Design, Synthesis and Biological Activity Evaluation of S-Substituted 1H-5-Mercapto-1,2,4-Triazole Derivatives as Antiproliferative Agents in Colorectal Cancer.

Marius Mioc,Cristina Dehelean,Sorin Avram,Camelia Oprean,Ludovic Kurunczi,Mihaela Balan-Porcarasu,Codruta Soica,Vasile Bercean,Alexandra Mioc,Roxana M Ghiulai,Dorina E Coricovac,Calin Tatu

doi:10.3389/fchem.2018.00373

Abstract

Colon cancer is a widespread pathology with complex biochemical etiology based on a significant number of intracellular signaling pathways that play important roles in carcinogenesis, tumor proliferation and metastasis. These pathways function due to the action of key enzymes that can be used as targets for new anticancer drug development. Herein we report the synthesis and biological antiproliferative evaluation of a series of novel S-substituted 1H-3-R-5-mercapto-1,2,4-triazoles, on a colorectal cancer cell line, HT-29. Synthesized compounds were designed by docking based virtual screening (DBVS) of a previous constructed compound library against protein targets, known for their important role in colorectal cancer signaling: MEK1, ERK2, PDK1, VEGFR2. Among all synthesized structures, TZ55.7, which was retained as a possible PDK1 (phospholipid-dependent kinase 1) inhibitor, exhibited the most significant cytotoxic activity against HT-29 tumor cell line. The same compound alongside other two, TZ53.7 and TZ3a.7, led to a significant cell cycle arrest in both sub G0/G1 and G0/G1 phase. This study provides future perspectives for the development of new agents containing the 1,2,4-mercapto triazole scaffold with antiproliferative activities in colorectal cancer.

Highlights

Colorectal cancer was reported as the third most common diagnosed malignancy worldwide and occupies the fourth place in the hierarchy of cancer-related deaths (Arnold et al, 2017)
From the selection corresponding to the ERK2 protein, the compound TZ53.3 proved to be well accommodated in the protein binding site
It appears that in this case, the observed binding pattern of each compound docked in ERK2 suggests that the triazole ring is responsible for two of the three hydrogen bridges formed, while the hydrogen bonds (HBs) with Gln103 is only present for compounds containing a HB donor atom on the S-substituted side chain

Summary

INTRODUCTION

Colorectal cancer was reported as the third most common diagnosed malignancy worldwide and occupies the fourth place in the hierarchy of cancer-related deaths (Arnold et al, 2017). Active key proteins in the above mentioned pathways, with an important role in transmitting these intracellular signals, such as EGFR1 (epidermal growth factor receptor 1), VEGFR2 (endothelial vascular endothelial growth factor receptor 2), PI3Kα, AKT, MEK1 (MAP kinase/ERK kinase 1), ERK2 (extracellular regulated signaling kinase 2) and PDK1 (phospholipid-dependent kinase 1) are currently extensively studied as targets for novel drug discovery in the treatment of various types of cancer. The important part these intermediaries play within the carcinogenesis process justifies their selection as targets for the development of new anticancer agents. In the current study we report the synthesis and antiproliferative activity evaluation of a series of novel S-substituted 1H-3-R-5-mercapto-1,2,4-triazoles selected trough DBVS of a previously described compound library

MATERIALS AND METHODS

RESULTS AND DISCUSSIONS

CONCLUSIONS