In vitro identification of oridonin hybrids as potential anti-TNBC agents inducing cell cycle arrest and apoptosis by regulation of p21, γH2AX and cleaved PARP.

TNBC has been recognized as the most highly aggressive breast cancer without chemotherapeutic drugs. A collection of oridonin hybrids consisting of conventional antitumor pharmacophores including nitrogen mustards and adamantane-1-carboxylic acid were synthesized by deletion or blockade of multiple hydroxyl groups and structural rearrangement. Compound 11a showed the most promising anti-TNBC activity with nearly 15-fold more potent antiproliferative effects than oridonin against MDA-MB-231 and HCC1806. Moreover, 11a significantly inhibited HCC1806, MDA-MB-231 and MDA-MB-468 cell proliferation by arresting cells at the G2/M phase in a dose-dependent manner. Furthermore, 11a could trigger dose-dependently early and late apoptosis in those indicated cell lines. More importantly, 11a could significantly increase p21, γH2AX and cleaved PARP accumulation in a dose-dependent manner. Furthermore, compound 11a exhibited better stability than oridonin in a plasma assay. Taken together, all results demonstrated that 11a may warrant further investigation as a promising anticancer drug candidate for the treatment of TNBC.