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Cyclosquaramides as Kinase Inhibitors with Anticancer Activity
Author(s) -
Villalonga Priam,
Fernández de Mattos Silvia,
Ramis Guillem,
ObradorHevia Antònia,
Sampedro Angel,
Rotger Carmen,
Costa Antoni
Publication year - 2012
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.201200157
Subject(s) - kinase , chemistry , cell culture , biological activity , protein kinase c , phosphorylation , structure–activity relationship , cancer cell lines , biochemistry , cancer research , stereochemistry , biology , in vitro , cancer , cancer cell , genetics
We report the synthesis and biological evaluation of a new series of oligosquaramide‐based macrocycles as anticancer agents. Compound 7 , considered as representative of this series, exhibited significant antiproliferative activity against the NCI‐60 human tumor cell line panel, with IC 50 values ranging from 1 to 10 μ M . The results show that sensitivity to cyclosquaramides is clearly dependent on cell type, underscoring a degree of biological selectivity. The observed antiproliferative effects appear to be related to deregulation of protein phosphorylation, as compounds 7 and 8 are effective inhibitors of several important kinases such as ABL1, CDK4, CHK1, PKC, c‐MET, and FGFR, among others. The corresponding acyclic oligosquaramides and smaller cyclosquaramides did not show antitumor activity, suggesting that a macrocyclic structure with minimal molecular size plays a key role in the observed antitumor activity.