Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 μM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

By virtue of an efficient rhodium(III)-catalyzed redox-neutral C-H activation/ring-opening of a strained ring/[4+2] annulation cascade of N-methoxybenzamides with propargyl cycloalkanols, diverse 3-acyl isoquinolin-1(2H)-ones were directly obtained in good yields and with excellent functional group compatibility. Additionally, their antitumor activities against various human cancer cells including HepG2, A549, MCF-7 and SH-SY5Y were evaluated and the action mechanism of the selected compound was also investigated in vitro. The results revealed that these products possessed a potent efficacy, by inhibiting proliferation and inducing apoptosis in a time-dependent and dose-dependent manner, suggesting that such compounds can serve as promising candidates for anti lung cancer drug discovery.