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Eur J Med Chem. 2018 Jan 20;144:797-816. doi: 10.1016/j.ejmech.2017.11.050. Epub 2017 Dec 12.

Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents.

Author information

1
Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland. Electronic address: tstefanski@ump.edu.pl.
2
Department of Inorganic and Analytical Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland.
3
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
4
Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland.
5
Department of Toxicology, Poznan University of Medical Sciences, Dojazd 30, 60-631 Poznań, Poland.
6
Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Święcickiego 4, 60-781 Poznań, Poland.
7
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznań, Poland.
8
Department of Immunology, Poznan University of Medical Sciences, Rokietnicka 5D, 60-806 Poznań, Poland.

Abstract

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC50 values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.

KEYWORDS:

Anticancer agents; Combretastatin A-4; Synthesis; Tubulin polymerization inhibitors; Virtual screening

PMID:
29291446
DOI:
10.1016/j.ejmech.2017.11.050
[Indexed for MEDLINE]

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