Synthesis, Antiproliferative Activity, and Molecular Simulation Study of Novel Nootkatone Derivatives Containing Pyrazole‐amide Moiety

To explore new types of anticancer drugs, a series of novel nootkatone-derived pyrazole-amide compounds were synthesized by the multi-step reaction using natural product nootkatone as starting material. The structures of the synthesized compounds were confirmed by Fourier-transform infrared, proton nuclear magnetic resonance (¹H NMR), carbon-13 NMR, and high-resolution mass spectrometry. In vitro antiproliferative activity of the target compounds against human hepatocellular carcinoma cells (SMMC-7721, Huh7, and HepG2) and human breast cancer cell lines (MCF-7) has been assessed by the Cell Counting Kit-8 method. It was found that compounds 4i, 4q, 4r, and 4t exhibited good antiproliferative activity against all the tested cancer cells, in which compound 4r had the best activity with half-maximal inhibitory concentration values of 26.19, 1.51, 10.63, and 10.43 µM against SMMC-7721, HepG2, Huh7, and MCF-7 cell lines, respectively. Meanwhile, the three-dimensional quantitative structure-activity relationship model with predictive ability was established by the Comparative Molecular Field Analysis method to investigate the relationship between substituents on the target compounds and antiproliferative activity. Furthermore, the possible interaction mode of compound 4r with Survivin protein was probed by molecular docking, and found that compound 4r shared similar binding patterns with that of Survivin protein inhibitors YM155 and NSC80467. The work can bring new inspiration to the exploration of new types of anticancer drugs.