Design, synthesis and in vitro antitumour activity of new goniofufurone and 7-epi-goniofufurone mimics with halogen or azido groups at the C-7 position

• Published in: European journal of medicinal chemistry Vol. 128; pp. 13 - 24
• Main Authors: Francuz, Jovana, Kovačević, Ivana, Popsavin, Mirjana, Benedeković, Goran, Zelenović, Bojana Srećo, Kojić, Vesna, Jakimov, Dimitar, Aleksić, Lidija, Bogdanović, Gordana, Srdić-Rajić, Tatjana, Lončar, Eva, Rodić, Marko V., Divjaković, Vladimir, Popsavin, Velimir
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 10-03-2017
• Subjects: Analogues; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumour activity; Apoptosis - drug effects; Azides - chemistry; Blotting, Western; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Detection of apoptosis; Drug Design; Drug Screening Assays, Antitumor; Fibroblasts - cytology; Fibroblasts - drug effects; Halogen isosteres; Halogens - chemistry; Humans; Lactones - pharmacology; Molecular Structure; Neoplasms - drug therapy; Neoplasms - pathology; Structure-Activity Relationship; Structure-activity relationships; Styryl lactones; Antitumour activity; Structure-activity relationships; Analogues; Styryl lactones; Halogen isosteres; Detection of apoptosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.01.024

A series of new antitumour lactones containing the [3.3.0] bicyclic furano-lactone core and the halogen or azido group at the C-7 position have been designed, synthesized, and evaluated for their in vitro antitumour activity against a panel of human tumour cell lines. Some of the analogues displayed powerful antiproliferative effects to certain human tumour cells, but all of them were devoid of any cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that may affect their antiproliferative activity. These are: the nature of substituent present at the C-7 position, stereochemistry at the C-7 position, the absence of phenyl group at the C-7 position. Flow cytometry data indicate that the cytotoxic effects of the synthesized analogues in a culture of K562 cells are mediated by apoptosis, additionally revealing that these molecules induced changes in cell cycle distribution of these cells. Results of Western blot analysis suggested that the most of synthesized compounds induce apoptosis in K562 cells in caspase-dependent way.
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•New halogen isosteres of goniofufurone and 7-epi-goniofufurone were synthesized.•The most of synthesized compounds inhibit the growth of human tumour cell lines.•SAR analysis revealed the structural requirements for antitumour effects of analogues.•The most of analogues induced apoptosis in K562 cells in caspase-dependant way.