Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-05, Vol.28 (9), p.3912
• Main Authors: Cui, Jingyi, Wang, Yujie, Li, Xiaoxin, Xiao, Fei, Ren, Hongjun, Wu, Meng
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biodegradation; Cancer; cancer treatment; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; dimer spiroindolinone pyrrolidinecarboxamide; Genes; Genetic aspects; Health aspects; Humans; Hydrochloric acid; In vivo methods and tests; Influence; MDM2 inhibitor; MDM2 protein; Mice; Mutation; p53 activation; p53 Protein; Prevention; Prostate cancer; Proteins; Proteolysis; Proto-Oncogene Proteins c-mdm2 - metabolism; Regulatory approval; Toxicity; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Western blotting; Xenotransplantation
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28093912

The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2-p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes and levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.