- Preliminary communication
- Open Access
Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer
© Krasavin et al 2010
- Received: 2 December 2009
- Accepted: 9 March 2010
- Published: 9 March 2010
A new chemical series of antiproliferative compounds was identified via high-throughput screening on DU-145 human prostate carcinoma cell line (hit compound potency - 5.7 μM). Exploration of the two peripheral diversity vectors of the hit molecule in a hit-targeted library and testing of the resulting compounds led to SAR generalizations and identification of the 'best' pharmacophoric moieties. The latter were merged in a single compound that exhibited a 200-fold better potency than the original hit compound. Specific cancer cell cytotoxicity was confirmed for the most potent compounds.
- Inhibitory Potency
- Human Prostate Carcinoma
- Carcinoma HepG2 Cell Line
- Human Prostate Carcinoma Cell Line
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 . In the US alone, it has been estimated  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 . 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 .
The present study was a part of an ongoing effort  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) that would be specifically inhibitory to DU-145 human prostate carcinoma cell line (a 'classical' cell line of androgen-independent prostate cancer ) 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.
Herein we report on the synthesis and potency characterization of twenty analogs of the hit compound 1 leading to the initial SAR generalizations in this chemical class and to significant improvement of the inhibitory potency as well as to confirmation that the most potent compounds synthesized in this work inhibit DU-145 proliferation in a cell-specific manner rather than via general cytotoxicity.
Structures, preparative yields (from 3), and DU-145 proliferation inhibition data of compounds 2a-s.
IC50, μM a
2.2 ± 0.30
0.86 ± 0.10
1.6 ± 0.25
2.6 ± 0.35
1.0 ± 0.01
1.0 ± 0.12
2.7 ± 0.22
1.6 ± 0.14
0.64 ± 0.025
0.55 ± 0.010
0.084 ± 0.005
2.7 ± 0.50
0.96 ± 0.08
0.93 ± 0.009
1.8 ± 0.30
2.1 ± 0.17
0.91 ± 0.07
1.5 ± 0.09
0.38 ± 0.024
Cell sources: the prostate cancer Du-145 cell line was purchased from the American Type Cell Collection (HTB-81). Du-145 was cultured in RPMI-1640 complemented with 10% fetal bovine serum and 2 mM L-glutamine. To our delight, 80% of the library screened exhibited >20% inhibition of DU-145 proliferation. The hepatocellular carcinoma HepG2 cell line was purchased from the American Type Cell Collection (HB-8065) and was cultured in DMEM complemented with 10% fetal bovine serum and 2 mM L-glutamine.
1. Biological assay to determine inhibition of proliferation of the DU-145 cells
F negative : DMSO added to the cells (viable cells) and
F positive : taxol (1 uM) added to cells (cell count on 1st day of incubation)
2. Cytotoxicity assay
F negative - DMSO was added to cells (viable cells)
F positive - digitonin was added to cells (dead cells)
In conclusion, we have undertaken hit expansion and SAR exploration of a new antiproliferative chemical series, N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines. This study led to identification of the new 'best' peripheral moieties which, when combined in the same compound (2t) led to significant improvement of the DU-145 proliferation inhibitory potency (>200-fold compared to the initial hit compound 1). We also demonstrated that the observed antiproliferative activity of the compounds belonging to the studied chemotype was not due to non-specific cytotoxicity. The compound 2t represents a promising new lead for development of novel therapeutic agents for treatment of androgen-independent prostate cancer. The specific cellular mechanism of action of this compound remains to be investigated and will be presented in subsequent communication.
This research was supported by the Global IPP program through the International Science and Technology Center (ISTC). Oak Ridge National Laboratory is managed and operated by UT-Battelle, LLC, under U.S. Department of Energy contract DE-AC05-00OR22725. This paper is a contribution from the Discovery Chemistry Project.
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