Triad pyrazole–thiazole–coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis

Abstract

Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole–Thiazol–Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coumarin
• pyrazole
• thiazole
• molecular docking
• HSP
• cancer

Acknowledgements

Synthesis studies were carried out within the scope of Mehmet Gümüş’s PhD thesis (Gümüş, 2016).

Authors’ contributions

All authors have made essential contributions to this study. Establishing the outline of the study: İK, YT; Synthesis and characterization: MG, AD, İK; Biological activity: ENYT, LT, YT; Theoretical and Molecular Docking studies: YS; Manuscript drafting; İK, YS, YT. All authors read and approved the final manuscript.

Disclosure statement

All authors declare that they have no conflict of interests.

Additional information

Funding

The authors would like to thank Science and Technology Practice & Research Centre of Yozgat Bozok University for financial support (Project no: 2015FEF/A172).