New oxazole-bridged combretastatin A-4 analogues as potential vascular-disrupting agents

摘要

The cis-stilbene combretastatin A-4 (CA-4) is a metabolite of the South-African bush willow Combretum caffrum with remarkable antitumoral properties. Its mode of action is based on its high affinity for the colchicine binding site of (3-tubulin and the resulting destabilization of the microtu-bule cytoskeleton [1]. CA-4 is also known to target the vasculature of solid tumors and to induce blood vessel shutdown leading to secondary tumor cell death [2]. The metabolic conversion of CA-4 to its inactive trans-homer and its poor solubility are drawbacks that limit its applicability in anticancer thefapy. Recent efforts to stabilize the cis-configuration by integration into heterocycles led to CA-4 derivatives with imidazole and oxazole rings the activity of which is dependent on the pattern of substituents in the phenyl rings [3, 4, 5, 6].