Antitumor effect of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole down-regulating the Gas6-Axl axis

• Published in: European journal of medicinal chemistry 2023-05, Vol.251, p.115274-115274, Article 115274
• Main Authors: Bae, Dawon, Chaudhary, Prakash, Been, Jae-Hui, Gautam, Jaya, Lee, Jisu, Shah, Sajita, Kim, Euijung, Lee, Hyunji, Nam, Tae-gyu, Jeong, Byeong-Seon, Kim, Jung-Ae
• Format: Article
• Language: English
• Subjects: 7-Azaoxindole; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Axl; Bax/Bcl-2; Cell Line, Tumor; Gas6; Humans; Mice; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Signal Transduction; Sunitinib - pharmacology; TAM family Receptor tyrosine kinase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115274

In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 compounds, compound 6–15, with a quinoline moiety, showed cytotoxic IC50 values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFRβ, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 –3000-fold weaker than that of sunitinib. Interestingly, compound 6–15 exerted a 3.6-fold stronger cytotoxicity than sunitinib in the gemcitabine-resistant PANC-1 cell line and significantly inhibited Axl, which was in contrast with the effect of sunitinib. Nonetheless, both compounds suppressed the expression of growth arrest-specific 6 (Gas6), the ligand of Axl. The inhibitory effect of compound 6–15 on the Gas6-Axl axis was similar to that of Gas6 knockdown by siRNA in PANC-1 cells in terms of apoptosis induction, increase in Bax/Bcl-2 ratio, Axl down-regulation, and PI3K/Akt inhibition. The inhibitory effect of compound 6–15 on tumor growth in mouse tumor models with A549 and PANC-1 xenografts was much greater than that of cisplatin or gemcitabine. Taken together, the current findings demonstrate that compound 6–15 is a promising anticancer drug candidate that acts by inhibiting the Gas6-Axl axis. [Display omitted] •A series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds were synthesized.•Compound 6–15 showed excellent cancer-selective cytotoxic activity in a variety of cancer cells.•Compound 6–15 down-regulated Gas6 and Axl expression, resulting in apoptosis of cancer cells.•The anticancer activity of compound 6–15 was similar to that of Gas6 gene silencing.•Compound 6–15 has greater antitumor effects than cisplatin or gemcitabine in A549 and PANC-1 xenograft mouse tumor models.