Synthesis and biological activity of 5-chloro-N⁴-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents.
Synthesis and biological activity of 5-chloro-N⁴-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents.
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DOI：
10.1016/j.bmc.2013.01.040
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Ihnat, Michael A.
中科院分区：
文献类型：
--
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Disch, Bryan C.;Thorpe, Jessica E.;Bastian, Anja;Ihnat, Michael A.
关键词：
受体酪氨酸激酶（RTK）信号通路的抑制是开发新型抗癌药物的重要领域。许多多激酶抑制剂（MKI）最近已被批准用于治疗癌症。血管内皮生长因子受体-2（VEGFR-2）是肿瘤血管生成的主要介质。为了开发ATP竞争性VEGFR-2选择性抑制剂，设计了5-氯-N4-取代苯基-9H-嘧啶并[4，5-B]吲哚-2，4-二胺支架。目标化合物的合成涉及N-（4，5-二氯-9H-嘧啶并[4，5-B]吲哚-2-基）-2，2-二甲基丙酰胺）作为共同中间体。中间体的4-氯基被适当取代的苯胺进行亲核取代得到目标化合物。生物学评价表明，化合物5是与舒尼替尼和semaxinib相当的有效和选择性VEGFR-2抑制剂。
Inhibition of receptor tyrosine kinase (RTK) signaling pathways is an important area for the development of novel anticancer agents. Numerous multikinase inhibitors (MKIs) have been recently approved for the treatment of cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the principal mediator of tumor angiogenesis. In an effort to develop ATP-competitive VEGFR-2 selective inhibitors the 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold was designed. The synthesis of the target compounds involved N-(4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)-2,2-dimethylpropanamide) as a common intermediate. A nucleophilic displacement of the 4-chloro group of the common intermediate by appropriately substituted anilines afforded the target compounds. Biological evaluation indicated that compound 5 is a potent and selective VEGFR-2 inhibitor comparable to sunitinib and semaxinib.
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影响因子：
7.3
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Ihnat, Michael;Shenoy, Satyendra;Kisliuk, Roy L.
通讯作者：
Kisliuk, Roy L.
影响因子：
7.3
作者：
Bold, G;Altmann, KH;Wood, JM
通讯作者：
Wood, JM
影响因子：
7.3
作者：
Bamborough, Paul;Drewry, David;Schneider, Klaus
通讯作者：
Schneider, Klaus
影响因子：
11.5
作者：
Deininger, Michael W.
通讯作者：
Deininger, Michael W.
影响因子：
4.6
作者：
Choowongkomon, Kiattawee;Sawatdichaikul, Orathai;Limtrakul, Jumras
通讯作者：
Limtrakul, Jumras