18β-Glycyrrhetinic acid (18β-GA) is the main active component of licorice and one of the most promising lead compounds in traditional Chinese herbal medicine. Previous studies have shown that 18β-GA can act as a PPARγ agonist to exert antitumor activity. However, the number of reported 18β-GA derivatives as PPARγ agonists is limited and they have significant toxic side effects, which greatly restricts their application and development. To obtain highly effective and low-toxic PPARγ agonists, through structure-activity relationship (SAR) analysis, we constructed a molecular library of 18β-GA derivatives containing 13,440 compounds and screened out 14 novel 18β-GA ester derivatives. The selected compounds were evaluated for their antitumor activity in vitro. The results showed that most of the compounds exhibited strong anti-proliferative activity against five human cancer cell lines, especially the human colon cancer cell line HT-29, without significant toxicity to normal cell lines. Among them, C1 had the strongest anti-proliferative activity against HT-29, with an IC 50 value of 12.25 μM, which was 12 times higher than that of its parent nucleus 18β-GA. C1 can block the cell cycle of HT-29 cells in G2/M phase, significantly inhibit their migration and induce their apoptosis. Molecular docking and dynamics simulation results suggested that C1 could stably bind to the active pocket of PPARγ. Further PPARγ activity analysis and drug-likeness prediction results indicated that C1 could act as a PPARγ agonist to exert antitumor effects and had certain drug-likeness, which is worthy of further study.
Ligustrazine (TMP) is a natural pyrazine alkaloid extracted from the roots of Ligusticum Chuanxiong Hort, which has the potential as an antitumor agent. A series of 33 ligustrazine–heterocycle (TMPH) derivatives were designed, synthesized, and investigated via antitumor screening assays, molecular docking analysis, and prediction of drug-like properties. TMP was attached to other heterocyclic derivatives by an 8–12 methylene alkyl chain as a linker to obtain 33 TMPH derivatives. The structures were confirmed by 1H-NMR, 13C-NMR, and high-resolution mass spectroscopy spectral (HR-MS) data. The antiproliferative activity against human breast cancer MCF-7, MDA-MB-231, mouse breast cancer 4T1, mouse fibroblast L929, and human umbilical vein endothelial HUVEC cell lines was evaluated by MTT assay. Compound 12–9 displayed significant inhibitory activity with IC50 values in the low micromolar range (0.84 ± 0.02 µM against the MDA-MB-231 cell line). The antitumor effects of compound 12–9 were further evaluated by plate cloning, Hoechst 33 342 staining, and annexin V-FITC/PI staining. The results indicated that compound 12–9 inhibited the proliferation and apoptosis of breast cancer cells. Furthermore, molecular docking of compound 12–9 into the active site of the Bcl-2, CASP-3, and PSMB5 target proteins was performed to explore the probable binding mode. The 33 newly synthesized compounds were predicted to have good drug-like properties in a theoretical study. Overall, these results indicated that compound 12–9 inhibited cell proliferation through PSMB5 and apoptosis through Bcl-2/CASP-3 apoptotic signaling pathways and had good drug-like properties. These results provided more information, and key precursor lead derivatives, in the search for effective bioactive components from Chinese natural medicines.
危险品化学品经营许可证（带存储）