Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer

Prostate cancer is the number one cancer diagnosed in men today. While it occurs to certain extent throughout the world (least commonly in Eastern/Southern Asia), it is viewed as the major public health threat in Western Europe and, especially, the United States [1]. In the US alone, it has been estimated [2] that 186,295 new cases of prostate cancer (mostly - among men over fifty) were diagnosed in 2008, accounting for 25% of all cancers diagnosed in men that year and 10% of the total cancer-related mortality. Appropriate diet (including dietary supplements) and exercise are currently the common themes for prostate cancer prevention while classical treatments are limited to surgery, radiation therapy, and hormone therapy. Chemotherapy of late-stage prostate cancer is still largely experimental; however, it may lead to increased survival in the future [3]. Specifically, small molecules as well as antibodies targeted at disrupting vital signaling pathways in cancerous cells have a potential to provide new basis for innovative treatment of proliferative disorders as prostate cancer in the years to come [4].The present study was a part of an ongoing effort [5] in our laboratories to find novel antiproliferative agents as potential treatments for prostate cancer. It was aimed at identifying new small heterocyclic molecules in Chemical Diversity Research Institute collection (parts of that can be accessed at http://www.chemdiv.com webcite) that would be specifically inhibitory to DU-145 human prostate carcinoma cell line (a 'classical' cell line of androgen-independent prostate cancer [6]) while exhibiting no non-specific (general) cytotoxicity. High-throughput screening of a highly diverse set of over 5,000 compounds comprising over 200 chemical classes led to several confirmed hit classes.Among these, one hit compound, 1 (Figure 1), that exhibited inhibition of DU-145 cell proliferation in dose-response manner, attracted our attention due to its drug-likeness [7], stru