Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity

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Victor 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^⊥∥, and Alex S. Kiselyov^⊥

^† N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991, Moscow, Russian Federation

^‡ Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334, Moscow, Russian Federation

^§ Chemical Block Ltd., 3 Kyriacou Matsi, 3723, Limassol, Cyprus

^⊥ Life Sciences Center, Moscow Institute of Physics and Technology, Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation

^∥ Institute of Cell Biophysics, RAS, Institutskaya Street, 3, Pushchino, Moscow Region 142290, Russian Federation

J. Nat. Prod., 2016, 79 (5), pp 1429–1438

DOI: 10.1021/acs.jnatprod.6b00173

Publication Date (Web): April 21, 2016

Copyright © 2016 The American Chemical Society and American Society of Pharmacognosy

*Tel: +7 916 620 9584. Fax: +7 499 137 2966. E-mail: vs@zelinsky.ru (V. V. Semenov).

Abstract

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.