Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents
PBN-AR
Instytucja
Instytut Chemii Bioorganicznej Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
en
Czasopismo
European Journal of Medicinal Chemistry (40pkt w roku publikacji)
ISSN
0223-5234
EISSN
Wydawca
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI
URL
Rok publikacji
2018
Numer zeszytu
Strony od-do
797-816
Numer tomu
144
Identyfikator DOI
Liczba arkuszy
Autorzy
(liczba autorów: 12)
Pozostali autorzy
+ 11
Słowa kluczowe
en
Anticancer agents
Tubulin polymerization inhibitors
Combretastatin A-4
Virtual screening
Synthesis
Streszczenia
Język
en
Treść
A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely alpha-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 anti proliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC50 values of 0.86,1.05, and 0.85 mu M, 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
Inne
System-identifier
PX-5a9e3c37d5dedce488a57703
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