Abstract
Background: Gefitinib and sorafenib have been proved effective for the treatment of cancers in clinical practice for years. Materials & methods: We intended to integrate the structural features of gefitinib and sorafenib and construct structurally unique 7-aromatic ureido-4-anilinoquinazolines. Results: Most of the targets exhibited promising antitumor activities. 8u showed excellent antitumor activities against the three tested cell lines (IC50, 0.81–2.49 μM). The enzymatic, apoptosis assay of 8u were also performed to study their preliminary action of mechanism. Conclusion: 8u deserve further research as antitumor agents.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Understanding and targeting resistance to anti-angiogenic therapies. J. Gastrointest. Oncol. 4(3), 253–263 (2013).
- 2. . FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 36(7), 422–439 (2015).
- 3. . Synthesis of piperazine-based thiazolidinones as VEGFR2 tyrosine kinase inhibitors inducing apoptosis. Future Med. Chem. 9(15), 1709–1729 (2017).
- 4. . The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res. 5(3), 203–220 (2007).
- 5. Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors. Eur. J. Med. Chem. 71, 1–14 (2014).
- 6. Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor. Cancer Sci. 105(6), 723–730 (2014).
- 7. Novel 5-anilinoquinazoline-8-nitro derivatives as inhibitors of VEGFR-2 tyrosine kinase: synthesis, biological evaluation and molecular docking. Org. Biomol. Chem. 11(26), 4367–4378 (2013).
- 8. Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents. Bioorg. Med. Chem. 24(2), 179–190 (2016). •• 4-anilinoquinazolines have multiple biological activities, notably as EGFR inhibitors.
- 9. Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control 10(5), 388–395 (2003).
- 10. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold. J. Med. Chem. 54(23), 8030–8050 (2011).
- 11. . Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist 8(6), 576–586 (2003). •• The interaction between 4-anilinoquinazoline and EGFR.
- 12. . Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006). Am. J. Pathol. 169(5), 1875–1885 (2006).
- 13. 7141 POSTER Phase II trial of the oral multikinase inhibitor regorafenib (BAY 73-4506) as first-line therapy in patients with metastatic or unresectable renal cell carcinoma (RCC). Eur. J. Cancer 47, S517 (2011).
- 14. . Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem. 50, 409–424 (2007). •• The interaction between urea group and VEGFR-2.
- 15. . Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc. Natl Acad. Sci. USA 109(45), 18281–18289 (2012).
- 16. . Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 277(48), 46265–46272 (2002).
- 17. . Design, synthesis and in vitro anti-proliferative activity of 4,6-quinazolinediamines as potent EGFR-TK inhibitors. Eur. J. Med. Chem. 61, 132–145 (2013).
- 18. . Design of EGFR kinase inhibitors: a ligand-based approach and its confirmation with structure-based studies. Bioorg. Med. Chem. 11(21), 4643–4653 (2003).
- 19. . Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. Future J. Pharm. Sci. 2(1), 9–19 (2016).
- 20. CN103382182 A (2013). • Synthesis methods of target compounds.
- 21. Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2. Eur. J. Med. Chem. 125, 245–254 (2017).