Download PDF
Synthesis 2009(15): 2471-2491  
DOI: 10.1055/s-0029-1216891
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Advances in Synthetic Approaches for the Preparation of Combretastatin-Based Anti-Cancer Agents

Rohit Singh*, Harneet Kaur
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
Fax: +1(612)6252633; e-Mail: singh109@umn.edu;
Further Information

Publication History

Received 13 March 2009
Publication Date:
10 July 2009 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

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

Key words

natural products - drugs - combretastatin - inhibitors - antitumor­ agents - medicinal chemistry

50

The conformation from the X-ray crystal structure was utilized in molecular dynamics simulations by docking it into the colchicines binding site of tubulin by Zhang et al.48