Fluevirosines A–C: A Biogenesis Inspired Example in the Discovery of New Bioactive Scaffolds from Flueggea virosa

Abstract

Biogenesis inspired chemical investigation of a Chinese folk medicine, Flueggea virosa, returned three unprecedented C,C-linked trimeric Securinega alkaloids, fluevirosines A-C (1-3). Their absolute structures were characterized on the basis of spectroscopic data and computational analysis. Compounds 2 and 3 showed inhibition against the splicing of XBP1 mRNA.

The Securinega Alkaloids

“…To assign the relative stereochemistry of fluerovirosine A, a ROESY experiment was carried out and the data were compared to those of flueggenines A (48) and B (49), as well as flueggine B (47). 53 This hypothesis was further confirmed by NMR data analysis and a good matching with the NMR data of fluevirosine A (52) was observed. However, some additional signals were pointed out and a related structure was proposed in which the dihydronorsecurinine subunit C was replaced by a dihydrosecurinine unit.…”

“…The relative stereochemistry was proposed to be identical to that of flueggenine C (50) on the basis of an excellent NMR data matching of these two compounds. 53 The molecular formula C 36 H 39 N 3 O 6 was established by HREIMS analysis (m/z 609.2838). In the IR spectrum, the typical a,b-unsaturated g-lactone was identified (n 1643, 1624 and 1755 cm À1 ).…”

“…Elucidation of the structure of fluevirosine C (54) was straightforward because this compound shared a great similarity with its homolog fluevirosine B (53). 53 Thus, efforts were directed toward the differences between these two compounds to propose a structure and it was evidenced from the NMR data that the subunit C was, in this case, a dihydrovirosecurinine fragment. Also the connection between B and C was the same as fluevirosine B (53) The Securinega Alkaloids derivative of norsecurinine.…”

“…Fluevirosines A (52), B (53), C (54) correspond to trimeric structures composed of two norsecurinine units plus one additional norsecurinine unit (fluevirosine A (52)) or a securinine-type unit (fluevirosines B (53) and C (54)). The central norsecurinine unit of these trimers is subtituted in position C12 0 and C15'.…”

“…Their biogenesis was supposed to involve first the formation of the C14-C15 0 norsecurinine dimer flueggenine A (48) via the intermediacy of compound 283, the corresponding closed lactonering form of flueggenine B (49) (Scheme 50). 53 Then, incorporation of the third unit, either a norsecurinine (27), a virosecurinine (2), or a viroallosecurinine (4) molecule, to form the C12 0 -C15 00 bond would give the corresponding trimer. Flueggenine A (48) and the fluevirosines A (52), B (53), C (54) were all isolated from Flueggea virosa (Roxb.…”