Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy

• Published in: Bioorganic & medicinal chemistry 2017-01, Vol.25 (1), p.27-37
• Main Authors: Ding, Chao, Chen, Shaopeng, Zhang, Cunlong, Hu, Guangnan, Zhang, Wei, Li, Lulu, Chen, Yu Zong, Tan, Chunyan, Jiang, Yuyang
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; EGFR; Green Fluorescent Proteins - antagonists & inhibitors; HDAC; HER2; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Molecular Docking Simulation; Multitarget; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Resistance; Structure-Activity Relationship; Synergy; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.10.006

[Display omitted] •6-(1,2,3-Triazol-4-yl)-4-aminoquinazolins were designed and synthesized.•Final compounds displayed outstanding inhibitory activity on EGFR, HER2 and HDAC.•Compounds 9b and 9d showed potent activity against five cancer cell lines.•Compound 9d regulated the cellular level of p-EGFR, p-HER2 and histone H3.•Compound 9d induced remarkable apoptosis in BT-474 cells. By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0.49 and 8.76μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.