Click chemistry based synthesis, cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR

Reham R Khattab; Asma K Alshamari; Allam A Hassan; Hussein H Elganzory; Wael A El-Sayed; Hanem M Awad; Eman S Nossier; Nasser A Hassan

doi:10.1080/14756366.2020.1871335

Click chemistry based synthesis, cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR

J Enzyme Inhib Med Chem. 2021 Dec;36(1):504-516. doi: 10.1080/14756366.2020.1871335.

Authors

Reham R Khattab¹, Asma K Alshamari², Allam A Hassan^{3

4}, Hussein H Elganzory⁵, Wael A El-Sayed^{1

5}, Hanem M Awad⁶, Eman S Nossier⁷, Nasser A Hassan^{1

8}

Affiliations

¹ Photochemistry Department (Synthetic Unit), National Research Centre, Cairo, Egypt.
² Chemistry Department, College of Science, Ha'il University, Ha'il, KSA.
³ Chemistry Department, Faculty of Science, Suez University, Suez, Egypt.
⁴ Department of Chemistry, College of Science, Shaqra University, Shaqra, KSA.
⁵ Department of Chemistry, College of Science, Qassim University, Buraydah, KSA.
⁶ Tanning Materials and Leather Technology Department, National Research Centre, Cairo, Egypt.
⁷ Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
⁸ Pharmaceutical Chemistry Department, College of Pharmacy, Shaqra University, Shaqra, KSA.

Abstract

In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13-18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13-18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.

Keywords: Click chemistry; EGFR; anticancer; glycosides; thienopyrimidines.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Click Chemistry
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Glycosides / chemistry
Glycosides / pharmacology*
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Glycosides
Protein Kinase Inhibitors
Pyrimidines
Triazoles
thienopyrimidine
EGFR protein, human
ErbB Receptors