title: Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics.
abstract: Despite having the second highest mortality associated with cancer, currently Sorafenib is the only FDA-approved chemotherapeutic agent available for liver cancer patients which can only improve survival for few months. In this study, various pyrazolic chalcone analogous compounds were synthesized and evaluated as potential chemotherapeutic agents for the treatment of hepatocellular carcinoma (HCC). Modifying the central pyrazole ring at the C(3)-position with different heteroaryl rings and substituting the C(4)-position of pyrazole with differently substituted chalcone moiety produced fouthy two variant compounds. For all these compounds, cytotoxicity was evaluated using sulforhodamine B assay and real time cell growth tracking, respectively. Based on 50% inhibitory concentration (IC50) values, compounds 39, 42, 49, and 52 were shown to exhibit potent cytotoxic activity against all the cancer cell lines tested, and had better cytotoxic activities than the well-known chemotherapeutic drug 5-FU. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Flow cytometric analysis of HCC cells treated with compounds 39, 42, 49, and 52 demonstrated that these compounds caused cell cycle arrest at G2/M phase followed by the apoptotic cell death and impaired cell growth as shown by real-time cell growth surveillance. Consistent with these results, western blotting of HCC cells treated with the compounds resulted in molecular changes for cell cycle proteins, where p21 levels were increased independent of p53 and the levels of the key initiators of mitosis Cyclin B1 and CDK1 were shown to decrease upon treatment. In conclusion, chalcone derivatives 42 and 52 show potent bioactivities by modulating the expression of cell-cycle related proteins and resulting in cell-cycle arrest in the HCC cell lines tested here, indicating that the compounds can be considered as preclinical candidates.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
authors.forename: Mohammed M A
authors.initials: MM
authors.lastname: Hawash
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, 06800, Ankara, Turkey.
authors.forename: Deniz Cansen
authors.initials: DC
authors.lastname: Kahraman
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
authors.forename: Fikriye
authors.initials: F
authors.lastname: Eren
authors.affiliation: Cancer Systems Biology Laboratory, Graduate School of Informatics, METU, 06800, Ankara, Turkey. Electronic address: rengul@metu.edu.tr.
authors.forename: Rengul
authors.initials: R
authors.lastname: Cetin Atalay
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey. Electronic address: baytas@gazi.edu.tr.
authors.forename: Sultan Nacak
authors.initials: SN
authors.lastname: Baytas
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002599:Chalcone / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011720:Pyrazoles; C031280:pyrazole; D002599:Chalcone
keywords: Apoptosis; Cell cycle; Chalcone derivatives; Cyclin B1/CDK1 inhibitors; Cytotoxic activity; Hepatocellular carcinoma; Pyrazoles