Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities |
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Authors: | Lücking Ulrich Siemeister Gerhard Schäfer Martina Briem Hans Krüger Martin Lienau Philip Jautelat Rolf |
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Affiliation: | Medicinal Chemistry, Research Center Europe, Schering AG, 13342 Berlin, Germany. ulrich.luecking@schering.de |
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Abstract: | X-ray structures from CDK2-aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late-stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF-RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated. |
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Keywords: | antitumor agents biological activity cyclization macrocycles medicinal chemistry |
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