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Pyrazolo4,3-bpyrimido4,5-e1,4diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR.

08:00 EDT 12th September 2018 | BioPortfolio

Summary of "Pyrazolo4,3-bpyrimido4,5-e1,4diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR."

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 IC 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.

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Journal Details

This article was published in the following journal.

Name: European journal of medicinal chemistry
ISSN: 1768-3254
Pages: 428-441

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