Design, synthesis and biological evaluation of CDC20 inhibitors for treatment of triple-negative breast cancer.

The involvement of CDC20 in promoting tumor growth in different types of human cancers and it disturbs the process of cell division and impedes tumor proliferation. In this work, a novel of Apcin derivatives targeting CDC20 were designed and synthesized to evaluate for their biological activities. The inhibitory effect on the proliferation of four human tumor cell lines (MCF-7, MDA-MB-231, MDA-MB-468 and A549) was observed. Among them, compound E1 exhibited the strongest inhibitory effect on the proliferation of MDA-MB-231 cells with an IC50 value of 1.43 µM, which was significantly superior to that of Apcin. Further biological studies demonstrated that compound E1 inhibited cancer cell migration and colony formation. Furthermore, compound E1 specifically targeted CDC20 and exhibited a higher binding affinity to CDC20 compared to that of Apcin, thereby inducing cell cycle arrest in the G2/M phase of cancer cells. Moreover, it has been observed that compound E1 induces autophagy in cancer cells. In 4T1 Xenograft Models compound E1 exhibited the potential antitumor activity without obvious toxicity. These findings suggest that E1 could be regarded as a CDC20 inhibitor deserved further investigation.

Design, synthesis, and biological evaluation of novel diphenylamine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site.

A novel series of diphenylamine derivatives were designed and synthesized, and their biological activities were evaluated. The anti-proliferative activities of the derivatives were tested against five human cancer cell lines (MCF-7, MDA-MB-231, A549, HeLa and HT29). Among them, compound 5f exhibited the promising anti-proliferative activity against HT29 cell lines with the IC50 value of 23 nM. Further biological studies depicted that compound 5f inhibited cancer cell migration, colony formation and angiogenesis. Besides, dynamics studies and molecular docking studies revealed that compound 5f inhibited tubulin polymerization which may be a result of the compound binding to the colchicine site of tubulin. Furthermore, compound 5f arrested HT29 cell cycle at G2/M phase, and induced HT29 cell apoptosis by upregulating cyclin B1, Bcl-2, Bax, Cleaved-caspase9, Cleaved-caspase3, PARP, Cleaved-PARP proteins, and downregulating p-cdc25c (S216), p-cdc2 (T15) proteins. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also determined to confirm the cell apoptosis process. Finally, compound 5f greatly inhibited the tumor growth in HT29 xenograft mice by 75.5% at 10 mg/kg. Meanwhile, compound 5f owned the good pharmacokinetic properties. All the results promised that 5f is of potential to act as an antitumor candidate and worthy of further investigation.

Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site.

A novel series of shikonin-benzo[b]furan derivatives were designed and synthesized as tubulin polymerization inhibitors, and their biological activities were evaluated. Most compounds revealed the comparable anti-proliferation activities against the cancer cell lines to that of shikonin and simultaneously low cytotoxicity to non-cancer cells. Among them, compound 6c displayed powerful anti-cancer activity with the IC50 value of 0.18 µM against HT29 cells, which was significantly better than that of the reference drugs shikonin and CA-4. What's more, 6c could inhibit tubulin polymerization and compete with [3H] colchicine in binding to tubulin. Further biological studies depicted that 6c can induce cell apoptosis and cell mitochondria depolarize, regulate the expression of apoptosis related proteins in HT29 cells. Besides, 6c actuated the HT29 cell cycle arrest at G2/M phase, and influenced the expression of the cell-cycle related protein. Moreover, 6c displayed potent inhibition on cell migration and tube formation that contributes to the antiangiogenesis. These results prompt us to consider 6c as a potential tubulin polymerization inhibitor and is worthy for further study.