Vindorosine

Antagonism of Ca2+ influx via L-type Ca2+ channels mediates the vasorelaxant effect of Catharanthus roseus-derived vindorosine in rat renal artery.[Pubmed:25340466]

Planta Med. 2014 Dec;80(18):1672-7.

Catharanthus roseus is a traditional herbal medicine used in Asian and African countries for the treatment of various diseases including hypertension. The present study examined possible cellular mechanisms for the relaxation of rat renal arteries induced by Vindorosine extracted from C. roseus. Intrarenal arteries were isolated from 200-300 g male Sprague-Dawley rats and treated with different pharmacological blockers and inhibitors for the measurement of vascular reactivity on a Multi Myograph System. Fluorescence imaging by laser scanning confocal microscopy was utilized to determine the intracellular Ca(2+) level in the vascular smooth muscles of the renal arteries. Vindorosine in micromolar concentrations relaxes renal arteries precontracted by KCl, phenylephrine, 11-dideoxy-9alpha,11alpha-epoxymethanoprostaglandin F2alpha, and serotonin. Vindorosine-induced relaxations were unaffected by endothelium denudation or by treatment with the nitric oxide synthase inhibitor N (G)-nitro-L-arginine methyl ester hydrochloride, the guanylyl cyclase inhibitor 1H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, the cyclooxygenase inhibitor indomethacin, or K(+) channel blockers such as tetraethylammonium ions, glibenclamide, and BaCl2. Vindorosine-induced relaxations were attenuated in the presence of 0.1 microM nifedipine (an L-type Ca(2+) channel blocker). Vindorosine also concentration-dependently suppressed contractions induced by CaCl2 (0.01-5 mM) in Ca-free 60 mM KCl solution. Furthermore, fluorescence imaging using fluo-4 demonstrated that 30 min incubation with 100 microM Vindorosine reduced the 60 mM KCl-stimulated Ca(2+) influx in the smooth muscles of rat renal arteries. The present study is probably the first report of blood vessel relaxation by Vindorosine and the possible underlying mechanisms involving the inhibition of Ca(2+) entry via L-type Ca(2+) channels in vascular smooth muscles.

Asymmetric total synthesis of vindorosine, vindoline, and key vinblastine analogues.[Pubmed:20809620]

J Am Chem Soc. 2010 Sep 29;132(38):13533-44.

Concise asymmetric total syntheses of vindoline (1) and Vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Delta(6,7)-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Delta(6,7)-double bond.