Cell cycle ckeckpoints are activated in response to DNA damage. Their role consists in blocking the cell cycle to allow time for DNA repair. The activity of the G1 checkpoint is depending on p53 protein. In more than 50% of human tumor cells, the p-53 gene is mutated. In the p-53 mutated cells, the G1 checkpoint is lacking. In these cells, only the G2 checkpoint, although weaker than in healthy cells, provides cancer cells with the opportunity to repair the DNA after damage. Therefore, combining a G2 checkpoint inhibitor with a DNA damaging agent should force, selectively cancer cells, into a premature and lethal mitosis, due to an accumulation of DNA lesions. Among the regulators of the G2 checkpoint, Checkpoint 1 kinase (Chk1) plays a major role. A widespread interest has been devoted to the discovery of Chk1 inhibitors. Granulatimide and isogranulatimide, natural products isolated from the ascidian Didemnum granulatum, inhibit Chk1 with IC50 values of 0.25 and 0.1 μM values, respectively. We will report the synthesis of granulatimide analogues in which the imidazole moiety has been replaced by a maleimide heterocycle and bearing various substituents on the indole unit. The biological activities of these new compounds will be described.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]