Synthesis and in vitro antitumour activity of crassalactone D, its stereoisomers and novel cinnamic ester derivatives

Kovačević Ivana; Popsavin Mirjana; Benedeković Goran; Kesić Jelena; Kojić Vesna; Jakimov Dmitar; Srdić-Rajić Tatjana; Bogdanović Gordana; Divjaković Vladimir; Popsavin Velimir

doi:10.5281/zenodo.3842912

Published April 13, 2017 | Version v.1

Journal article Open

Synthesis and in vitro antitumour activity of crassalactone D, its stereoisomers and novel cinnamic ester derivatives

1. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
2. Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia
3. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
4. Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000 Novi Sad, Serbia

Naturally occurring styryl lactone, crassalactone D (1), unnatural 4-epi-crassalactone D (2), and the
corresponding 7-epimers (3 and 4) have been synthesized starting from D-glucose. The key step of the
synthesis is a new one-pot sequence that commenced with a Z-selective Wittig olefination of suitably
functionalized sugar lactols with a stabilized ylide, (methoxycarbonylmethylene)-triphenylphosphorane,
in dry methanol, to afford 1 or 3, in the mixtures with the corresponding 4-epimers (2 or 4, respectively).
A number of 6-O-cinnamoyl derivatives of styryl lactones 1e4 have been prepared, bearing electron
donating or electron withdrawing functionalities in the C-4 position of cinnamic acid residue. The
synthesized products were evaluated for their in vitro antiproliferative activity against selected human
tumour cell lines, whereupon very potent cytotoxicities have been recorded in many cases. SAR analysis
indicated some important structural features responsible for biological activity, such as stereochemistry
at the C-4 and C-7 positions, as well as the nature of a substituent at the C-4 position in the aromatic ring
of cinnamoate moiety. Flow cytometry and Western blot analysis data gave insight in the mechanism
underlying antiproliferative effects of the synthesized compounds.

Notes

The work is also supported by a research project from the Serbian Academy of Sciences and Arts (Grant No. F-130). Supplementary data: Contains the results of: X-ray crystal structure determination, SAR analysis, flow cytometry and Western blot analysis. Copies of 1H and 13C NMR spectra of final products are also disclosed. This material is available free of charge via the Internet.

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