Products Cited in Publications Worldwide Conception, synthèse, caractérisation physicochimique et évaluation biologique de nouveaux agents

Conception, synthèse, caractérisation physicochimique et évaluation biologique de nouveaux agents

Ouellette, Vincent

Abstract

Cancer is a major public health concern and represents the leading cause of death in Canada. Approximately two out of five Canadians will be diagnosed with cancer during their lifetime and one out of four will die from it. Despite advances in treatments, cancer remains a challenging disease to treat still claiming lives today. Therefore, it is imperative to develop new treatments to treat this lethal disease. As a result, my doctoral project primarily focuses on the development of two new families of anticancer agents: 1) antimicrotubule prodrugs targeting breast cancer cells expressing cytochrome P450 1A1 (CYP1A1) designated as N-alkyl phenylimidazolidones (AIMZs), and 2) dihydroorotate dehydrogenase (DHODH) inhibitors targeting acute myeloid leukemia (AML) cells named N-phenyl ureidobenzenesulfonates (PUB-SOs). One of the predominant issues during the development of new drugs is the water solubility of the newly prepared molecules and unfortunately our compounds are not exempt from this problem. Moreover, salt formation is an essential strategy used in the pharmaceutical industry to improve this property. In this context, we proposed that salt formation increases the water solubility of our compounds without altering their biological properties. Therefore, the main objective of my doctoral project was to design, prepare, and evaluate the physicochemical and biological properties of new AIMZs, PUB-SOs and their salts to optimize their biopharmaceutical properties. It is divided into three main phases: 1) design, synthesis, and characterization of AIMZs and PUB-SOs and their salts, 2) evaluation of their physicochemical and biological properties using various biofunctional assays, and 3) pharmacokinetic evaluation of the two best candidates in a mouse model. To this end, over 100 new derivatives and analogues of AIMZs and PUB-SOs were designed and prepared by adding an ionisable function to their molecular architecture to enable salt formation. They were subsequently chemically characterized and biologically evaluated. First, the new AIMZs and their salts exhibit potent antiproliferative activity in the nanomolar to low micromolar range and significant selectivity against breast cancer cells expressing CYP1A1. Moreover, the most potent compounds arrest cell cycle progression in the G2/M phase, inhibit microtubule polymerization, and disrupt the cytoskeleton by binding to the colchicine-binding site. They are also bioactivated by CYP1A1 microsomes into their potent antimitotic derivatives by N-dealkylation and exhibit suitable physicochemical properties and in vitro hepatic stability profiles for in vivo studies. Second, the new PUB-SOs and their salts show antiproliferative activity ranging from hundreds of nanomolar to low micromolar on AML cell lines. The most potent compounds arrest the cell cycle in the S-phase and induce phosphorylation of histone H2AX, a marker of replicative stress. They inhibit DHODH activity, induce differentiation of leukemia cells, and exhibit physicochemical properties and hepatic stability profiles on murine and human liver microsomes suitable for animal studies. The new salts of both families exhibit higher solubility compared to their corresponding neutral counterparts without altering their biological activity. Finally, the half-life (t1/2) of the two most promising salts of PUB-SO derivatives were evaluated in a healthy female CD-1 mice. Both compounds showed t1/2 in the range of ten minutes. Overall, my project has enabled the preparation of new AIMZ and PUB-SO analogues and their salts with improved aqueous solubility while retaining their biological activity and an adequate physicochemical properties profile. These results highlight that salt formation on the chemical structure of AIMZs and PUB-SOs is an appropriate strategy to improve the water solubility and facilitate the formulation of these compounds. Nonetheless, further studies will need to be performed to understand and improve their short t1/2. My work will ultimately contribute to the optimization of more effective and less toxic therapies to improve the quality of life for patients with breast and leukemia cancers.

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