Catharanthine

The herbs of Catharanthus roseus (L.) G.Don

Catharanthine inhibits nicotinic receptor mediated diaphragm contractions with IC50 of 59.6 μM. Target: nAChR Catharanthine evokes a concentration-dependent attenuation of carbachol responses in the rat ileum preparation, producing rightward curve displacements and decreases in maximal agonist responses. The mixture of serpentine, plus ajmalicine and catharanthine reveals a concentration-dependent inhibitory effect of acethylcholinesterase (AchE), with an IC50 at ca. 2.25 μg/Ml [1]. Catharanthine can induce the self-association of tubulin into linear indefinite polymers with an efficacy that is 75% that of vinblastine or vincristine. Catharanthine binds to tubulin alpha-beta dimer with binding constant of 2.8 mM [2]. Catharanthine stimulates release of amylase from pancreatic fragments and to cause extensive degranulation of pancreatic acinar cells with accumulation of membrane material in the Golgi region. Catharanthine induces a delayed release of Ca2+ from prelabeled pancreatic fragments as compared to bethanechol [3]. Catharanthine inhibits epibatidine-induced Ca(2+) influx in TE671-α, -β, -γ, -δ cells in a noncompetitive manner with similar potencies IC50 of 17 mM-25 mM. Catharanthine inhibits [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR. Catharanthine enhances [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties [4].

References:
[1]. Pereira, D.M., et al., Pharmacological effects of Catharanthus roseus root alkaloids in acetylcholinesterase inhibition and cholinergic neurotransmission. Phytomedicine, 2010. 17(8-9): p. 646-52. [2]. Prakash, V. and S.N. Timasheff, Mechanism of interaction of vinca alkaloids with tubulin: catharanthine and vindoline. Biochemistry, 1991. 30(3): p. 873-80. [3]. Williams, J.A., Catharanthine: a novel stimulator of pancreatic enzyme release. Cell Tissue Res, 1978. 192(2): p. 277-84. [4]. Arias, H.R., et al., Catharanthine alkaloids are noncompetitive antagonists of muscle-type nicotinic acetylcholine receptors. Neurochem Int, 2010. 57(2): p. 153-61.

Synthesis of fluorinated catharanthine analogues and investigation of their biomimetic coupling with vindoline.[Pubmed:23903701]

Org Biomol Chem. 2013 Sep 21;11(35):5885-91.

The syntheses of 20,20-difluoroCatharanthine and congeners, starting from the naturally occurring Catharanthine, are reported. The fluorinated Catharanthine analogues were investigated as potential precursors to dimeric Vinca alkaloids of the vinflunine family. However, the biomimetic coupling of the fluorinated Catharanthine derivatives with vindoline led to unexpected alkaloid structures, the formation of which was rationalized.

Catharanthine dilates small mesenteric arteries and decreases heart rate and cardiac contractility by inhibition of voltage-operated calcium channels on vascular smooth muscle cells and cardiomyocytes.[Pubmed:23532933]

J Pharmacol Exp Ther. 2013 Jun;345(3):383-92.

Catharanthine is a constituent of anticancer vinca alkaloids. Its cardiovascular effects have not been investigated. This study compares the in vivo hemodynamic as well as in vitro effects of Catharanthine on isolated blood vessels, vascular smooth muscle cells (VSMCs), and cardiomyocytes. Intravenous administration of Catharanthine (0.5-20 mg/kg) to anesthetized rats induced rapid, dose-dependent decreases in blood pressure (BP), heart rate (HR), left ventricular blood pressure, cardiac contractility (dP/dt(max)), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentration-dependent decreases (I(max) >98%) in endothelium-independent tonic responses of aortic rings to phenylephrine (PE) and KCl (IC(50) = 28 microM for PE and IC(50) = 34 microM for KCl) and of third-order branches of the small mesenteric artery (MA) (IC(50) = 3 microM for PE and IC(50) = 6 microM for KCl). Catharanthine also increased the inner vessel wall diameter (IC(50) = 10 microM) and reduced intracellular free Ca(2+) levels (IC(50) = 16 microM) in PE-constricted MAs. Patch-clamp studies demonstrated that Catharanthine inhibited voltage-operated L-type Ca(2+) channel (VOCC) currents in cardiomyocytes and VSMCs (IC(50) = 220 microM and IC(50) = 8 microM, respectively) of MA. Catharanthine lowers BP, HR, left ventricular systolic blood pressure, and dP/dt(max) and ESPVR likely via inhibition of VOCCs in both VSMCs and cardiomyocytes. Since smaller vessels such as the third-order branches of MAs are more sensitive to VOCC blockade than conduit vessels (aorta), the primary site of action of Catharanthine for lowering mean arterial pressure appears to be the resistance vasculature, whereas blockade of cardiac VOCCs may contribute to the reduction in HR and cardiac contractility seen with this agent.

Liquid chromatography mass spectrometry simultaneous determination of vindoline and catharanthine in rat plasma and its application to a pharmacokinetic study.[Pubmed:24828449]

Biomed Chromatogr. 2015 Jan;29(1):97-102.

Vinblastine and vincristine, both of which are bisindole alkaloids derived from vindoline and Catharanthine, have been used for cancer chemotherapy; their monomeric precursor molecules are vindoline and Catharanthine. A simple and selective liquid chromatography mass spectrometry method for simultaneous determination of vindoline and Catharanthine in rat plasma was developed. Chromatographic separation was achieved on a C18 (2.1 x 50 mm, 3.5 microm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. The flow rate was set at 0.4 mL/min. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification. Mean recoveries were in the range of 87.3-92.6% for vindoline in rat plasma and 88.5-96.5% for Catharanthine. Matrix effects for vindoline and Catharanthine were measured to be between 95.3 and 104.7%. Coefficients of variation of intra-day and inter-day precision were both <15%. The accuracy of the method ranged from 93.8 to 108.1%. The method was successfully applied in a pharmacokinetic study of vindoline and Catharanthine in rats. The bioavailability of vindoline and Catharanthine were 5.4 and 4.7%, respectively.

Interaction between abscisic acid and nitric oxide in PB90-induced catharanthine biosynthesis of catharanthus roseus cell suspension cultures.[Pubmed:23554409]

Biotechnol Prog. 2013 Jul-Aug;29(4):994-1001.

Elicitations are considered to be an important strategy to improve production of secondary metabolites of plant cell cultures. However, mechanisms responsible for the elicitor-induced production of secondary metabolites of plant cells have not yet been fully elucidated. Here, we report that treatment of Catharanthus roseus cell suspension cultures with PB90, a protein elicitor from Phytophthora boehmeriae, induced rapid increases of abscisic acid (ABA) and nitric oxide (NO), subsequently followed by the enhancement of Catharanthine production and up-regulation of Str and Tdc, two important genes in Catharanthine biosynthesis. PB90-induced Catharanthine production and the gene expression were suppressed by the ABA inhibitor and NO scavenger respectively, showing that ABA and NO are essential for the elicitor-induced Catharanthine biosynthesis. The relationship between ABA and NO in mediating Catharanthine biosynthesis was further investigated. Treatment of the cells with ABA triggered NO accumulation and induced Catharanthine production and up-regulation of Str and Tdc. ABA-induced Catharanthine production and gene expressions were suppressed by the NO scavenger. Conversely, exogenous application of NO did not stimulate ABA generation and treatment with ABA inhibitor did not suppress NO-induced Catharanthine production and gene expressions. Together, the results showed that both NO and ABA were involved in PB90-induced Catharanthine biosynthesis of C. roseus cells. Furthermore, our data demonstrated that ABA acted upstream of NO in the signaling cascade leading to PB90-induced Catharanthine biosynthesis of C. roseus cells.

Catharanthine is an alkaloid isolated from Madagascar periwinkle, inhibits voltage-operated L-type Ca2+ channel, with anti-cancer and blood pressure-lowering activity.

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