Design and synthesis of tetrahydropyridine analogs as selective COX-2 inhibitors and anti-breast cancer agents

Abstract According to the World Health Organization, breast cancer has become the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide. In the US, it is estimated that there will be women with an estimated 281,550 new cases of invasive breast cancer and 49,290 non-invasive (in situ) breast cancer in 2021. Female breast cancer has also been rated as the second-highest mortality rate following lung cancer. Hence, there is a dire need for discovering more effective treatment agents. Drug discovery, by way of rational design, has paved the way for the development of novel small molecules as effective anticancer agents. It is known that chronic inflammation has a direct correlation to cancer. Cyclooxygenase-2 (COX-2) has been reported that it is present and overexpressed in many cancers. Thus, it is of great interest to study COX-2 inhibition and its relationship to cancer therapy. Tetrahydropyridines (THPs) are structures that are found in numerous natural products and possess anti-inflammatory, chemotherapeutic, and antioxidant properties. Thus, substituted phenycarbonylamino-5-ethyl-1,2,3,6-tetrahydropyridine analogs have been designed as COX-2 inhibitors in our laboratory. The objective of this project is to utilize computer-aided drug design, including molecular modeling and drug-likeness studies for the basis of drug targeting studies. Molinspiration online software was used for in silico screening of molecular properties and bioactivity prediction scores. For the molecular docking studies, Schrodinger suite software was used to examine the interactions of the THP ligands with the COX-2 enzyme. More than a dozen THP analogs that were synthesized in the lab showed favorable properties aligning well with Lipinski's rule. Most of the analogs reported average to moderate bioactivity scores as enzyme inhibitors. Lastly, the docking studies predicted several interactions with residues within the COX-2 active site, although none of the compounds scored better than the reference drug, Celecoxib. N-(5-ethyl-3,6-dihydropyridin-1(2H)-yl)-2-(trifluoromethyl)benzamide has the best docking score in comparison to Celecoxib. The preliminary data obtained through computer-based investigation showed that appropriate substitutions on the THP molecule would likely produce more effective COX-2 inhibitors. The THP preparation involves a 4-step synthesis. N-amination of 3-Ethylpyridine by the aminating agent, O-mesytelenesulfonylhydroxylamine, and treated with substituted acyl chlorides gives stable pyridinium ylides. These products are purified and reducing them using sodium borohydride gives the target THP compounds. The novel THP analogs will undergo testing as COX-2 inhibitors (arachidonic acid inhibition assay) as well as determining their anti-breast cancer activities using MCF-7 and Ishikawa cell lines assessing their anti-proliferative effects. Citation Format: Shasline Gedeon, Madhavi Gangapuram, Suresh Eyunni, Bereket Mochona, Tiffany Ardley, Kinfe Ken Redda. Design and synthesis of tetrahydropyridine analogs as selective COX-2 inhibitors and anti-breast cancer agents [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-103.