Identification of novel quinoline analogues bearing thiazolidinones as potent kinase inhibitors for the treatment of colorectal cancer

Abstract

In this investigation, a novel series of quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 11k, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N-isopropylpiperidine-1-carboxamide, possessed submicromolar c-Met and Ron inhibitory activities. In addition, enzymatic assays against a mini-panel of kinases (c-Kit, B-Raf, c-Src, IGF1R, PDGFRα and AXL) were performed, the results showed that compound 11k exhibited moderate inhibitory activity against PDGFRα, c-Src and AXL. MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 11k with an IC₅₀ value of 0.31 μM which was 9.3- and 34.2-fold more potent than that of Regorafenib (IC₅₀ = 2.87 μM) and Cabozantinib (IC₅₀ = 10.6 μM). Preliminary antitumor mechanisms were also investigated by cellular assays. Considerable cytotoxicity, antiproliferation and induction of apoptosis of compound 11k in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Treatment with compound 11k caused slight G2-or M-phase arrest in HT-29 cells. Further cell selectivity of compound 11k showed that it was not active against human normal colorectal mucosa epithelial cell FHC at 10.0 μg/mL. The above results support further structural modification of compound 11k to improve its inhibitory activity, which will lead to more potent anticancer agents.

Keywords: 1; 3-Thiazolidin-4-one; Anticancer; Inhibitors; Quinoline; Tyrosine kinase.