Mitotic arrest induced by propargylic enol ethers derivatives

Abstract

The generation of diversity‐oriented libraries is a valuable tool for the discovery of new anticancer agents. The objective was to evaluate the anti‐proliferative activity of a set of 27 propargylic enol ethers derivatives in cancer cells. The antiproliferative activity was performed against the human solid tumor cell lines SW1573, HBL‐100 and HeLa. Additionally, cell cycle phase distribution was investigated by flow cytometry and protein expression by western blotting. The most active compound gave GI50 values in the range of 0.24–2.8 μM in all the cell lines. Cell cycle studies showed the ability of the drug to induce a prominent G2/M arrest. The cell arrest occurred with little evidence of DNA damage, as determined by the lack of γ‐H2AX signal. The persistence of cyclin B1 in HeLa cells correlates with their entry into mitosis. High levels of histone H3 phosphorylated at serine 10 confirmed that cells accumulate in mitosis in a time‐dependent manner. Mitotic arrest was consistent with the activation of BubR1 which delayed the progression to anaphase. Our findings provide insight into the mechanism of chemotherapeutic action of this family of compounds.Funding co‐financed by EU‐FEDER: MICIIN (CTQ2008‐06806‐C02–01/BQU, CTQ2008‐06806‐C02–02/BQU, BFU2006‐01813/BMC), MSC (RTICC RD06/0020/1046, RD06/0020/0041); ACIISI (PI 2007/021); FUNCIS(PI 01/06, 35/06). LGL: MSC‐FIS contract. JMP: MEC‐FSE RyC contract.