Cyclosquaramides as Kinase Inhibitors with Anticancer Activity

Abstract

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 μM. 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.

Macrocyclic squaramides: anion receptors with high sulfate binding affinity and selectivity in aqueous media

“…While Costa and co-workers have previously demonstrated the self-templated formation of macrocycles containing both squaramides and a hydrogen-bond acceptor unit, 32 , 33 attempts to prepare a macrocycle containing two squaramide units linked by alkyl chains ( i.e. lacking the hydrogen bond acceptor) have been reported to be unsuccessful, giving only traces of the desired compound.…”

Squaramides as Bioisosteres in Contemporary Drug Design

“…202−204 Pleasingly, 111 demonstrated reasonable inhibition of several therapeutically important kinases (ABL1, CDK4, CHK1, PKC, c-MET, and FGFR) as well as Jeko-1 and Z-138 cell lines. 199 Peptide Mimics. Unsurprisingly, peptide analogues in which one of the amides forming the peptide backbone is replaced with a squaramide have also been reported.…”

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

“…The core structure of these molecules is derived from squaric acid ( Figure 1 ). While a few examples of squaric acid diamides with antiplasmodial or other biological activities are known [ 22 , 23 , 24 , 25 ], up to now only a single 3,4-bis(indol-3-yl)cyclobut-3-ene-1,2-dione was prepared in a meager yield (0.67%) [ 26 ], and biological activity of this congener was not reported.…”