Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase

Yaling Zhang; Hongliang Gao; Renjie Liu; Juan Liu; Li Chen; Xiabing Li; Lijun Zhao; Wei Wang; Baolin Li

doi:10.1016/j.bmcl.2017.08.035

Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4309-4313. doi: 10.1016/j.bmcl.2017.08.035. Epub 2017 Aug 18.

Authors

Yaling Zhang¹, Hongliang Gao¹, Renjie Liu¹, Juan Liu¹, Li Chen¹, Xiabing Li², Lijun Zhao¹, Wei Wang¹, Baolin Li³

Affiliations

¹ Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710062, PR China.
² Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710062, PR China. Electronic address: [email protected].
³ Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710062, PR China. Electronic address: [email protected].

PMID: 28838691
DOI: 10.1016/j.bmcl.2017.08.035

Abstract

A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC₅₀: 1.79-10.71nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC₅₀=0.14, 0.09 and 0.25µM, respectively) were obvious higher than that of miglitol (IC₅₀=2.43µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFR^wt tyrosine kinase (IC₅₀=1.79nM), also to α-glucosidase (IC₅₀=0.39µM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.

Keywords: 1-Deoxynojirimycin; Enzyme inhibitors; Epidermal growth factor receptor (EGFR); Hybrids; Quinazoline; α-Glucosidase.

MeSH terms

1-Deoxynojirimycin / analogs & derivatives*
1-Deoxynojirimycin / chemical synthesis
1-Deoxynojirimycin / chemistry
1-Deoxynojirimycin / pharmacology
Dose-Response Relationship, Drug
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship
alpha-Glucosidases / metabolism*

Substances

Glycoside Hydrolase Inhibitors
Protein Kinase Inhibitors
Quinazolines
quinazoline-1-deoxynojirimycin
1-Deoxynojirimycin
ErbB Receptors
alpha-Glucosidases