Design and synthesis of a novel curcumin–combretastatin A4 molecular skeleton: two pharmacophores†

Abstract

The logical design and synthesis of a novel compound combretastatin A-4-integrated curcumin is presented. Claisen condensation of phenylacetone with ethyl acetates formed 1,5-diphenylpentane-2,4-dione. Condensation of the dione with benzaldehyde via a modified Pabon procedure formed combretastatin A-4-integrated curcumin. The single-crystal X-ray structure of one of the CA-4 integrated CURs was established as a representative example. Curcumin (CUR) and combretastatin A-4 (CA-4) are well-known bioactive natural products; however, their poor pharmacokinetic profiles and cis–trans isomerization under in vivo conditions, respectively, have limited their biological applications. Herein, coupling of an aryl group at the olefinic C2 and/or C6 position of CUR integrates a CA-4-like structure with cis-configuration locked to CUR. At the same time, aryl coupling created steric hindrance around the olefinic bond and could resist the reductive metabolism of CUR and contribute to a better pharmacokinetic profile. Remarkably, this modification did not disturb the functional groups in both the natural products (CUR and CA-4), which is promising for their therapeutic effects. Thus, the synthesized CA-4-integrated CUR molecular architecture offers a new molecular skeleton to be explored for bio-application.