Investigating the Anticancer Activity of Novel Norethindrone Derivatives in PC3 Prostate Cancer Cells

Abstract

It is estimated that over 248,000 new cases of prostate cancer will be diagnosed this calendar year (2021) representing upwards of 20% of newly diagnosed cancer cases in men.1,2 Despite these numbers, prostate cancer‐related deaths have significantly declined over the period of time from 1993 to 2016, yet prostate cancer was expected to be responsible for almost 10% of cancer‐related deaths in 2018.1 Metastasis and cancer cell resistance results in treatment failure and progressive disease, and this remains a significant concern in the care of men with prostate cancer.To address the significant need for novel agents in the treatment of resistant prostate cancer, we designed and synthesized a small library of norethindrone (NE) derivatives with varying substituents attached to the 17‐position (Compounds A‐D) with the hopes of identifying androgen receptor antagonists. Click chemistry was utilized to facilitate the formation of a triazole linking NE to alkyl and aryl substituents. The corresponding azides were synthesized in situ from alkyl bromides or aryl bromides in a one‐pot microwave‐assisted reaction in an Anton Parr Monowave‐50 reactor at 150℃ for 20 minutes.Here we present initial data of our small library of NE derivatives which were screened for anticancer activity using the XTT cell viability assay in PC3 prostate cancer cells. Two of the compounds (A and D) failed to induce an anticancer response. Compound B demonstrated weak anticancer activity with an IC50 of greater than 100 µM, whereas Compound C demonstrated low micromolar activity with an IC50 of 19 µM. Further studies are ongoing to determine the mechanism(s) by which Compound C elicits its anticancer activity in the metastatic‐derived PC3 prostate cancer cells. Additionally, these results will assist with further rational design using NE as a scaffold in an attempt to increase the potency against PC3 and other prostate cancer cell lines.1. American Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 20212. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7‐34. doi: 10.3322/caac.21551. Epub 2019 Jan 8. PMID: 30620402.