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Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF‐R Inhibitors with Potent Antiproliferative Activities
Author(s) -
Lücking Ulrich,
Siemeister Gerhard,
Schäfer Martina,
Briem Hans,
Krüger Martin,
Lienau Philip,
Jautelat Rolf
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600199
Subject(s) - chemistry , cyclin dependent kinase , combinatorial chemistry , vegf receptors , stereochemistry , cyclin dependent kinase 1 , computational biology , biochemistry , cancer research , biology , cell , cell cycle
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.