Advances in synthetic approaches for the preparation of combretastatin-based anti-cancer agents

The natural product combretastatin A-4 (CA4) is a potent anti-cancer agent known for its antimitotic and antiangiogenic properties. The basic structure of CA4 has inspired the design and synthesis of a variety of medicinally active analogues that take advantage of the relatively simple stilbenoid architecture of the molecule. Here, we examine recent advances in the synthesis of various CA4-based analogues. A significant focus is placed on the modifications to the bridging alkene moiety of the stilbene scaffold for conformationally restricting the structure in a bioactive form. An effort is also made to discuss promising ring modifications and replacements, including the incorporation of indazole and oxindole rings, as well as the design and synthesis of amino-substituted analogues. 1 Introduction 2 New Approaches for the Synthesis of CA4 3 Synthetic Approaches for the Preparation of CA4 Analogues 3.1 Modification of the Bridging Moiety 3.2 Modification of the Bridging Moiety via Heterocyclic Functionalities 3.3 Macrocyclic Rings Affording Conformational Restriction to Combretastatin Analogues 4 Amine Substituents on Aryl Rings of Combretastatin Analogues 5 Conclusions.