title: Combretastatin A-4 analogues with benzoxazolone scaffold: Synthesis, structure and biological activity.
abstract: In order to design and synthesize a new class of heterocyclic analogues of natural combretastatin A-4 and its synthetic derivative AVE8062, the benzoxazolone ring was selected as a scaffold for a bioisosteric replacement of the ring B of both molecules. A library of 28 cis- and trans-styrylbenzoxazolones was obtained by a modified Wittig reaction under Boden's conditions. Structures of the newly synthesized compounds bearing the 3,4,5-trimethoxy-, 3,4-dimethoxy-, 3,5-dimethoxy-, and 4-methoxystyryl fragment at position 4, 5, 6 or 7 of benzoxazolone core were determined on the basis of spectral and X ray data. The in vitro cytotoxicity of styrylbenzoxazolones against different cell lines was examined. Stilbene derivative 16Z, (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzoxazolone, showed highest antiproliferative potential of the series, with IC50 of 0.25 μM against combretastatin resistant cell line HT-29, 0.19 μM against HepG2, 0.28 μM against EA.hy926 and 0.73 μM against K562 cells. Furthermore, the results of flow cytometric analysis confirmed that 16Z induced cell cycle arrest in G2/M phase in the cell lines like combretastatin A-4. This arrest is followed by an abnormal exit of cells from mitosis without cytokinesis into a pseudo G1-like multinucleate state leading to late apoptosis and cell death. Accordingly, synthetic analogue 16Z was identified as the most promising potential anticancer agent in present study, and was selected as lead compound for further detailed investigations.
authors.affiliation: University of Sofia "St. Kliment Ohridski", Faculty of Chemistry and Pharmacy, Department of Pharmaceutical and Applied Organic Chemistry, 1 James Bourchier Blvd, 1164 Sofia, Bulgaria.
authors.forename: Mariana S
authors.initials: MS
authors.lastname: Gerova
authors.affiliation: Bulgarian Academy of Sciences, Institute of Molecular Biology, Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria.
authors.forename: Silviya R
authors.initials: SR
authors.lastname: Stateva
authors.affiliation: Bulgarian Academy of Sciences, Institute of Molecular Biology, Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Radonova
authors.affiliation: Bulgarian Academy of Sciences, Institute of Molecular Biology, Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria.
authors.forename: Rositsa B
authors.initials: RB
authors.lastname: Kalenderska
authors.affiliation: Bulgarian Academy of Sciences, Institute of Mineralogy and Crystallography, Acad. G. Bonchev Str., bl. 107, 1113 Sofia, Bulgaria.
authors.forename: Rusi I
authors.initials: RI
authors.lastname: Rusew
authors.affiliation: Bulgarian Academy of Sciences, Institute of Mineralogy and Crystallography, Acad. G. Bonchev Str., bl. 107, 1113 Sofia, Bulgaria.
authors.forename: Rositsa P
authors.initials: RP
authors.lastname: Nikolova
authors.affiliation: University of Sofia "St. Kliment Ohridski", Faculty of Chemistry and Pharmacy, Department of Pharmaceutical and Applied Organic Chemistry, 1 James Bourchier Blvd, 1164 Sofia, Bulgaria.
authors.forename: Christo D
authors.initials: CD
authors.lastname: Chanev
authors.affiliation: Bulgarian Academy of Sciences, Institute of Mineralogy and Crystallography, Acad. G. Bonchev Str., bl. 107, 1113 Sofia, Bulgaria.
authors.forename: Boris L
authors.initials: BL
authors.lastname: Shivachev
authors.affiliation: Bulgarian Academy of Sciences, Institute of Molecular Biology, Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria.
authors.forename: Margarita D
authors.initials: MD
authors.lastname: Apostolova
authors.affiliation: University of Sofia "St. Kliment Ohridski", Faculty of Chemistry and Pharmacy, Department of Pharmaceutical and Applied Organic Chemistry, 1 James Bourchier Blvd, 1164 Sofia, Bulgaria.
authors.forename: Ognyan I
authors.initials: OI
authors.lastname: Petrov
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry*; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis*
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D001632:Bibenzyls; D054852:Small Molecule Libraries; C017057:benzoxazolone; C040105:combretastatin
keywords: Anticancer agents; Benzoxazolone; Combretastatin A-4; Stilbene; Tubulin binding agents; X-ray