当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR.

Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR.

Abstract：

:Aurora A, Aurora B and Kinase Insert Domain-containing Receptor (KDR) play essential roles in sustained cancer growth. In the present study, eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized. Most of the prepared compounds exhibited obviously enzymatic (Aurora A/B and KDR) activities. Among these analogs, compound 17g displayed significant Aurora A/B and KDR potencies with IC50 values of 46.2 nM, 37.6 nM and 21.6 nM, respectively. The results of further biological assays showed that compound 17g possessed moderate anti-proliferative activities against SNU-5, MKN-45 and MKN-74 cells lines, induced G2/M cell cycle arrest and apoptosis in MKN-45, MKN-74, SGC-7901 and SNU-5 cell lines, provided acceptable pharmacokinetic profiles (F = 63.8%), and inhibited the proliferation of SNU-5 tumors in vivo of mice. All of the above results suggested that pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine could be developed as a promising scaffold of multiple Aurora A/B and KDR inhibitors and 17g was worth of further research as a multi-targeted lead compound.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Zhang Q,Shen Q,Gao L,Tong L,Li J,Chen Y,Lu W

doi

10.1016/j.ejmech.2018.09.032

subject

Has Abstract

pub_date

2018-10-05 00:00:00

pages

428-441

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30804-3

journal_volume

158

pub_type

杂志文章

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