar surface and Log P descriptors also revealed a linear relationship with the S. zeamais repellent effect for cinnamaldehyde analogues. Cinnamaldehyde did not show toxicity in the parameters evaluated in mice. From the phenylpropanoid components studied, the natural compound that had the best insecticidal and repellent action against S. zeamais was cinnamaldehyde. It presented no mammalian toxicity. © 2018 Society of Chemical Industry.

Cinnamaldehyde Analogues as Potential Therapeutic Agents.

Cinnamaldehyde analogues are a class of chemical substances originated from derivatization of cinnamaldehyde, and are structurally characterized by the presence of cinnamoyl moiety. Due to the presence of highly reactive α,α-unsaturated carbonyl pharmacophore (Michael acceptor) in their structures, these molecules are apt to react with some enzymes and/or receptors as electrophiles, and consequently produce diverse therapeutically relevant pharmacological functions. Naturally occurring molecules, trans-cinnamaldehyde (CA), 2-benzoyloxycinnam-aldehyde (2-BCA), and 2- hydroxycinnamaldehyde (2-HCA) are representatives of this group, and have attracted lots of interest for their bioactivities, especially the anti-cancer and anti-inflammatory properties. Owing to the potential of CA, 2-BCA, and 2-HCA as therapeutic agents, researches on chemical syntheses and modifications have been carried out to gain chemical entities with potent bioactivity and favorable druggability. This review summarizes the progress on phytochemical and pharmacological aspects of natural cinnamaldehyde analogues, illustrate the representative of synthetic molecules with potent bioactivity, and discuss their potential as therapeutic agents.

Cinnamaldehyde Analogs as CYP2A6 Inhibitors: A Structure‐Activity Study

Cinnamaldehyde Analogs as CYP2A6 Inhibitors: A Structure‐Activity Study

Insecticidal Activity of Cinnamon Essential Oils, Constituents, and (E)- Cinnamaldehyde Analogues against Metcalfa pruinosa Say (Hemiptera: Flatidae) Nymphs and Adults

본 연구에서는 계피 정유 3종의 구성성분을 분석하였고, 미국선녀벌레에 대한 살충활성을 검정하였다. (E)-Cinnamaldehyde을 포함한 9종의 계피 정유 구성성분과 21종의 유사 물질을 미국선녀벌레 약충에 대해 살충활성을 검정한 결과, hydro-cinnamic acid가 반수치사농도 $1.55mg/cm^2$ 로 가장 좋은 살충활성을 보였으며, geranic acid도 $1.59mg/cm^2$ 로 높은 살충 활성을 보였다. Cinnamaldehyde를 포함한 hydro-cinnamaldehyde, (E)-cinnamaldehyde, cinnamdyl alcohol, cinnamyl acetate, dibutyl phtalate, anethole, a-cyano cinnamic acid, (s)-perillyl alcohol, methyl cinnamaldehyde, bonyl acetate 12종이 중간정도의 활성( $1.60-4.94mg/cm^2$ )을 보였으며, 다른 물질들은 살충활성이 낮거나 없었다. 미국선녀벌레 성충에 대해서는 eugenol 이 반수치사 농도 10.81 mg로 가장 높은 살충활성을 보였으며, geranic acid (30.68 mg)도 높은 살충력을 보였다. Cinnamaldehyde 등 9종이 반수 치사 농도 105.44~255.76 mg의 살충활성을 보였다. 다른 18종의 물질은 활성이 낮거나 없었다. 실제 포장인 인삼포장에 발생하는 미국선녀벌레에 대한 적용시험에서 cinnamon bark 정유와 cinnamon green leaf 정유가 각각 82.3%와 82.9%의 높은 살충활성을 보였다. 농업환경에서 고독성 합성살충제의 사용을 줄일 수 있는 방안으로 본 논문에서 선발한 계피정유가 미국선녀벌레의 약충 및 성충 방제에 유용한 수단으로 이용될 수 있을 것으로 사료된다. 【The insecticidal activity of the constituents of cinnamon essential oils and structurally related compounds against both the nymphs and adults of the citrus flatid planthopper Metcalfa pruinosa was examined using a direct-contact application. The toxicity of the cinnamon oil constituents and 21 (E)-cinnamaldehyde related compounds regarding the nymphs of M. pruinosa was evaluated using a leaf-dipping bioassay. Based on 24 h $LC_{50}$ values, hydro-cinnamic acid ( $1.55mg/cm^2$ ) is the most toxic compound, followed by geranic acid ( $1.59mg/cm^2$ ). The $LC_{50}$ values of 11 of the compounds including cinnamaldehyde are between $1.60mg/cm^2$ and $4.94mg/cm^2$ . Low toxicities and no toxicity were observed with the other 15 ( $5.24mg/cm^2$ to $13.47mg/cm^2$ ) and two compounds, respectively. Also, the toxicities of the cinnamon oil constituents and 21 cinnamaldehyde related compounds regarding the M. pruinosa adults were evaluated using a direct-spray method. The toxicity of eugenol (10.81 mg) is the most toxic compound for the adults of M. pruinosa, followed by geranic acid (30.68 mg). The $LC_{50}$ values of nine of the compounds including cinnamaldehyde are between 59.16 mg and 96.70 mg. Low toxicities and no toxicity were observed with the other 15 (105.44 mg to 255.76 mg) and three compounds, respectively. The spray formulations that comprise cinnamon bark and cinnamon green leaf oils resulted in 82.3% and 82.9% mortalities, respectively, toward the M. pruinosa adults in a ginseng field. Global efforts to reduce the level of highly toxic synthetic insecticides in agricultural environments justify further studies on cinnamon oils to ascertain whether the corresponding active principles can act as insecticides, when they are applied as a direct spray with contact action, for the control of M. pruinosa populations.】

Activity prediction of Schiff base compounds using improved QSAR models of cinnamaldehyde analogues and derivatives

In past work, QSAR (quantitative structure-activity relationship) models of cinnamaldehyde analogues and derivatives (CADs) have been used to predict the activities of new chemicals based on their mass concentrations, but these approaches are not without shortcomings. Therefore, molar concentrations were used instead of mass concentrations to determine antifungal activity. New QSAR models of CADs against Aspergillus niger and Penicillium citrinum were established, and the molecular design of new CADs was performed. The antifungal properties of the designed CADs were tested, and the experimental Log AR values were in agreement with the predicted Log AR values. The results indicate that the improved QSAR models are more reliable and can be effectively used for CADs molecular design and prediction of the activity of CADs. These findings provide new insight into the development and utilization of cinnamaldehyde compounds.

Synthesis and structure–activity relationship of N-(cinnamyl) chitosan analogs as antimicrobial agents

The current study focuses on the preparation of new N-(cinnamyl) chitosan derivatives as antimicrobial agents against nine types of crop-threatening pathogens. Chitosan was reacted with a set of aromatic cinnamaldehyde analogs by reductive amination involving formation of the corresponding imines, followed by reduction with sodium borohydride to produce N-(cinnamyl) chitosan derivatives. The structural characterization was confirmed by 1H and 13C NMR spectroscopy and the degrees of substitution ranged from 0.08 to 0.28. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens and Erwinia carotovora. A higher inhibition activity was obtained by N-(α-methylcinnamyl) chitosan with MIC 1275 and 1025mg/L against A. tumefaciens and E. carotovora, respectively followed by N-(o-methoxycinnamyl) chitosan (MIC=1925 and 1550mg/L, respectively). The antifungal assessment was evaluated in vitro by mycelial radial growth technique against Alternaria alternata, Botrytis cinerea, Botryodiplodia theobromae, Fusarium oxysporum, Fusarium solani, Pythium debaryanum and Phytophthora infestans. N-(o-methoxycinnamyl) chitosan showed the highest antifungal activity among the tested compounds against the airborne fungi A. alternata, B. cinerea, Bd. theobromae and Ph. infestans with EC50 of 672, 796, 980 and 636mg/L, respectively. However, N-(p-N-dimethylaminocinnamyl) chitosan was the most active against the soil born fungi F. oxysporum, F. solani and P. debaryanum (EC50=411, 566 and 404mg/L, respectively). On the other hand, the chitosan derivatives caused significant reduction in spore germination of A. alternata, B. cinerea, F. oxysporum and F. solani compared to chitosan and the reduction in spore germination was higher than that of the mycelia inhibition. The synthesis and characterization of new chitosan derivatives are ongoing in our laboratory aiming to obtain derivatives with higher antimicrobial activities and used as safe alternatives to harmful microbicides.

Relationship between antimold activity and molecular structure of cinnamaldehyde analogues

A quantitative structure–activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R2=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work.

Structure-Activity Relationship of Cinnamaldehyde Analogs as Inhibitors of AI-2 Based Quorum Sensing and Their Effect on Virulence of Vibrio spp

BackgroundMany bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs.Methodology/Principal FindingsBy evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus.Conclusions/SignificanceSeveral new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

Effects of cinnamaldehyde on the glucose transport activity of GLUT1

There is accumulating evidence that cinnamon extracts contain components that enhance insulin action. However, little is know about the effects of cinnamon on non-insulin stimulated glucose uptake. Therefore, the effects of cinnamaldehyde on the glucose transport activity of GLUT1 in L929 fibroblast cells were examined under both basal conditions and conditions where glucose uptake is activated by glucose deprivation. The data reveal that cinnamaldehyde has a dual action on the glucose transport activity of GLUT1. Under basal conditions it stimulates glucose uptake and reaches a 3.5 fold maximum stimulation at 2.0 mM. However, cinnamaldehyde also inhibits the activation of glucose uptake by glucose deprivation in a dose dependent manner. Experiments with cinnamaldehyde analogs reveal that these activities are dependent on the α,β-unsaturated aldehyde structural motif in cinnamaldehyde. The inhibitory, but not the stimulatory activity of cinnamaldehyde was maintained after a wash-recovery period. Pretreatment of cinnamaldehyde with thiol-containing compounds, such as β-mercaptoethanol or cysteine, blocked the inhibitory activity of cinnamaldehyde. These results suggest that cinnamaldehyde inhibits the activation of GLUT1 by forming a covalent link to target cysteine residue/s. This dual activity of cinnamaldehyde on the transport activity of GLUT1 suggests that cinnamaldehyde is not a major contributor to the anti-diabetic properties of cinnamon.

Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention

Trans-cinnamaldehyde (CA) and its analogs 2-hydroxycinnamaldehyde and 2-benzoyloxycinnamaldehyde have been reported to possess antitumor activity. CA is also a known Nrf2 activator. In this study, a series of ortho-substituted cinnamaldehyde analogs was synthesized and screened for antiproliferative and thioredoxin reductase (TrxR)-inhibitory activities. Whereas CA was weakly cytotoxic and TrxR inhibiting, hydroxy and benzoyloxy substitutions resulted in analogs with enhanced antiproliferative activity paralleling increased potency in TrxR inactivation. A novel analog, 5-fluoro-2-hydroxycinnamaldehyde, was identified as exhibiting the strongest antitumor effect (GI 50 1.6 μM in HCT 116 cells) and TrxR inhibition (IC 50 7 μM, 1 h incubation with recombinant TrxR). CA and its 2-hydroxy- and 2-benzoyloxy-substituted analogs possessed dual TrxR-inhibitory and Nrf2-inducing effects, both attributed to an active Michael acceptor pharmacophore. At lethal concentrations, TrxR-inhibitory potencies correlated with the compounds' antiproliferative activities. The penultimate C-terminal selenocysteine residue was shown to be a possible target. Conversely, at sublethal concentrations, these agents induced an adaptive antioxidant response through Nrf2-mediated upregulation of phase II enzymes, including TrxR induction. We conclude from the results obtained that TrxR inactivation contributes at least partly to cinnamaldehyde cytotoxicity. These Michael acceptor molecules can potentially be exploited for use in different concentrations in chemotherapeutic and chemopreventive strategies.

Structure–activity analysis of 2′-modified cinnamaldehyde analogues as potential anticancer agents

The natural product 2′-hydroxycinnamaldehyde (HCA) and its analogue, 2′-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure–activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2′-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

3D QSAR studies on cinnamaldehyde analogues as farnesyl protein transferase inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on 59 cinnamaldehyde analogues as Farnesyl Protein Transferase (FPTase) inhibitors were investigated using comparative molecular field analysis (CoMFA) with the PLS region-focusing method. Forty-nine training set inhibitors were used for CoMFA with two different grid spacings, 2A and 1A. Ten compounds, which were not used in model generation, were used to validate the CoMFA models. After the PLS analysis, the best predictive CoMFA model showed that the cross-validated value (r2cv) and the non-cross validated conventional value (r2ncv) are 0.557 and 0.950, respectively. From the CoMFA contour maps, the steric and electrostatic properties of cinnamaldehyde analogues can be identified and verified.

Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor cells.

Cinnamaldehydes and related compounds were synthesized from various cinnamic acids based on the 2'-hydroxycinnamaldehyde isolated from the bark of Cinnamomum cassia Blume. The cytotoxicity to human solid tumor cells such as A549, SK-OV-3, SK-MEL-2, XF498 and HCT15 were measured. Cinnamic acid, cinnamates and cinnamyl alcohols did not show any cytotoxicity against the human tumor cells. Cinnamaldehydes and related compounds were resistant to A549 cell line up to 15 micrograms/ml. In contrast, HCT15 and SK-MEL-2 cells were much sensitive to these cinnamaldehyde analogues which showed ED50 values 0.63-8.1 micrograms/ml. Cytotoxicity of the saturated aldehydes was much weak compared to their unsaturated aldehydes. From these studies, it was found that the key functional group of the cinnamaldehyde-related compounds in the antitumor activity is the propenal group.