Abstract
Herein, we describe the synthesis of novel unsymmetrical polycarbo-substituted 4-anilinoquinazolines derived from the 2-aryl-6-bromo-8-iodoquinazolines via one-pot three-step reaction sequences involving initial amination and subsequent double cross-coupling (bis-Suzuki, Sonogashira/Stille or Sonogashira/Suzuki-Miyaura) reactions with different cross coupling partners for the two carbon–carbon bond formation steps. The 4-anilinoquinazolines were evaluated for potential cytotoxicity against three cancer cell lines, namely, human breast adenocarcinoma (MCF-7) cells, human cervical cancer (HeLa) and human lung cancer (A549) cells. The most active compounds, 2b, 2c, 3c, 4a, 4c and 5a, were found to be more selective against the MCF-7 and HeLa cell lines than the human lung carcinoma (A549) cells. We selected compounds 2c, 3c and 7a as representatives for further evaluation for potential to induce apoptosis and/or necrotic properties in the three cancer cell lines. Compound 2c induced apoptosis of MCF-7 cells through cell membrane alteration. Treatment of Hela and A549 cell lines with compounds 3c and 7a, respectively, led to caspase-3 activation in both cell lines. Compound 3c, on the other hand, caused more necrosis than apoptosis induction in the membrane alteration assay.
Highlights
Quinazolines constitute an important class of compounds with a wide-range of biological properties including anticancer [1,2,3], antibacterial [4], antimicrobial [5] and antihypertensive [6]activities
Lapatinib A, a 6-heteroaryl substituted 4-anilinoquinazoline derivative, for example, is an oral dual tyrosine kinase inhibitor (TKI) that targets both epidermal growth factor receptor (EGFR) and HER2 to inhibit the proliferation of breast cancer cells (Figure 1) [11]
4-position of the 2-aryl-6-bromo-4-chloro-8-iodoquinazoline framework to serve as a template for the design of unsymmetrical polycarbo-substituted 4-anilinoquinazolines
Summary
Among this class of heterocycles, the 4-anilinoquinazolines have established themselves as selective inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation, which results from competitive binding at the ATP site [7]. Alkenyl and aryl/heteroaryl substituents are prevalent in biologically relevant 4-anilinoquinazolines such as potent EGFR tyrosine kinase inhibitors [8] and liver X-receptor modulators [9]. These π-conjugated groups when linked to the 4-anilinoquinazoline scaffold have been found to produce potent “turn-on” fluorescent ligands that target the ATP-binding pocket of the EGFR/ERBB family of receptor tyrosine kinases [10].
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