Polar 3-alkylidene-5-pivaloyloxymethyl-5′-hydroxymethyl-γ-lactones as protein kinase C ligands and antitumor agents

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-α ligands and antitumor agents. Extensive analysis of structure–activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of Ki= 3–5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines.

Graphical abstractDAG-lactones 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of Ki = 3–5 nM and excellent antitumor profiles.Figure optionsDownload full-size imageDownload as PowerPoint slide