2. Academic Validation
  3. Synthesis and in vitro antitumour activity of crassalactone D, its stereoisomers and novel cinnamic ester derivatives

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

  • Eur J Med Chem. 2017 Jul 7:134:293-303. doi: 10.1016/j.ejmech.2017.03.088.
Ivana Kovačević 1,  Mirjana Popsavin 1,  Goran Benedeković 1,  Jelena Kesić 1,  Vesna Kojić 2,  Dimitar Jakimov 2,  Tatjana Srdić-Rajić 3,  Gordana Bogdanović 2,  Vladimir Divjaković 4,  Velimir Popsavin 5
Affiliations

Affiliations

  • 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.
  • 5 Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: velimir.popsavin@dh.uns.ac.rs.
PMID: 28427016 DOI: 10.1016/j.ejmech.2017.03.088
Abstract

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 1-4 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.

Keywords

Antitumour lactones; Apoptosis; Cinnamoates; Crassalactone D; SAR analysis.

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