trans-Cinnamaldehyde

Overview

Cinnamaldehyde, an old flavourant derived from Cinnamon trees and other species of the genus Cinnamomum^[1], has now attracted rising interests for its ability of preventing the development of diabetes and its complications^[2,3]. As a yellow and viscous liquid, cinnamaldehyde constitutes 98% of essential oil of Cinnamon bark, and was first isolated by Dumas and Péligot^[4] and then synthesized in the laboratory by the Italian chemist, Luigi Chiozza (1828-1889) in 1854^[5]. In 2007, Subash et al. firstly reported a hypoglycemic and hypolipidemic effect of cinnamaldehyde on streptozotocin (STZ)-induced male diabetic Wistar rats^[6]. Cinnamaldehyde has been since extensively studied in animal models of diabetes and obesity.
Cassia or Chinese cinnamon is a widely used spice extracted from the inner bark of the cinnamon tree. Cassia has been used for thousands of years for medicinal purposes and is considered to be one of the 50 fundamental herbs in traditional Chinese medicine. Several parts of the Cassia plant are used for medicinal purposes, including the root, bark, leaves, and flowers. Cinnamon extracts have been reported to have various beneficial effects, including antiallergenic, antimicrobial, antiviral, antioxidative, gastroprotective, antiangiogenic, and anti-Alzheimer effects, as well as insulin-like biological activities ^[7-12]. Cinnamon extracts contain several active compounds, including essential oils (cinnamaldehyde and cinnamyl aldehyde), tannins, mucus, and carbohydrates^[13]. Interestingly, cinnamaldehyde, also known as cinnamic aldehyde, shows anti-obesity effects by reducing lipid accumulation and downregulating the peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1. Furthermore, cinnamaldehyde inhibits lipopolysaccharideinduced microglial activation by targeting the low-density lipoprotein receptor-related protein-1^[14]. It was also reported that cinnamaldehyde has antimutagenic effects in cancer cells^[15].

Figure 1 the chemical structure of Cinnamaldehyde

Pharmacokinetics

Cinnamaldehyde naturally exists in trans-cinnamaldehyde form^[16]. In an experiment performed by Zhao et al. evaluates the pharmacokinetics of cinnamaldehyde in rats using relative sensitive approach of gas chromatography–mass spectrometry (GC-MS) via oral (500 mg/kg) and intravenous injection (i.v.,20 mg/kg) administration^[17]. The results reveals that AUC0-t of cinnamaldehyde via oral administration and via i.v. administration are 1984 ± 531 and 355 ± 53 ng h/ml, respectively. The T1/2 and Tmax of cinnamaldehyde are longer for oral administration (6.7 ± 1.5 h and 1.6 ± 0.5 h) than for i.v. administration (1.7 ± 0.3 h and 0.033 h). The Cmax is 249±36 ng/ml for oral administration, and 547±142 ng/ml for i.v. administration, respectively. The results indicate that the bioavailability of cinnamaldehyde is better improved by i.v. administration than by oral administration.
Further, the authors demonstrate that Cmax and AUC0–t are proportional to the dose (from 125 to 500 mg), whereas Tmax and mean residence time does not change in response to dose escalation^[17]. Given that cinnamaldehyde and cinnamyl alcohol could transform into each another in rats^[17], the authors also analyzes pharmacokinetic property of cinnamyl alcohol in rats plasma. The pharmacokinetic data of cinnamyl alcohol are 1105±337 ng•h/ml for AUC0–t, 6.7±2.8 h for T1/2, 1.5±0.7 h for Tmax, and 221±66 ng/ml for Cmax, at oral dosage of 500 mg/kg. Interestingly, methyl cinnamate has also been discovered in the metabolites. For pharmacokinetic property of methyl cinnamate, interested readers are encouraged to consult Zhao et al. article^[17]. In short, cinnamaldehyde is well distributed throughout the body after absorption. Cinnamaldehyde has an option to transform into cinnamyl alcohol and also can be oxidized to cinnamic acid after entering the body. In order to fully understand pharmacokinetic properties of cinnamaldehyde, methyl cinnamate and cinnamyl alcohol should also be determined in the plasma. However, the instability of cinnamaldehyde calls into question that the bioactivity of cinnamaldehyde is likely due to the sum of its metabolites. Therefore, further attempts are expected to address the potential concerns. In addition, the newly developed SME-cinnamaldehyde with improved bioavailability also needs further investigation of anti-diabetic effect.

Applications

Cinnamon extracts have various beneficial effects including antiallergenic, antimicrobial, antiviral, antioxidative, gastroprotective, antiangiogenic and anti-Alzheimer effects as well as insulin-like biological activities. Cinnamaldehyde shows anti-obesity effects by reducing lipid accumulation and downregulating the peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1. Furthermore, cinnamaldehyde inhibits lipopolysaccharideinduced microglial activation by targeting the low-density lipoprotein receptor-related protein-1. It was also reported that cinnamaldehyde has antimutagenic effects in cancer cells^[15]. The effect of cinnamaldehyde on the treatment of cancer and diabetes is highlighted below:
Anticancer
Kwon et al.^[18] reported for the first time that cinnamon extracts induce in vitro and in vivo melanoma cell death through the inhibition of NF-κB and AP-1. A subsequent study showed that HCA is the major antitumorigenic compound found in cinnamon extracts, exerting its growth inhibitory effects in 29 types of human cancer cells in vitro and in SW620 human tumor xenografts in vivo^[19].
Other research teams have also reported antitumorigenic effects of cinnamon extracts. They inhibit melanoma cancer cells by inducing the expression of pro-angiogenic factors; they also improved the antitumorigenic activities of CD8[+] T cells by increasing their cytolytic activity^[20]. Cinnamon extracts also inhibit vascular endothelial growth factor[VEGF], which was discovered by screening compounds for their inhibitory activity against VEGFR2^[21]. Most of the antitumorigenic effects of cinnamon extracts can be attributed to cinnamaldehydes, the main component of the essential oil, responsible for the flavor and aroma of the whole cinnamon. It was reported that cinnamaldehydes inhibited cancer cell proliferation by inhibiting cyclin D1 in several types of tumors^[22]. Cinnamaldehydes also induce apoptosis by generating reactive oxygen species[ROS] in HL-60 leukemia cells^[23] and through activation of pro-apoptotic Bcl-2 family proteins and the MAPK signaling pathway in human hepatoma cells^[24]. Furthermore, dimeric cinnamaldehydes derived from HCA showed greater antitumorigenic effects than monomeric cinnamaldehydes by inducing apoptosis and cell cycle arrest^[25]. In addition, a number of studies have revealed that the antitumorigenic effects of HCA and its derivatives are mediated through several molecular mechanisms. A recent study showed that polyphenols bearing a cinnamaldehyde scaffold triggered cell cycle arrest at the G2/M phase and apoptotic cell death in cisplatinresistant human ovarian cancer cells^[26], suggesting that cinnamaldehyde compounds could be effective in combination chemotherapies for cancer patients. Overall, the molecular mechanisms underlying the anticancer and antimetastatic effects of cinnamaldehydes are diverse, suggesting that cinnamaldehyde is a multitargeting compound. The differential responsiveness of various cancers to different cinnamaldehyde derivatives must be evaluated to allow selection of the most effective compound for each cancer type.
Anti-diabetes
Emerging studies have been performed over the past decades to evaluate its beneficial role in management of diabetes and its complications. It is demonstrated that oral administration of cinnamaldehyde ranging from 20 mg/kg•body weight[BW] to 40 mg/kg•BW per day for a duration lasting from 21 to 60 days resulted in a significant improvement in the levels of blood glucose and glycosylated hemoglobin[HbA1C] as well as insulin sensitivity in STZ-induced diabetic rats^{[27, 28]}. And 20 mg/kg•BW is assumed to be the effective dose for preventing the development of diabetes in animals. Further, cinnamaldehyde treatment for 4 weeks increases plasma insulin levels and liver glycogen content, as well as decreases triglyceride[TG] and low-density lipoprotein-cholesterol[LDL] levels in STZ and/or HFD insulted male Wistar rats^[29,30]. Furthermore, Camacho et al. found that administration with cinnamaldehyde for 5 weeks to HFD fed C57BL/6J mice significantly led to a reduction in body fat mass gain. However, they claimed that cinnamaldehyde treatment did not alter plasma fasting insulin levels and feed consumption^[31]. The reason for the inconsistence regarding insulin regulation could be attributed to that genetic backgrounds of C57BL/6J mice are altered in some production facilities^[32,33]. The different substrains of mice may exhibit significant differences in phenotypes^{[34, 35]}. In addition, cinnamaldehyde may exhibit glucose-lowering effect through improving insulin sensitivity in the periphery in Camacho’s study^[31].
Cinnamaldehyde has the capacity of improving diabetic adipose tissues by reducing visceral fat deposition, and promoting lipolysis and fatty acid oxidation and thermogenesis, which is associated with an upregulation of energy expenditure genes[UCP1, FOXP2, BPMP4 and PRDM16], an inhibition of PPARγ/CEBP-α and SREBP1, an upregulation of HSL and PNPLA2 and MGL, an induction of AMPK phosphorylation, and an increase in Cpt1a in WAT and Acsl4 in BAT, as well as a stimulation of the sympathetic nervous system. In addition, cinnamaldehyde prevents inflammatory genes expression, and improves GLUTs expression in diabetic animals. Cinnamaldehyde may protect against diabetes by improving insulin sensitivity and glucose uptake through regulating PI3K/IRS-1 and RBP4-GLUT4 pathway in skeletal muscle tissue^{[37, 38]}, as well as regulating mitochondria metabolism through PGC-1α/MEF2/GLUT4 pathway in C2C12 cells^[36]. Cinnamaldehyde also has positive effects on diabetic liver through improving glycogen syntheses by regulating activities of PK and PEPCK and decreasing RBP4 level as well as normalizing the aberrant liver enzymes, suggesting a beneficial role of this compound in glucose metabolism and insulin sensitivity in diabetic liver^[39-41].
Anti-microbial effects
Study has confirmed the antimicrobial activity of cinnamaldehyde, cloves, thyme, and rosemary against E. coli O157:H7 and Salmonella[42-44]. Wendakoon and Sakaguchi[1995]^[45] reported that the carbonyl group of cinnamaldehyde binds to the proteins, preventing amino acid decarboxylase activity in Enterobacter aerogenes. Smid et al.[1996]^[46] observed the damage to cytoplasmic membrane of Saccharomyces cerevisiae when treated with cinnamaldehyde, leading to excessive leakage of metabolites and enzymes from the cell, and finally loss of viability. Most studies have suggested that the modes of action of essential oils depend on the type of microorganisms, mainly on their cell wall structure and to their outer membrane arrangement. They observed damages due to the significant differences in the outer membranes of gram-negative and gram-positive bacteria^{[42, 43]}.

Toxicity

Even now, cinnamaldehyde is still assumed to be a safe natural ingredient agent and well tolerated in human and animals^[47]. The concept is also well accepted by FDA and the council of Europe with suggestion of the acceptable daily intake of 1.25 mg/kg.
Acute toxicity
Cinnamaldehyde is reported to have the high margin of safety, and administered 20 times of effective dose(20 mg/kg) of this compound did not cause abnormal behavioral signs and disturbed serum chemistry values throughout the study^[48]. The acute toxicity of cinnamaldehyde is low, with oral median lethal dose(LD50) values ranging from a low of 0.6 g/kg BW to a high of 3.4 g/kg BW in different species^[49].
Long-term toxicity
The results of a three-month study^[50] show that body weights are reduced in female rats exposed to 16,500 or 33,000 ppm and in female mice exposed to 8200 ppm or greater. In addition, feed consumption is reduced in all exposed groups of rats and in the highest dose group of mice. Further, exposure to cinnamaldehyde[8200 ppm or greater in rats and 33,000 ppm in female mice] increases the incidence of squamous epithelial hyperplasia of the forestomach. In addition, mice exposed to cinnamaldehyde[males and females exposed to 16,500 ppm and females exposed to 33,000 ppm] also exhibit increased incidence of olfactory epithelial degeneration of the nasal cavity. All rats survived throughout the three-month study.
Other
Cinnamaldehyde may also show cytotoxicity effects in F344 rat hepatocytes evidenced by depleting glutathione levels^[51], and in HepG2 cells evidenced by increasing micronucleus numbers^[52]. Behar et al.^[53] studied the potential toxicity of this product in human embryonic and lung cells. The results demonstrate that cinnamaldehyde treatment depolymerizes microtubules in human pulmonary fibroblasts. Cinnamaldehyde also decreases cell proliferation and differentiation by inhibiting cell growth and differentiation, and by altering cell morphology and motility as well as increasing DNA strand breaks and cell death. A study performed by Olsen et al. reveals that cinnamaldehyde causes skin irritant by increasing cold pain threshold and decreasing mechanical pain threshold as well as increasing skin temperature and perfusion in human^[54].

References

1. Zhou M, Chen Z, Shen S. Recent advanceson cinnamaldehyde. Journal of Economic Animal 2015;19:1-5.
2. Khare P, Jagtap S, Jain Y, Baboota RK, Mangal P, Boparai RK, Bhutani KK, Sharma SS, Premkumar LS, Kondepudi KK, Chopra K, Bishnoi M. Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice. BioFactors 2016;42:201-211.
3. Ma R, Zhu R, Wang L, Guo Y, Liu C, Liu H, Liu F, Li H, Li Y, Fu M, Zhang D. Diabetic osteoporosis: A review of its traditional chinese medicinal use and clinical and preclinical research. Evidence-based complementary and alternative medicine : eCAM 2016;2016:3218313.
4. Dumas JP, E. Organic chemistry research – on cinnamon oil, the hippuric acid and sebacic acid. Annales de chimie et de physique 1834;57:305-334.
5. Chiozza L. Sur la production artificielle de l´essence de cannelle"[on the artificial production of cinnamon oil]. Comptes rendus[in French] 1856;42:222-227.
6. Subash Babu P, Prabuseenivasan S, Ignacimuthu S. Cinnamaldehyde--a potential antidiabetic agent. Phytomedicine : international journal of phytotherapy and phytopharmacology 2007;14:15-22.
7. Hagenlocher Y, Bergheim I, Zacheja S, Schaffer M, Bischoff SC, Lorentz A. 2013. Cinnamon extract inhibits degranulation and de novo synthesis of inflammatory mediators in mast cells. Allergy 68: 490–497.
8. Matan N, Rimkeeree H, Mawson AJ, Chompreeda P, Haruthaithanasan V, Parker M. 2006. Antimicrobial activity of cinnamon and clove oils under modified atmosphere conditions. Int J Food Microbiol 107: 180–185.
9. Fink RC, Roschek B Jr, Alberte RS. 2009. HIV type-1 entry inhibitors with a new mode of action. Antivir Chem Chemother 19: 243–255.
10. Yang CH, Li RX, Chuang LY. 2012. Antioxidant activity of various parts of Cinnamomum cassia extracted with different extraction methods. Molecules 17: 7294–7304.
11. Peterson DW et al. 2009. Cinnamon extract inhibits tau aggregation associated with Alzheimer’s disease in vitro. J Alzheimers Dis 17: 585–597.
12. Cheng DM, Kuhn P, Poulev A, Rojo LE, Lila MA, Raskin I. 2012. In vivo and in vitro antidiabetic effects of aqueous cinnamon extract and cinnamon polyphenol-enhanced food matrix. Food Chem 135: 2994–3002.
13. Kim JE et al. 2015a. A novel cinnamon-related natural product with Pim-1 inhibitory activity inhibits leukemia and skin cancer. Cancer Res 75: 2716–2728.
14. Hwang H et al. 2011. 2′-Hydroxycinnamaldehyde targets low-density lipoprotein receptor-related protein-1 to inhibit lipopolysaccharide-induced microglial activation. J Neuroimmunol2011 230: 52–56.
15. Shaughnessy DT, Setzer RW, DeMarini DM. 2001. The antimutagenic effect of vanillin and cinnamaldehyde on spontaneous mutation in Salmonella TA104 is due to a reduction in mutations at GC but not AT sites. Mutat Res 480: 55–69.
16. Zhang LQ, Zhang ZG, Fu Y, Xu Y. Research progress of trans-cinnamaldehyde pharmacological effects. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 2015;40:4568-4572.
17. Zhao H, Xie Y, Yang Q, Cao Y, Tu H, Cao W, Wang S. Pharmacokinetic study of cinnamaldehyde in rats by gc-ms after oral and intravenous administration. Journal of pharmaceutical and biomedical analysis 2014;89:150-157.
18. Kwon BM et al. 1998. Synthesis and in vitro cytotoxicity of cinnamaldehydes to human solid tumor cells. Arch Pharm Res 21: 147–152.
19. Lee CW et al. 1999. Inhibition of human tumor growth by 2′-hydroxyand 2′-benzoyloxycinnamaldehydes. Planta Med 65: 263–266
20. Kwon HK et al. 2009. Cinnamon extract suppresses tumor progression by modulating angiogenesis and the effector function of CD8+ T cells. Cancer Lett 278: 174–182.
21. Lu J, Zhang K, Nam S, Anderson RA, Jove R,WenW. 2010. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis 31: 481–488.
22. Jeong HW et al. 2000. Cinnamaldehydes inhibit cyclin dependent kinase 4/cyclin D1. Bioorg Med Chem Lett 10: 1819–1822. 
23. Ka H et al. 2003. Cinnamaldehyde induces apoptosis by ROSmediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells. Cancer Lett 196: 143–152.
24. Wu SJ, Ng LT, Lin CC. 2005. Cinnamaldehyde-induced apoptosis in human PLC/PRF/5 cells through activation of the proapoptotic Bcl-2 family proteins and MAPK pathway. Life Sci 77: 938–951.
25. Shin DS et al. 2006. Synthesis and biological evaluation of dimeric cinnamaldehydes as potent antitumor agents. Bioorg Med Chem 14: 2498–2506.
26. Shin SY et al. 2014. Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatinresistant A2780/Cis ovarian cancer cells. Bioorg Med Chem 22: 1809–1820.
27. Lee SC, Xu WX, Lin LY, Yang JJ, Liu CT. Chemical composition and hypoglycemic and pancreas-protective effect of leaf essential oil from indigenous cinnamon[cinnamomum osmophloeum kanehira]. Journal of agricultural and food chemistry 2013;61:4905-4913.
28. El-Bassossy HM, Fahmy A, Badawy D. Cinnamaldehyde protects from the hypertension associated with diabetes. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2011;49:3007-3012.
29. Li M, Xu Y, Zhang W. Effects of cinnamaldehyde on the expression levels of irs-1 and p85 alpha in gastrocnemius of type 2 diabetic rats. Medical Journal of Wuhan University 2009;30:723-726=731.
30. Kumar S, Vasudeva N, Sharma S. Gc-ms analysis and screening of antidiabetic, antioxidant and hypolipidemic potential of cinnamomum tamala oil in streptozotocin induced diabetes mellitus in rats. Cardiovascular diabetology 2012;11:95.
31. Camacho S, Michlig S, de Senarclens-Bezencon C, Meylan J, Meystre J, Pezzoli M, Markram H, le Coutre J. Anti-obesity and anti-hyperglycemic effects of cinnamaldehyde via altered ghrelin secretion and functional impact on food intake and gastric emptying. Scientific reports 2015;5:7919.
32. Navarro SJ, Trinh T, Lucas CA, Ross AJ, Waymire KG, Macgregor GR. The c57bl/6j mouse strain background modifies the effect of a mutation in bcl2l2. G3 2012;2:99-102.
33. Mekada K, Abe K, Murakami A, Nakamura S, Nakata H, Moriwaki K, Obata Y, Yoshiki A. Genetic differences among c57bl/6 substrains. Experimental animals 2009;58:141-149.
34. Kiselycznyk C, Holmes A. All[c57bl/6] mice are not created equal. Frontiers in neuroscience 2011;5:10.
35. Attane C, Peyot ML, Lussier R, Zhang D, Joly E, Madiraju SR, Prentki M. Differential insulin secretion of high-fat diet-fed c57bl/6nn and c57bl/6nj mice: Implications of mixed genetic background in metabolic studies. PloS one 2016;11:e0159165.
36. Nicholas P G, Schnuckc. JK, Mermierd. CM, Conne. CA, Vaughanc. RA. Trans-cinnamaldehyde stimulates mitochondrial biogenesis through pgc-1α and pparβ/δ leading to enhanced glut4 expression. Biochimie 2015;119:45-51.
37. Zhang W, Xu YC, Guo FJ, Meng Y, Li ML. Anti-diabetic effects of cinnamaldehyde and berberine and their impacts on retinol-binding protein 4 expression in rats with type 2 diabetes mellitus. Chin Med J[Engl] 2008;121:2124-2128.
38. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 2005;54:2351-2359.
39. Saraswathi V, Ramnanan CJ, Wilks AW, Desouza CV, Eller AA, Murali G, Ramalingam R, Milne GL, Coate KC, Edgerton DS. Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice. Metabolism: clinical and experimental 2013;62:1673-1685.
40. Ohaeri OC. Effect of garlic oil on the levels of various enzymes in the serum and tissue of streptozotocin diabetic rats. Bioscience reports 2001;21:19-24.
41. Mahfouz MH, Assiri AM, Mukhtar MH. Assessment of neutrophil gelatinase-associated lipocalin (ngal] and retinol-binding protein 4[rbp4] in type 2 diabetic patients with nephropathy. Biomarker insights 2016;11:31-40.
42. SHAN, B., CAY, Y.-Z., BROOKS, J.D. and CORKE, H. 2007. Antibacterial properties and major bioactive components of cinnamon stick[Cinnamomum burmannii]: Activity against foodborne pathogenic bacteria. J. Agric. Food Chem. 55, 5484–5490
43. RHAYOUR, K., BOUCHIKHI, T., TANTAOUI-ELARAKI, A., SENDIDE, K. and REMMAL, A. 2003. The mechanism of bactericidal action of oregano and clove essential oils of their phenolic major components on Escherichia coli and Bacillus subtilis. J. Essent. Oil Res. 15, 356–362.
44. KIM, H.-O., PARK, S.-W. and PARK, H.-D. 2004. Inactivation of Escherichia coli O157:H7 by cinnamic aldehyde purified from Cinnamomum cassia shoot. Food Microbiol. 21, 105–110
45. WENDAKOON, C. and SAKAGUCHI, M. 1995. Inhibition of amino acid decarboxylase activity of Enterobacter aerogenes by active components in spices. J. Food Prot. 58, 280–283.
46. SMID, E.J., KOEKEN, J.P.G. and GORRIS, L.G.M. 1996. Fungicidal and fungistatic action of the secondary plant metabolites cinnamaldehyde and carvone. In Modern Fungicides and Antimicrobial Compounds[H. Lyr, P.E. Russell and H.D. Sisler, eds.] pp. 173–180, Intercept, Andover, U.K.
47. Dugoua JJ, Seely D, Perri D, Cooley K, Forelli T, Mills E, Koren G. From type 2 diabetes to antioxidant activity: A systematic review of the safety and efficacy of common and cassia cinnamon bark. Canadian journal of physiology and pharmacology 2007;85:837-847.
48. Anand P, Murali KY, Tandon V, Murthy PS, Chandra R. Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and glut4 translocation in experimental diabetic rats. Chemico-biological interactions 2010;186:72-81.
49. Gowder SJT. Safety assessment of food flavor -cinnamaldehyde. Biosafety 2014;3
50. Hooth MJ, Sills RC, Burka LT, Haseman JK, Witt KL, Orzech DP, Fuciarelli AF, Graves SW, Johnson JD, Bucher JR. Toxicology and carcinogenesis studies of microencapsulated trans-cinnamaldehyde in rats and mice. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2004;42:1757-1768.
51. Swales NJ, Caldwell J. Studies on trans-cinnamaldehyde ii: Mechanisms of cytotoxicity in rat isolated hepatocytes. Toxicology in vitro : an international journal published in association with BIBRA 1996;10:37-42.
52. Sanyal R, Darroudi F, Parzefall W, Nagao M, Knasmuller S. Inhibition of the genotoxic effects of heterocyclic amines in human derived hepatoma cells by dietary bioantimutagens. Mutagenesis 1997;12:297-303.
53. Behar RZ, Luo W, Lin SC, Wang Y, Valle J, Pankow JF, Talbot P. Distribution, quantification and toxicity of cinnamaldehyde in electronic cigarette refill fluids and aerosols. Tobacco control 2016
54. Olsen RV, Andersen HH, Moller HG, Eskelund PW, Arendt-Nielsen L. Somatosensory and vasomotor manifestations of individual and combined stimulation of trpm8 and trpa1 using topical l-menthol and trans-cinnamaldehyde in healthy volunteers. European journal of pain 2014;18:1333-1342.

Chemical Properties

Combustible, yellowish, oily liquid (thickens on exposure to air). Strong pungent, spicy, cinnamon odor.

Chemical Properties

CLEAR YELLOW LIQUID

Chemical Properties

trans-Cinnamaldehyde is the main component of cassia oil (about 90%) and Sri Lanka cinnamon bark oil (about 75%). Smaller quantities are found in many other essential oils. In nature, the trans-isomer is predominant.
trans-Cinnamaldehyde is a yellowish liquid with a characteristic spicy odor, strongly reminiscent of cinnamon. Being an ??,??-unsaturated aldehyde, it undergoes many reactions, of which hydrogenation to cinnamic alcohol, dihydrocinnamaldehyde, and dihydrocinnamic alcohol is important. Cinnamic acid is formed by autoxidation.
On an industrial scale, cinnamaldehyde is prepared almost exclusively by alkaline condensation of benzaldehyde and acetaldehyde. Self-condensation of acetaldehyde can be avoided by using an excess of benzaldehyde and by slowly adding acetaldehyde.
Cinnamaldehyde is used in many compositions for creating spicy and oriental notes (e.g., soap perfumes). It is the main component of artificial cinnamon oil. In addition, it is an important intermediate in the synthesis of cinnamic alcohol and dihydrocinnamic alcohol.

Uses

trans-Cinnamaldehyde is used in the flavor and perfume industry. It is also used in medicine. It reacts with glutathione to get an adduct 1'-(glutathion-S-yl)-dihydrocinnamaldehyde. It is used to prepare cinnamylidene-bisacetamide by reacting with acetamide. Further, it inhibits xanthine oxidase.

Uses

Buildingblock - Cinnamaldehyde is an unsaturated aldehyde so it can easily react to many different compounds to be used in a wide range of fragrance compositions. It is also a building block for several agrochemicals (miticides) or for derivatives like cinnamic alcohol, 3-phenylpropanol, cinnamonitrile, 3-phenylpropionylaldehyde (fragrances and as an alternative to enalapril, lisinopril and ramipril).

Definition

ChEBI: The E (trans) stereoisomer of cinnamaldehyde, the parent of the class of cinnamaldehydes.

Synthesis Reference(s)

Chemistry Letters, 12, p. 1207, 1983
Journal of the American Chemical Society, 93, p. 2080, 1971 DOI: 10.1021/ja00737a057
Tetrahedron Letters, 18, p. 1215, 1977

General Description

Clear yellow liquid with an odor of cinnamon and a sweet taste.

Air & Water Reactions

May be sensitive to prolonged exposure to air and light. Insoluble in water.

Reactivity Profile

trans-Cinnamaldehyde is incompatible with strong oxidizing agents and strong bases. trans-Cinnamaldehyde can also react with sodium hydroxide.

Fire Hazard

trans-Cinnamaldehyde is combustible.

Potential Exposure

Botanical fungicide and insecticide. Used as an antifungal agent, corn rootworm attractant, and dog and cat repellent. Can be used on soil casing for mushrooms, row crops, turf, and all food commodities. Not listed for use in EU countries.

Shipping

UN1989 Aldehydes, n.o.s., Hazard Class: 3; Labels: 3-Flammable liquid

Incompatibilities

Aldehydes are frequently involved in selfcondensation or polymerization reactions. These reactions are exothermic; they are often catalyzed by acid. Aldehydes are readily oxidized to give carboxylic acids. Flammable and/or toxic gases are generated by the combination of aldehydes with azo, diazo compounds, dithiocarbamates, nitrides, and strong reducing agents. Aldehydes can react with air to give first peroxo acids, and ultimately carboxylic acids. These autoxidation reactions are activated by light, catalyzed by salts of transition metals, and are autocatalytic (catalyzed by the products of the reaction). The addition of stabilizers (antioxidants) to shipments of aldehydes retards autoxidation. Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides, ketones, azo dyes, caustics, boranes, hydrazines

Waste Disposal

Incineration. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers.