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Int J Mol Sci. 2019 Nov 8;20(22). pii: E5592. doi: 10.3390/ijms20225592.

Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors.

Author information

1
Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt.
2
Chemistry department, Faculty of Science, Taibah University, Medina 30002, Saudi Arabia.
3
Chemistry Department, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia.
4
Pharmacognosy Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt.
5
Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt.

Abstract

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4-33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 μM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

KEYWORDS:

anti-proliferative; extracellular signal-regulated kinases (ERK); pyrazole; pyrimidine; rational design; sulfonamides

PMID:
31717402
DOI:
10.3390/ijms20225592
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