Abstract 1664: New moieties mimicking the trimethoxyphenyl (ring A) of combretastatin A-4: Synthesis and biological evaluation
Authors: Gagné-Boulet Mathieu , Fortin Sébastien , Lacroix Jacques , Lefebvre Carole-Anne , Côté Marie-France , C-Gaudreault René 
Published: August 2015

Combretastatin A-4 (CA-4), its phosphate disodium (CA-4P) and serine hydrochloride salts (AVE8062) are part of a new class of anticancer agent named vascular disrupting agent (VDA). In addition to act as potent antimicrotubule agents in cancer cells, these drugs have the ability to target and disrupt the cytoskeleton of neo-endothelial vascular cells leading to selective and rapid shutdown of blood flow through tumors. The recent success of CA-4 salts in preclinical studies and its achievement in clinical studies prompted the comprehensive study of the structure-activity relationships related to CA-4. Several thousand derivatives and analogs were synthesised and biologically evaluated by modifying the ring B and the ethenyl bridge of CA-4; only few studies have been done on the trimethoxyphenyl (TMP) ring A since it had been previously found crucial for anticancer potency.

In the course of our own structure-activity relationship studies, we recently reported two new families of antimicrotubule agents where the ethenyl bridge of CA-4 was substituted by a sulfonate group and the TMP was replaced either by a phenylimidazolidin-2-one (IMZ) or phenylchloroethylurea (CEU) moieties. IMZs are potent antiproliferative agents exhibiting IC50 in the nanomolar range while CEU are soft alkylating agent normally active in micromolar range. IMZ and CEU arrest the cell cycle in G2/M phase, bind to the colchicine-binding site (C-BS) on β-tubulin leading to the disruption of the cytoskeleton and apoptosis. Although the structure-activity relationship studies of IMZ and CEU derivatives suggest that they mimic the TMP moiety of CA-4, molecular modeling experiments show that IMZs replace the ring B of CA-4 instead of ring A.

In this context, we synthesized 3 series of CEU and IMZ where the sulfonate bridge was replaced by an ethenyl bridge to confirm that IMZ and CEU mimic the TMP moiety of CA-4. First, IMZ and CEU analogs to CA-4 exhibited antiproliferative activities in nanomolar range and in micromolar range, respectively as their parent compounds. Moreover, the most potent compounds blocked the cell cycle progression in G2/M-phase, disrupted the cytoskeleton and bind also the C-BS.

Our results strongly suggest that IMZ and CEU mimic the TMP (ring A) of CA-4. These two moieties could be used as bioisosteric equivalents to circumvent some problems that might be encountered during the clinical development of CA-4. In addition, they could be used also to replace the TMP moiety found in several other antimitotics such colchicine, podophyllotoxin and steganacin to design new potent antimicrotubule agents.

Citation Format: Mathieu Gagné-Boulet, Sébastien Fortin, Jacques Lacroix, Carole-Anne Lefebvre, Marie-France Côté, René C-Gaudreault. New moieties mimicking the trimethoxyphenyl (ring A) of combretastatin A-4: Synthesis and biological evaluation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1664. doi:10.1158/1538-7445.AM2015-1664