N-(indazolyl)benzamido derivatives as CDK1 inhibitors: design, synthesis, biological activity, and molecular docking studies.
A series of N-1H-indazole-1-carboxamides has been synthesized and their effects on both CDK1/cyclin B and the K-562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e, f, i-n exhibited the same binding mode of purvanalol A in the ATP-binding cleft. Although they were able to moderately inhibit the leukemic cell line K-562 and to show inhibitory activity against the Cdc2-Cyclin B kinase in the low micromolar range, they turned out to be non-cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by the above-mentioned compounds.
Dipartimento di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Palermo, Italy. demraffa@unipa.it
Demetrio
D
Raffa
Benedetta
B
Maggio
Stella
S
Cascioferro
Maria Valeria
MV
Raimondi
Giuseppe
G
Daidone
Salvatore
S
Plescia
Domenico
D
Schillaci
Maria Grazia
MG
Cusimano
Lucina
L
Titone
Claudia
C
Colomba
Manlio
M
Tolomeo
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000037:antagonists & inhibitors; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020014:K562 Cells; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001549:Benzamides; D019926:Cyclin B; D007093:Imidazoles; D016203:CDC2 Protein Kinase