virosecurinine and securinine

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 μM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.

Topics: Alkaloids; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azepines; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Mice, Inbred BALB C; Mice, Nude; Piperidines; Verapamil

Time-dependant density functional theory-electronic circular dichroism spectra prediction was carried out to study the absolute configuration of phyllanthidine-type derivatives 5 and 6, derived from securinine (1) and its enantiomer virosecurinine (2), respectively. This method demonstrated to be very reliable in this alkaloid series. Thus, 5 and 6 shared the same stereochemistry as their parent precursors, confirming the retentive nature of the oxidation sequence. In addition, this study highlighted the key role of the methylene bridge (BC ring) in the chiroptical activity of these compounds. These results fully clarified the stereochemical relationships between the phyllanthidine and the securinine subgroups.

Topics: Alkaloids; Azepines; Circular Dichroism; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Models, Molecular; Molecular Structure; Piperidines; Plant Components, Aerial; Stereoisomerism

A new and versatile synthetic route to Securinega alkaloids is reported. The first synthesis of allosecurinine has been accomplished in seven steps and 40% yield, starting from (+)-menisdaurilide, using a vinylogous Mannich reaction as the key transformation. Similarly, viroallosecurinine has been synthesized from (-)-menisdaurilide.

Topics: Alkaloids; Azepines; Benzofurans; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Stereoisomerism

Investigations on callus cultures of Securinega suffruticosa indicated that the cell line of S. suffruticosa callus was able to accumulate four known Securinega alkaloids with dextro rotation but not levo rotation as reported before: virosecurinine (1), viroallosecurinine (2), 14,15-dihydrovirosecurinine (3) and ent-phyllanthidine (4). Time course studies on the growth of callus cultures were carried out. The effects of different plant growth regulators, sucrose concentrations on callus growth and virosecurinine production were also reported.

Topics: Alkaloids; Azepines; Cell Division; Cell Line; Chromatography, High Pressure Liquid; Culture Media; Cytokinins; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Indoleacetic Acids; Lactones; Magnetic Resonance Spectroscopy; Piperidines; Plant Stems; Stereoisomerism

Pharmacological activities of virosecurinine (Vse) and securinine (Sec) were studied. The results showed that acute toxicity of Vse was 1/13.6 that of Sec, and Vse had no convulsive effects on rats or frogs, while Sec had. The results also showed that Vse and Sec could elevate blood pressure and excite respiration in cats.

Topics: Alkaloids; Animals; Azepines; Blood Pressure; Cats; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Ranidae; Rats; Respiration

Topics: Alkaloids; Azepines; Chemistry Techniques, Analytical; Chemistry, Pharmaceutical; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research; Stereoisomerism