Oridonin Ring A-Based Diverse Constructions of Enone Functionality: Identification of Novel Dienone Analogues Effective for Highly Aggressive Breast Cancer by Inducing Apoptosis

Abstract

Oridonin (1) has attracted considerable attention in recent years due to its unique and safe anticancer pharmacological profile. Nevertheless, it exhibits moderate to poor effects against highly aggressive cancers including triple-negative and drug-resistant breast cancer cells. Herein, we report the rational design and synthesis of novel dienone derivatives with an additional α,β-unsaturated ketone system diversely installed in the A-ring based on this class of natural scaffold that features dense functionalities and stereochemistry-rich frameworks. Efficient and regioselective enone construction strategies have been established. Meanwhile, a unique 3,7-rearrangement reaction was identified to furnish an unprecedented dienone scaffold. Intriguingly, these new analogues have been demonstrated to significantly induce apoptosis and inhibit colony formation with superior antitumor effects against aggressive and drug-resistant breast cancer cells in vitro and in vivo, while also exhibiting comparable or lower toxicity to normal human mammary epithelial cells in comparison with 1.

Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis

“…Furthermore, oridonin significantly reduced the expression of TGF-β stimulated-ECM proteins compared to control in activated HSC. Because it has been shown as a relatively safe biological agent [11] and protective of liver tissue in an experimental rodent model [16], oridonin is a very promising natural compound to use in the development of hepatic fibrosis drugs.…”

Discovery and development of natural product oridonin-inspired anticancer agents

“…In accordance with the general SAR analysis of enone systems, the construction of an additional enone pharmacophore in the A-ring is likely to be favorable for biological activity and sensitivity enhancement against drug resistance. To this end, oridonin A-ring based derivatives of the enone functionality were explored as novel dienone analogues effective for highly aggressive breast cancer by inducing apoptosis [66]. Dienone analogues 42 – 46 (Fig.…”

“…Compound 45 shows growth inhibition against triple-negative breast cancer MDA-MB-231 cells with an EC 50 value of 5.6 μM, and induces apoptosis of MDA-MB-231 cells in a dose-dependent manner (1.0–10.0 μM) by regulation of Bcl-2/Bax, NF-κB and PARP signaling pathways. Moreover, in comparison with the natural product oridonin, dienone analogue 45 displays lower toxicity to normal mammary epithelial cells, and is more efficacious regarding antitumor activity (ip, growth inhibition > 55% at 5.0 mg/kg) with no significant loss of body weight in the MDA-MB-231 xenograft tumor model [66]. …”

“…As mentioned above, the presence of the enone system as a core pharmacophore in the D-ring appears to be critical for its biological effects, and removal of this enone system may abrogate its anticancer activity [66]. Nan et al have modified the enone system in the D ring to synthesize cyclopentanedione derivative 51 , reduction product 52 , and nitrogen-containing heterocycle fused D-ring oridonin analogues such as 53 and 54 (Fig.…”

Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents

“…More extensive synthetic efforts and efficient methodologies are needed due to the challenges in structural diversifications on the ring A/C. To this end, our previous work on the concise synthesis of novel oridonin A-ring structural diversification with the success to yield superior diterpenoids may provide some useful and efficient synthetic strategies [49-52]. (2) To increase the efficiency in terms of structural modifications, and especially the efficacy in animal models, the synthesis and extensive pharmacological evaluation of a larger library of UA derivatives are imperative to establish useful criteria for the further drug design and development.…”