SYNTHESIS, ANTICANCER EVALUATION AND MOLECULAR MODELING OF SOME SUBSTITUTED THIAZOLIDINONYL AND THIAZOLYL PYRAZOLE DERIVATIVES

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

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.Research supported by FAPESP (2010/11005-5 and 2010/04462) and CNPq (#471939/2010-2 and 483005/2012-6

Novel synthesis of pyrazole-containing thiophene, 2-alkyloxy-pyridine and thieno[2,3-d]pyrimidine scaffolds as analgesic agents

ABSTRACT. A group of trisubstituted pyrazoles containing thiophen, 2-alkyloxypyridine and thieno[2,3-d]pyrimidine heterocycles were synthesized in a study for possible analgesic agents. The desired products were obtained by reaction of 2-((1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)methylene)malononitrile with sulfur in presence of TEA, followed by treatment with different reagents. Newer products were examined for their analgesic properties, among them, analog 7 showed significant analgesic effects in comparison with reference medicines activity. KEY WORDS: Trisubstituted pyrazoles, Thiophene, Alkyloxypyridine, Fused pyrimidine, Analgesic activities Bull. Chem. Soc. Ethiop. 2019, 33(3), 505-515. DOI: https://dx.doi.org/10.4314/bcse.v33i3.1

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-<i>d</i>]pyrimidines based thienopyrimidine system and their derived <i>N</i>-glycosides and thioglycosides

A series of new substituted triazolo[4,5-d]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N1-glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a, 8 b, 9 b, 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.</p