新型 2-氯-4-苯胺基喹唑啉衍生物作为 EGFR 和 VEGFR-2 双重抑制剂。
Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors.
机构信息
Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1); Graduate Program of Chemistry (PGQu), Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1).
出版信息
Eur J Med Chem. 2014 Jan;71:1-14. doi: 10.1016/j.ejmech.2013.10.058. Epub 2013 Oct 31.
Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites.
新型 2-氯-4-苯胺基喹唑啉类化合物被设计为 EGFR 和 VEGFR-2 双重抑制剂，并对其抑制效果进行了评估。EGFR 和 VEGFR-2 是癌症治疗中的有效靶点，联合抑制可能对抗肿瘤活性和耐药性预防具有协同作用。获得的生物学数据证明了 2-氯-4-苯胺基喹唑啉衍生物作为 EGFR 和 VEGFR-2 双重抑制剂的潜力，其中化合物 8o 的活性最强，对 VEGFR-2 的活性约为原型化合物 7 的 7 倍，对 EGFR 的活性约为原型化合物 7 的 11 倍。SAR 和对接研究确定了两个激酶的药效团，并证明了苯胺部分对位上的氢键供体对于与 EGFR 和 VEGFR-2 结合位点中的保守 Glu 和 Asp 氨基酸相互作用的重要性。
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