Cyclosquaramides as kinase inhibitors with anticancer activity.
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.
Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Carretera Valldemossa km 7.5, Spain.
Priam
P
Villalonga
Silvia
S
Fernández de Mattos
Guillem
G
Ramis
Antònia
A
Obrador-Hevia
Angel
A
Sampedro
Carmen
C
Rotger
Antoni
A
Costa
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism
D000577:Amides; D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases