Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas.

Abstract

In an effort to combat cancer, the development of a relatively new type of anti-cancer drugs known as vascular disrupting agents (VDAs) seems to be a promising clinical approach. VDAs selectively interfere with blood flow in the microvessels that carry nutrients and oxygen to the tumor. Blockage of these vessels will stop tumor growth, produce necrosis, and hence prevent proliferation of cancer cells through the body. The discovery of a group of VDAs known as combretastatins (CA) has sparked an exciting area of anti-cancer drug discovery due to their robust biological activity as evidenced through clinical success, particularly for combretastatin A-4 phosphate (CA-4P) and one nitrogen-based combretastatin CA-4 analogue, AVE8062 which are currently in clinical development. Herein, a small library of seventeen new synthetic oxygen and nitrogen-bearing CA-1 and CA-4 analogues is described. Three of these analogues showed significant inhibition of tubulin assembly (IC50= 2-3 μM) as well as in vitro cytotoxicity against selected human cancer cell lines and in vivo blood flow reduction in SCID mice (23-25% at 10 mg/Kg) suggesting that they have potential for further prodrug modification and development as vascular disrupting agents for the treatment of solid tumor cancers. A separate research project has concentrated on the development of cysteine protease inhibitors, primarily focused toward the inhibition of cruzain, the major cysteine protease of Trypanosoma cruzi which is the agent of the parasitic disease called Chagas’ disease. Currently there is no satisfactory treatment for this disease, and the two accepted drugs, nifurtimox and benznidazole, are associated with significant clinical toxicity. A library of fourteen small non-peptidic thiosemicarbazones has been successfully designed, synthesized and tested against cruzain and cathepsin L from which five compounds showed significant cruzain inhibition in the low namolar range. Although the most active compound synthesized, which is a bromotetrahydronaphthalene thiosemicarbazone, exhibited an IC50=12 nM against cruzain, it also showed activity against cathepsin L (IC50=134 nM). This new pharmacophore introduced may prove useful as a lead compound for further optimization. In addition, this research revealed further insights into the complex structure-activity relationship parameters which may lead to the further development of more selective cruzain inhibitors.