Evodiamine

Evodiamine is a naturally occurring indole alkaloid, being the main bioactive component of Evodia rutaecarpa. It has various kinds of pharmacological activities including anti-tumor, protecting the heart, causing weight loss and anti-inflammatory, analgesic and anti-senile dementia. Evodiamine, as a natural anti-cancer drug, can inhibit the proliferation of a variety of tumor cells, including cervical cancer, colon cancer, lung cancer, melanoma, T lymphocytic leukemia, prostate cancer and breast cancer. It also has other biological activities, such as regulating body temperature, anti-anoxia, dermatological applications, and bronchoconstriction as well as hormone secretion regulation. In addition, evodiamine has good binding capability to a variety of proteins, so it can be used as a multi-target compound to play a variety of biological activity.

Evodiamine belongs to tryptamine indole alkaloid, appearing as yellow flaky crystals or crystalline powder. It has a melting point of 278 °C and specific rotation [α] D20 of +3 52 ° (acetone). It is soluble in acetone and slightly soluble in chloroform but insoluble in water, benzene and petroleum ether. When coming across concentrated sulfuric acid or concentrated hydrochloric acid, it exhibits orange-red color with turning into reddish brown when placed with diluted with water becoming blue while generating blue stain precipitate after being alkalized. It is extracted and separated from the evodia fruit and can cause elevated blood pressure.

Evodiamine is extracted and isolated from the fruit of Rutaceae Evodia rutaecarpa (Juss.) Benth. Evodia is small deciduous trees or shrubs with a height of 3~10m. Its twig is hairy while old branches are reddish brown with lenticels. Bark is dark red, being shiny.
Leaf blade 5 to 9, opposite, oblong or elliptic, apically mucronate or acuminate, base cuneate or broadly cuneate, margin entire, puberulent coated in the upper part and shorter pilose coated in the lower part; Unisexual Flowers appears as yellow-white and dioecious with mostly florets. Thyrsus basidixed; stout floral axis and is densely coated with yellow-brown villous. Fruit, flat spherical, purple, with a large glandular point coated on the surface, 1 seed, oval, black gloss. Flowering period: June to August; fruit period: August to September. From August to November when the fruit has not yet cracked, cut the fruit branches for dried under sunshine or low temperature, remove the branches, leaves, fruiting and so on. It is born in warm areas of mountain, roadside or under the forest. It is mainly produced in Guizhou, Guangxi, Hunan, Yunnan, Shaanxi, Zhejiang, Sichuan and other places.
It contains volatile oil in the fruit with the main components including Evoden, Ocimene, Evodin, Evodia acid (Goshuynic acid) as well as many kinds of alkaloids such as Rutaevin, Evodiamine, Rutaecarpine, Rutaecarpine, Wuchuyine and Hydroxyevodiamine. Evodiamine, through boiling under alcoholic liquor, is converted into iso-evodiamine. Rutaecarpine is decomposed into Rutamine.
 
Figure 1 is Evodia
The traditional extraction method of Evodiamine includes water extraction, ultrasonic extraction and Soxhlet extraction. Ultrasonic extraction is of high extraction efficiency and can save time, is the ideal extraction method. For different concentration of methanol solution, the 100% methanol has the highest extraction efficiency on evodiamine. The extraction rate of evodiamine can also be affected by many factors. The optimum extraction conditions were as follows: solvent methanol, ultrasonic power 300W, frequency 61kHz, extraction temperature 60 ℃, solid-liquid ratio 1g: 10mL, extraction time: 60min.
An overview of evodiamine, physical and chemical properties, chemical synthesis, pharmacological effects are is edited by Shi Yan from Chemicalbook. (2015-10-23)

N-methyl anthranilic acid is used as the starting material, after subjecting to acylation and going through the intermediates 2, 3, generating the key oximinoketone 4, followed by reaction with 3, 4-dihydrocarboline to obtain evodiamine. The reaction is as follows:

1. Antitumor activity
Evodiamine can inhibit the proliferation of a variety of tumor cells, including cervical cancer, colon cancer, lung cancer, melanoma, T lymphocytic leukemia, prostate cancer and breast cancer. The more obvious inhibition of proliferation is through the role of Cdc2/cyclin B cell cycle arrest in the G2/M period. The results showed that evodiamine promoted apoptosis by inhibiting the expression of related genes regulated by nuclear factor kappa B, such as CycD1, apoptosis inhibitor, Bcl-2 and Bcl-xL. In addition, evodiamine can increase the expression of pro-apoptotic factor Bax and decrease the expression of Bcl-2, and induce the apoptosis through the aspartic acid-specific cysteine protease pathway. At the same time, reactive oxygen species and nitric oxide regulate the expression of p53, p21, protein tyrosine kinase and other signaling proteins during evodiamine-induced apoptosis. Phosphatidylinositol 3-kinase/protein kinase B and extracellular signal-regulated protein kinase signaling also play an important role in evodiamine-induced apoptosis of tumor cells. In addition to anti-proliferative and anti-apoptotic effects, evodiamine can inhibit tumor invasion and metastasis.
2. The role of Anti-Alzheimer
Alzheimer disease (AD) is a progressive, irreversible brain disease, mainly caused by degeneration of neurite synapses and death of nerve cells, leading to the lesion of recognition, memory and behavior of patients. Further studies have shown that evodiamine can increase the uptake of glucose in brain tissue and inhibit the expression of inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α and cyclooxygenase-2 in murine AD models with no effect on amyloid beta protein deposition. Therefore, the effect of evodiamine on improving the behavior of AD mice model is considered to be through the inhibition of inflammation. The results showed that dehydroevodiamine, a homologue of evodiamine, exhibits a more effective biological effect on AD. The chemical structure of dehydroevodiamine had been used to develop new cholinesterase inhibitors.
3. The impact on the endocrine system
Evodiamine can reduce the activity of intracellular cyclic adenosine monophosphate (cAMP)-related pathways, inhibit the activity of 3β-HSD and other steroid-related enzymes, reduce and influence signal transduction and RNA activation Protein (StAR) expression. It can directly take effect on the rat cortical adrenal cortex mesh cell for inhibition of corticosterone secretion. Incubation of rat Leydig cells (TICs) with 10-4 mol • L-1 evodiamine could significantly decrease the level of testosterone and the secretion of testosterone stimulated by human chorionic gonadotropin, and inhibit the testosterone release caused by forskolin. Evodiamine can also inhibit the 8-Br-cAMP and androstenedione-induced testosterone release.
4. Weight loss, hypoglycemic effect
After rats were treated with evodiamine for 13 weeks, the body weight and Lee's index of obese rats were decreased, the visceral fat weight and visceral fat weight index of obese rats were decreased, and the serum total cholesterol and triglyceride were decreased. Evodiamine could reverse the obesity complicated with vascular hypertrophy. Compared with normal rats, the expression of TRPV1 in the thoracic aorta and DRG of obese rats decreased, and the serum and abdominal aortic CGRP were increased. Evodiamine and capsaicin could increase the expression of TRPV1 in thoracic aorta and DRG. Evodiamine could decrease the contents of CGRP in serum and abdominal aorta, and its mechanism might be related to the regulation of CGRP and TRPV1 expression in serum, vascular tissue and DRG.
5. Anti-inflammatory analgesic effect
Evodiamine can inhibit the expression of cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in a dose-dependent manner, and reduce the prostaglandin (E2) release. It can block the hypoxia-induced phosphorylation of the Akt, 70 Kda ribosomal protein S6 kinase (P70S6K) and 4E-binding protein (4E-BP), regulate the translation of hypoxia-inducible factor (HIF-1alpha). The mRNA and protein degradation rate is not affected. It was suggested that evodiamine inhibited the hypoxia-induced COX-2 expression mainly through mediating the dephosphorylation of Akt and p70S6K. Evodiamine significantly inhibited the number of writhing caused by acetic acid. The in vitro ileal of mice treated with evodiamine has lost its response to the sensory nerve stimulation while retained the response to vagal stimulation. Evodiamine plays its analgesic effect through desensitization of sensory nerve.
6. The role of the cardiovascular system
 (1) The effect on the heart; Low concentration of evodiamine in vitro can accelerate the spontaneous rhythm on guinea pig heart tissue, increase the contraction force while having opposite effect at high concentration. The inhibition effect will be enhanced in the cardiac-induced calcium overload situation, indicating that the drug can produce indirect excitation and direct inhibition effect on the isolated Cardiac tissue of guinea pig. The injury caused by anti-myocardial ischemic reperfusion and cardiac arrest and anti-ischemic arrhythmia are all related to the release of endogenous CGRP.
(2) blood pressure; the hypotensive effect of Evodiamine is realized achieved by the diastolic endothelial cells and smooth muscle cells, being able to inhibit the participation of aldosterone steroid synthesis of 11-hydroxylase activity to affect the aldosterone release and thus affect blood pressure. Evodia rutaecarpa methanol extract and three quinolone alkaloids can significantly inhibit the binding between angiotensin and rat liver membrane receptor, to some extent, explaining the efficacy of Evodia of regulating the blood pressure.
 (3) Relaxing vasodilating effect: the vascular smoothing effect of evodiamine is related to endothelium activation and inhibition of the receptor-mediated Ca2 + channel in the vascular smooth muscle, but the role of different blood vessels are different. Evodiamine can induce the non-vascular endothelium-dependent, concentration-dependent relaxation in rabbit corpus cavernosum, which was associated with initiation of QD channel and nonselective effects on phosphodiesterase to prevent cyclic nucleotide degradation.

Evodiamine (518-17-2) is a quinolone alkaloid isolated from Evodia rutaecarpa.1 Evodia Rutaecarpa is a very popular herb used in traditional chinese medicine to treat a variety of ailments. Evodiamine has been shown to elicit a variety of biological effects including induction of apoptosis, inhibiting cancer cell proliferation, promoting cell cycle arrest in G2/M, inhibiting invasion and metastasis of cancer cells, inhibiting angiogenesis, induction of oxidative stress and subsequent apoptosis and inhibition of NF-κB.2 It also functions as an activator of TRPV1 (EC50 = 1.03 μM)3 and acts as an anti-inflammatory agent4.

White powder

A chemical extracted from Evodia plants, and has been shown to reduce fat uptake.

A vanilloid receptor agonist that induces apoptosis in leukemia U937 cells

An antiangiogenic and antiinflammatory agonist of TRPV1.

ChEBI: Evodiamine is a member of beta-carbolines.

The fruit of Evodia rutaecarpa Benth. is a standout among the most prominent andmultipurpose herbs utilized in China for pharmacological application (Fei et al.2003). Phytochemical analysis demonstrated that evodiamine, an indole alkaloid,exists in elevated amounts in Chinese herb evodia. This has wide-ranging biologicalactivities with vasodilatory, anti-obesity, anticancer, and anti-inflammatoryeffects (Jiang and Hu 2009). Evodiamine represses PDGF-BB-induced vascularsmooth muscle cell proliferation in a dose-dependent manner. It inhibits cell cycleprogression by suppressing the activation of p38 and Erk/MAPK pathway andameliorates ROS generation (Yang et al. 2008b; Heo et al. 2009; Yang et al. 2013).Restraint of mitogenesis and p38/p Erk action may fill in as the molecular basis forthe capacity of evodiamine. Evodiamine causes continued initiation of Erk/MAPKsignaling pathway in 3T3-L1 and essential preadipocytes prompting a potentinhibitory impact for adipogenesis (Wang et al. 2008). The consequence of thisinvestigation showed that evodiamine hindered vascular smooth muscle cell(VSMC) multiplication by stifling cell cycle movement, p38 MAPK and Erk 1/2enactment, and generation of ROS. Moreover, evodiamine offers the potential oftreating cardiovascular infections connected with the strange expansion of vascularsmooth muscle cells.

1) Shoji et al. (1986) Isolation of evodiamine, a powerful cardiotonic principle, from Evodia Rutaecarpa Bentham (Rutaceae); J. Pharm. Sci. 75 612 2) Jiang and Hu et al. (2009) Evodiamine: A novel anti-cancer alkaloid from Evodia rutaecarpa; Molecules, 14 1852 3) Pearce et al. (2004) Evodiamine functions as an agonist for the vanilloid receptor; Org. Biomol. Chem., 2 2281 4) Choi et al. (2006) Anti-inflammatory principles from the fruits of Evodia rutaecarpa and their cellular action mechanisms; Arch. Pharm. Res., 29 293