Facile synthesis of C1-substituted β-carbolines as CDK4 inhibitors for the treatment of cancer

Cyclin-dependent kinase 4 (CDK4), which is involved in dynamic regulation of cell cycle, has gained particularly attention for its role in controlling tumor growth. Increasing evidence showed that beta-carboline derivatives have the potential to inhibit CDK4. Herein, on the basis of previous work, we designed and synthesized a series of novel beta-carbolines and evaluated their antitumor activity. Among them, compounds ZDLD13 and ZDLD20, with the most potent anti-proliferative activity and CDK4 enzymatic inhibition activity, were selected for further pharmacological research in vitro and in vivo. The results in vitro showed that ZDLD13 and ZDLD20 exhibited potent anti-HCT116 activity including inhibition of colony formation, inhibition of invasion and migration, inducing of apoptosis, and arresting of G1 phase in cell cycle. In vivo, ZDLD13 showed significant tumor growth inhibition in HCT116 tumor xenograft model without causing significant weight loss and toxicity consistent with the acute toxicity test. In addition, silico study showed ZDLD13 and ZDLD20 not only have good biological actions, but also acceptable predicted ADME and physicochemical properties. Taken together, compounds ZDLD13 and ZDLD20 could be selected for further modification and preclinical evaluation.

Automated summary

This study designed and synthesized a series of novel beta-carbolines and evaluated their antitumor activity. Among them, compounds ZDLD13 and ZDLD20 exhibited potent anti-proliferative activity and CDK4 enzymatic inhibition activity. The in vitro and in vivo studies showed that ZDLD13 and ZDLD20 had significant antitumor effects.