Ramakrishnan Elancheran1, Kuppusamy Saravanan2, Selvaraj Divakar3, Sima Kumari1, V Lenin Maruthanila1, Senthamarikannan Kabilan2, Muthiah Ramanathan3, Rajlakshmi Devi1, Jibon Kotoky1.
Abstract
BACKGROUND: Androgen receptor is an attractive target for the treatment of prostate cancer. The 1,3- thiazolidine-2,4-diones possess a wide diversity of important biochemical effects and interesting pharmacological properties.
OBJECTIVE: The aim of the study is to find the experimental and computational methods to investigate the interference of 1,3-thiazolidine-2,4-diones with androgen receptor against prostate cancer.
METHOD: Structural modification and molecular docking-based virtual screening approaches were imposed to identify the novel 1,3-thiazolidine-2,4-diones by using Schrödinger (Maestro 9.5). The best fit molecules (3-12 & 23-31) were synthesized and characterized using spectroscopic techniques, then in vitro antioxidant and antiprostate cancer activities were evaluated. Further, the structure of the intermediate (18) was confirmed by single crystal XRD analysis. The mechanism studies were performed through the gene expression for the compounds, 29, 30, and 31, the standards, dihydrotestosterone and R-bicalutamide.
RESULTS: The compounds, 29, 30 and 31 showed comparatively significant antioxidant activity and better antiproliferative activity against PC-3 and LNCaP cell lines. Also, very low cytotoxicity was observed in the noncancerous cell (3T3). The compounds, 29, 30 and 31 significantly decreased the mRNA expression of ARstimulated genes, PSA and TMPRSS2, which demonstrated their anti-prostate cancer activities. ADME/T properties prediction of the compounds (3-12 and23-31) showed the promising drug-likeness and pharmacokinetic parameters without toxicity. Moreover, DFT calculations apparently confirmed the stable conformer of the compound, 31.
CONCLUSION: These findings may provide the essential information for the development of anti-prostate cancer agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
BACKGROUND: Androgen receptor is an attractive target for the treatment of prostate cancer. The 1,3- thiazolidine-2,4-diones possess a wide diversity of important biochemical effects and interesting pharmacological properties.
OBJECTIVE: The aim of the study is to find the experimental and computational methods to investigate the interference of 1,3-thiazolidine-2,4-diones with androgen receptor against prostate cancer.
METHOD: Structural modification and molecular docking-based virtual screening approaches were imposed to identify the novel 1,3-thiazolidine-2,4-diones by using Schrödinger (Maestro 9.5). The best fit molecules (3-12 & 23-31) were synthesized and characterized using spectroscopic techniques, then in vitro antioxidant and antiprostate cancer activities were evaluated. Further, the structure of the intermediate (18) was confirmed by single crystal XRD analysis. The mechanism studies were performed through the gene expression for the compounds, 29, 30, and 31, the standards, dihydrotestosterone and R-bicalutamide.
RESULTS: The compounds, 29, 30 and 31 showed comparatively significant antioxidant activity and better antiproliferative activity against PC-3 and LNCaP cell lines. Also, very low cytotoxicity was observed in the noncancerous cell (3T3). The compounds, 29, 30 and 31 significantly decreased the mRNA expression of ARstimulated genes, PSA and TMPRSS2, which demonstrated their anti-prostate cancer activities. ADME/T properties prediction of the compounds (3-12 and23-31) showed the promising drug-likeness and pharmacokinetic parameters without toxicity. Moreover, DFT calculations apparently confirmed the stable conformer of the compound, 31.
CONCLUSION: These findings may provide the essential information for the development of anti-prostate cancer agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Entities:
Keywords:
ADME/T; AR antagonist; Androgen receptor; prostate cancer; synthesis; thiazolidinedione
Mesh：
Substances：
Year: 2017
PMID： 28403781 DOI： 10.2174/1871521409666170412121820
Source DB: PubMed Journal: Anticancer Agents Med Chem ISSN： 1871-5206 Impact factor: 2.505