strychnine and isosungucine

The first chemical syntheses of complex, bis-Strychnos alkaloids (-)-sungucine (1), (-)-isosungucine (2), and (-)-strychnogucine B (3) from (-)-strychnine (4) is reported. Key steps included (1) the Polonovski-Potier activation of strychnine N-oxide; (2) a biomimetic Mannich coupling to forge the signature C23-C5' bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH3 CN-mediated reduction to fashion the ethylidene moieties in 1-3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.

Topics: Alkaloids; Cyclic N-Oxides; Indole Alkaloids; Indoles; Stereoisomerism; Strychnine; Strychnos

Isosungucine (1) is a quasi-symmetric bisindolomonoterpenoid alkaloid isolated from the roots of Strychnos icaja. The in vivo antimalarial activity against the P. vinckei petteri murine strain was determined. In the Peters 4-day suppressive test, 1 suppressed the parasitemia by almost 50 percent on day 4 at the dose of 30 mg/kg by intraperitoneal route.

Topics: Animals; Antimalarials; Female; Indole Alkaloids; Mice; Plasmodium; Strychnos

Sungucine and isosungucine are two bisindole alkaloids isolated from the roots of the African plant Strychnos icaja Baillon. They both exhibit antiplasmodial activities but also show cytotoxic effects against human cancer cell lines. In order to elucidate their mechanism of action, we have investigated the interaction of the alkaloids with DNA and their capacity to inhibit nucleic acids and protein synthesis in the human HL-60 promyelocytic leukemia cell line. Cell treatment with both sungucine and isosungucine leads to the appearance of a hypo-diploid DNA content peak. Western blotting analysis reveals that the two alkaloids induce cleavage of the poly(ADP-ribose) polymerase (PARP) and promote the cleavage of a caspase-3 DEVD peptide substrate. The activation of the caspase cascade is accompanied with a fragmentation of DNA in cells, as revealed by the TUNEL assay. Altogether, the results shed light on the mechanism of action of these two plant alkaloids and identify signaling factors involved in (iso)sungucine-induced apoptosis in HL-60 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Caspases; Cell Cycle; Chromatin; DNA; DNA Fragmentation; Drug Screening Assays, Antitumor; Enzyme Activation; HL-60 Cells; Humans; Indole Alkaloids; Leukemia; Loganiaceae; Nucleic Acid Synthesis Inhibitors; Protein Synthesis Inhibitors; Strychnine