Ring-Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation

Abstract

The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, ¹H-NMR and ¹³C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI₅₀ values of 4.87±0.23 μM and 9.97±1.44 μM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC₅₀ value of 0.135±0.041 μM, and its activity was approximately 1/3 of the positive control Palbociclib.

Keywords: CDK4/6 inhibitors; CDK6/cyclin D3 kinase; D-ring-contracted artemisinin derivatives; antiproliferative activities.