posted on 2016-04-21, 14:34authored byVictor V. Semenov, Dmitry V. Tsyganov, Marina
N. Semenova, Roman N. Chuprov-Netochin, Mikhail M. Raihstat, Leonid D. Konyushkin, Polina B. Volynchuk, Elena I. Marusich, Vera V. Nazarenko, Sergey V. Leonov, Alex
S. Kiselyov
A concise six-step protocol for the
synthesis of isoflavone glaziovianin
A (GVA) and its alkoxyphenyl derivatives 9 starting with
readily available plant metabolites from dill and parsley seeds was
developed. The reaction sequence involved an efficient conversion
of the key intermediate epoxides 7 into the respective
β-ketoaldehydes 8 followed by their Cu(I)-mediated
cyclization into the target series 9. The biological
activity of GVA and its derivatives was evaluated using a panel of
seven human cancer cell lines and an in vivo sea urchin embryo assay.
Both screening platforms confirmed the antimitotic effect of the parent
GVA (9cg) and its alkoxy derivatives. Structure–activity
relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings,
respectively, were less active than the parent 9cg. Of
the evaluated human cancer cell lines, the A375 melanoma cell line
was the most sensitive to the tested molecules. Notably, the target
compounds were not cytotoxic against human peripheral blood mononuclear
cells up to 10 μM concentration. Phenotypic readouts from the
sea urchin assay unequivocally suggest a direct microtubule-destabilizing
effect of isoflavones 9cg, 9cd, and 9cf.