Design, synthesis and evaluation of di-nitrogen derivatives of combretastatin and novel cruzain inhibiting compounds for the treatment of Chagas disease.




Ackley, J. Freeland.

Journal Title

Journal ISSN

Volume Title



Over the past years cancer statistics have continued to rise to the point that the World Health Organization said that in 2005 cancer was leading cause of death worldwide. Years of research have resulted in many new promising therapies and treatment agents and very recently the field of vascular targeting therapies has grown in a strong proportion. One especially promising technique focuses on the use of vascular disrupting agents (VDAs). This clinical approach targets the endothelial cells partially composed of the tubulin-microtubule protein system in microvessels in the tumor microenvironment. The vascular damage caused by these drugs has seen to be highly selective due, in part, to the chaotic nature of the vessels created by these rapidly proliferating endothelial cells in the tumor microenvironment. The continued success of combretastatin A4 and combretastatin A1 in human clinical development indicate the importance of preparing new synthetic analogs to further understand the role of these anti-mitotic agents. Accordingly, a small library of eleven functionalized Z-stilbenes was created containing various nitro and amine moieties substituted in a 2,3, 3,5, and 2,3 pattern. These compounds have showed impressive biological results with the leading compound 18 demonstrating an IC50 value of 2.8 [mu]M for the inhibition of tubulin assembly and in vitro GI50 values in selected human cancer cell lines that are sub-nanomolar. A separate research project has recently been focused on the design and synthesis of new cruzain inhibitors modeled around an initial small library of molecules previously prepared by the Pinney Research Group at Baylor University. These thiosemicarbazone bearing molecules were designed to target the major cysteine protease of Trypanosoma cruzi also known as cruzain. Selected compounds were successfully designed and synthesized and are awaiting biochemical and biological evaluation.


Includes bibliographical references (p. 1-6 [second group]).