Oridonin Derivatives Research Articles

Novel nitrogen-enriched oridonin analogues with thiazole-fused A-ring: protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility.

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens , has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones.

Abstract 2267: Natural product-inspired drug discovery: Chemistry and biology of oridonin analogs with unique scaffolds and enhanced anticancer profiles .

Abstract ABSTRACT: Oridonin, a complex ent-kaurane diterpenoid isolated from Chinese traditional herb Rabdosia rubescens (Chinese name "Donglingcao"), has demonstrated great potential in the treatment of various human cancers due to its unique, safe and remarkable anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility and bioavailability. Up to now, the oridonin-based structural modifications and relevant structure-activity relationship remain sparse partially because of the challenging synthesis and structural complexity. To develop novel oridonin derivatives with enhanced anticancer potency and solubility, a sizable compound library of oridonin analogs with unique scaffolds is being established in our laboratories through diversity-orientated synthesis. Our successful synthetic strategies include heterocycle-fused ring A construction, and ring A-based α,β-unsaturated enone formation, as well as other stereoselective and regioselective approaches. A number of novel nitrogen-enriched heterocyclic oridonin derivatives and dienone analogs such as CYD0554, CYD0618, CYD0628, CYD0630, CYD0686, and CYD0692 have been identified with potent anti-proliferation effects against breast, pancreatic, and prostate cancer cells with low micromolar to nanomolar IC50 values. Moreover, some of them also exhibit significantly improved aqueous solubility and enhanced anticancer profiles for the treatment of estrogen receptor (ER)-negative including triple-negative breast cancer in comparison with oridonin. Our success in the chemical design, synthesis and biological characterization of these new molecules opens new avenues to develop promising natural product-like drug candidates for cancer therapy. Key Words: Natural products, Oridonin analogs, Diversity-orientated synthesis, Anticancer agents, Drug discovery Citation Format: Chunyong Ding, Yusong Zhang, Haijun Chen, Zhengduo Yang, Lili Chu, Christopher Wild, Mark A. White, Qiang Shen, Jia Zhou. Natural product-inspired drug discovery: Chemistry and biology of oridonin analogs with unique scaffolds and enhanced anticancer profiles . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2267. doi:10.1158/1538-7445.AM2013-2267

Abstract 5573: Discovery of potent oridonin derivatives for the treatment of breast cancer.

Abstract Oridonin, a diterpenoid derived from the herbal Rabdosia rubescens, has been reported to have antitumor effects on various types of cancer cells. However, its relatively low aqueous solubility and bioavailability have limited its development into clinical applications. Herein, we chemically modified oridonin and generated a series of novel analogues. We then employed MTT assay to detect their effects on cell growth and a number of new and potent molecules have been identified. Among them, compounds CYD-6-86 and CYD-6-92 significantly inhibited the proliferation of human breast cancer MDA-MB-231 and MCF-7 cells. Furthermore, both compounds induced enhanced apoptosis in a dose- and time-dependent fashion when compared with oridonin. Cell cycle analysis indicated that both CYD-6-86 and CYD-6-92 induced S phase arrest in MDA-MB-231 cells and G0/G1 phase arrest in MCF-7 cells, while oridonin induced G2/M phase arrest in MDA-MB-231 and MCF-7 cells. Consistent with oridonin, Western blot analysis showed that CYD-6-86 and CYD-6-92 inhibited the expression of NF-κB and Bcl-2, and increased expression of Bax and cleaved PARP. Intriguingly, compounds CYD-6-86 and CYD-6-92 have demonstrated to suppress the growth of adriamycin-resistant MCF-7 clone, while at the same dosage oridonin displayed no effect on these cells. Our findings suggest that these new analogues may be superior to the natural product oridonin to overcome the chemo-resistance, and have great potential to be developed as novel therapeutics for the treatment of breast cancer. Citation Format: Yusong Zhang, Chunyong Ding, Zhengduo Yang, Haijun Chen, Lili Chu, Jia Zhou, Qiang Shen. Discovery of potent oridonin derivatives for the treatment of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5573. doi:10.1158/1538-7445.AM2013-5573

Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in human hepatoma Bel-7402 cells

A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a–j) were designed and synthesized. All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC50 values of 0.39 μM and 1.39 μM, respectively. The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar concentrations in human hepatoma Bel-7402 cells. These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability.

Synthesis and Biological Evaluation of Novel Furozan-Based Nitric Oxide-Releasing Derivatives of Oridonin as Potential Anti-Tumor Agents

To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9h exhibited the most potential anti-tumor activity with IC50 values of 1.82 µM against K562, 1.81 µM against MGC-803 and 0.86 µM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.

The conversion of oridonin to spirolactone-type or enmein-type diterpenoid: Synthesis and biological evaluation of ent-6,7-seco-oridonin derivatives as novel potential anticancer agents

Starting from commercial available natural product oridonin (1), a practical synthesis of ent-6,7-seco-oridonin derivatives (2, 3, 5, and 9) was accomplished and their biological activities were evaluated. The conversion of spirolactone-type diterpenoid to enmein-type was first completed. The results demonstrated that all synthesized ent-6,7-seco-oridonin derivatives could markedly inhibit the proliferation of cancer cells. Compared with Taxol, the most cytotoxic compound 5 has similar potency in A549 cell and slightly less cytotoxicity in Bel-7402 cell. Compound 5 was also more potent than parent compound oridonin in mice with MGC-803 gastric cancer in vivo. Then a series of novel 14-O-derivatives of 5 were further designed and synthesized, which showed better activity than 5 and similar activity as Taxol in vitro. The structure–activity relationships of oridonin derivatives were also discussed in the present investigations.

NMR spectra and structures of oridonin derivatives complexes with β‐cyclodextrin

Complexations between three oridonin derivatives and β-cyclodextrin (βCD) were studied by nuclear magnetic resonance (NMR) method. Job's plots for complexes were depicted by (1)H NMR spectra chemical shifts, which proved the 1:1 stoichiometry inclusion complex formation between each derivative and βCD. Two-dimensional rotating frame overhauser effect spectroscopy (2D ROESY) support the above conclusion and also proved that ring A of each oridonin derivative deeply enters into hydrophobic cavity from the wider rim and the other parts are outside the cavity. Apparent formation constants (Ka) of complexes between three oridonin derivatives and two CDs are calculated according to Scott's equation.

Antitumor activity of acylated oridonin.

14-O-Acyl derivatives of oridonin were prepared and tested for antitumor activity against Ehrlich ascites carcinoma cells in the mouse. In a series of derivatives 7-12, the activity increased with increase of the acyl carbon chain length. The 14-O-benzoyl derivative 5 was shown to have the same order of activity as oridonin. 6-O-Acyl derivatives were also prepared and tested. In a series of derivatives 13-15, no activity was observed at the doses of 5 mg/kg and 10 mg/kg in mice, at which doses oridonin did exhibit activity. Thus, the importance of the ester side chain and the hydrogen-bonding for antitumor activity was demonstrated in oridonin and its derivatives.