SYNTHESIS, ANTICANCER EVALUATION AND MOLECULAR MODELING OF SOME SUBSTITUTED THIAZOLIDINONYL AND THIAZOLYL PYRAZOLE DERIVATIVES
Keywords:
Anticancer, Pyrazole, GSTP1, Molecular modelingAbstract
Objective: The present work aimed to synthesize some new substituted thiazoles incorporated to pyrazole moiety starting from 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (1) in order to evaluate their anticancer activity and GSTP1 inhibition in a trail to explore new potential GST inhibitors and prevent the resistance of cells to anticancer drugs. In addition, investigate the probability of the most promising cytotoxic compounds to inhibit GSTP1 enzyme via molecular docking study.
Methods: The carboxaldehyde 1 was treated with substituted thiosemicarbazide in absolute ethanol to give the corresponding thiosemicarbazone derivatives 2a–d. Cyclization of 2a-d either by ethyl bromoacetate, phenacyl bromide or maleic acid anhydride furnished new thiazole derivatives 3, 4 and 5, respectively. These target compound 2-5 were screened for their GSTP1 inhibition and cytotoxic activity against HEPG-2 (human liver carcinoma), A549 (human lung carcinoma) and PC3 (human prostate carcinoma). Finally, molecular docking study of the most promising cytotoxic compounds against GSTP1 (PDB ID: 3GUS) is discussed.
Results: Compounds 4a, 4b, and 4d were found to be highly active against HEPG-2 and PC-3 cancer cell lines with IC50 values ranging from 0.2±0.81 to 9.3±2.08 μM compared to doxorubicin with IC50= 37.8±1.50 and 41.1±2.01 μM, respectively. Screening of 4a, 4b and 4d against GSTP1 showed higher inhibition activity with IC50 ranging from 1.5±0.18 to 4.3±0.29 μM. Docking studies revealed the promising binding affinities of the latter compounds which match with the binding mode of the ligand, NBDHEX toward the active site of GSTP1.
Conclusion: Compounds 4a, 4b and 4d were distinguished by the higher anticancer activity against HEPG-2, A-549 and PC-3 cell lines of tumor and the remarkable inhibitory activity against GSTP1.
Downloads
References
Shea TC, Kelley SL, Henner WD. Identification of an anionic form of glutathione transferase present in many human tumors and human tumor cell lines. Cancer Res 1988;48:527-33.
Tew KD, Monks A, Barone L, Rosser D, Akerman G, Montali JA, et al. Glutathione-associated enzymes in the human cell lines of the national cancer institute drug screening program. Mol Pharmacol 1996;50:149-59.
Aliya S, Reddanna P, Thyagaraju K. Does glutathione S-transferase Pi (GST-Pi) a marker protein for cancer? Mol Cell Biochem 2003;253:319–27.
Federici L, Sterzo CL, Pezzola S, Matteo AD, Scaloni F, Federici G, et al. Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)Hexanol to Human glutathione S-transferases. Cancer Res 2009;69:8025-34.
Wu B, Dong D. Human cytosolic glutathione transferases: structure, function, and drug discovery. Trends Pharmacol Sci 2012;33: 656-68.
Rotili D, Luca AD, Tarantino D, Pezzola S, Forgione M, Blasco Rocca Md, et al. Synthesis and structure-activity relationship of new cytotoxic agents targeting human glutathione-S-transferases. Eur J Med Chem 2015;89:156-71.
Wang X, Howell CP, Chen F, Yin J, Jiang Y. Gossypol-a polyphenolic compound from cotton plant. Adv Food Nutr Res 2009;58:215-63.
Abadi AH, Eissa AA, Hassan GS. Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents. Chem Pharm Bull 2003;51:838-44.
Ting L, Guyue L, Hongcai L, Xinmei Y, Yongkui J, Guisen Z. The synthesis of ethacrynic acid thiazole derivatives as glutathione S-transferase pi inhibitors. Bioorg Med Chem 2012;20:2316–22.
Fahmy HH, Khalifa NM, Nossier ES, Abdalla MM, Ismail MMF. Synthesis and anti-inflammatory evaluation of new substituted 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole derivatives. Acta Pol Pharm Drug Res 2012;69:411-21.
Mosmann T. Rapid colorimetric assays for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63.
El-Sawy ER, Mandour AH, El-Hallouty SM, Shaker KH, Abo-Salem HM. Synthesis, antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl hetero-cycles: 1st Cancer Update. Arabian J Chem 2013;6:67-78.
El-Hallouty SM, Fayad W, Meky NH, El-Menshawi BS, Wassel GM, Hasabo AA. View additional authors In vitro anticancer activity of some egyptian plant extracts against different human cancer cell lines. Int J Pharm Tech Res 2015;2:267-72.
Collier AC, Tingle MD, James WP, Murray DM, Keelan JA. Metabolizing enzyme localization and activities in the first trimester human placenta: the effect of maternal and gestational age, smoking and alcohol consumption. Hum Reprod 2002;17:2564-72.
Habig WH, Pabst MJ, Jakoby WB. Glutathione-S-transferases the first enzymatic step in mercapturic acid formation. J Biol Chem 1974;249:7130-9.
Molecular Operating Environment (MOE), V. 10, Chemical Computing Group Inc., Montreal, Quebec, Canada; 2008.
Nofal ZM, Fahmy HH, Mohamed HS. Synthesis and antimicrobial activity of new substituted anilino-benzimidazoles. Arch Pharm Res 2002;25:250-7.
El-Zahar MI, Abd El-Karim SS, Anwar MM. Synthesis and cytotoxicity screening of some novel benzofuranoyl-pyrazole derivatives against liver and cervix carcinoma cell lines. S Afr J Chem 2009;62:189-99.