Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Tu, Yuanbiao; Wang, Caolin; Xu, Shan; Lan, Zhou; Li, Wei; Han, Jiaqian; Zhou, Yuanzhang; Zheng, Pengwu; Zhu, Wufu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3148
• Page End: 3157
• Publication Date: 2017-06-15
• Subjects: Quinazoline -- Aryl semicarbazone scaffolds -- Synthesis -- Docking -- Anti-tumor activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a –o and10a –o ) were designed and synthesized. Most of the synthesized compounds showed moderate to significant antitumor activity. Hydroxy substitution were more preferred. Docking study was investigated to explore the binding modes of compounds with EGFR. Abstract: Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a –o and10a –o ) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32 ± 0.38 μM, 0.07 ± 0.01 μM, 0.91 ± 0.29 μM and 4.89 ± 0.69 μM, which were equal to more active than afatinib (1.40 ± 0.83 μM, 1.33 ± 1.28 μM, 2.63 ± 1.06 μM and 3.96 ± 0.59 μM), respectively. Activity of the most promising compound9o (IC50 56 nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6 nM) but more active than reference staurosporine (IC50 238 nM). The result of flow cytometry, with the dose of compound9o increasing, which indicated the compound9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure–activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.