Transactivation response (TAR) RNA-binding protein 2 (TRBP) plays a critical role in microRNA (miRNA) biosynthesis, with aberrant expression linked to various cancers. Previously, we identified CIB-3b, a phenyloxazole derivative that disrupts the TRBP-Dicer interaction in hepatocellular carcinoma (HCC). In this study, we optimized this scaffold and substituent, leading to the discovery of CIB-L43, a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar inhibitory activity (EC50 = 0.66 nM). CIB-L43 demonstrated superior TRBP binding affinity (KD = 4.78 nM) and enhanced disruption of TRBP-Dicer interactions (IC50 = 2.34 μM). Mechanistically, CIB-L43 suppressed oncogenic miR-21 biosynthesis, increasing PTEN and Smad7 expression and inhibiting AKT and TGF-β signaling, thereby reducing HCC cell proliferation and migration. In vivo, CIB-L43 exhibited favorable pharmacokinetics, including 53.9% oral bioavailability, and comparable antitumor efficacy to first-line anticancer drug, sorafenib, with lower toxicity. CIB-L43 emerges as a promising HCC treatment candidate with potent TRBP inhibition and favorable drug-like properties.

A series of novel erianin analogues were designed and synthesized based on the bioisosterism principle by altering the two aromatic rings of erianin, the substituents on the rings and the linker between them. The analogues were evaluated as pyruvate carboxylase (PC) inhibitors in hepatocellular carcinoma cells. It was found that compounds 35 and 36, where fluorine replaces a hydroxyl group, exhibited higher activity than erianin (IC50 value of 17.30 nM) in liver cancer cells with IC50 values of 15.15 nM and 10.05 nM, respectively. Additionally, at a concentration of 10 nM, compounds 35 and 36 inhibited PC with inhibitory rates of 39.10% and 40.15%, respectively, exhibiting nearly identical inhibitory activity to erianin (inhibitory rate of 40.07%). Additionally, a computer simulation docking study demonstrated the basis for better interactions between the receptors and ligands. The fluorine atom of 35 can not only form hydrogen bonds with Lys-1043 (NH...F, 2.04 angstrom), but also form fluorine bonds with the carbonyl groups of Lys-1043 (3.67 angstrom) and Glu-1046 (3.70 angstrom), due to the different orientations of the halogens on the B ring warhead. Conversely, the chlorine atom of 34 can only form alkyl hydrophobic interactions with the alkane chain in Lys-1043. Fluorinated compounds 35 and 36 also show better chemical stability and higher log P (clog P = 3.89 for 35 and 36) values than that of erianin (clog P = 3.07), and may be used as candidate com-pounds for further drug development.

The glycosylation of protecting-group-free pyranoses with flavonoids to generate flavonoid O-glycosides under Mitsunobu conditions was reported. The methodology allows to prepare a wide range of natural 7-flavonoid O-glycosides and their derivatives from commercially available chemicals in good to excellent yields with exclusive 1,2-trans-stereoselectivity regardless the anomeric configuration of employed pyranoses. The highly regioselective glycosylation was also achieved among different types of hydroxyl groups on the glycosyl acceptors.

MicroRNAs (miRNAs) are key players in human hepatocellular carcinoma (HCC) tumorigenesis. Therefore, small molecules targeting components of miRNA biogenesis may provide new therapeutic means for HCC treatment. By a high-throughput screening and structural simplification, we identified a small molecule, CIB-3b, which suppresses the growth and metastasis of HCC in vitro and in vivo by modulating expression profiles of miRNAome and proteome in HCC cells. Mechanistically, CIB-3b physically binds to transactivation response (TAR) RNA-binding protein 2 (TRBP) and disrupts the TRBP-Dicer interaction, thereby altering the activity of Dicer and mature miRNA production. Structure-activity relationship study via the synthesis of 45 CIB-3b derivatives showed that some compounds exhibited a similar inhibitory effect on miRNA biogenesis to CIB-3b. These results support TRBP as a potential therapeutic target in HCC and warrant further development of CIB-3b along with its analogues as a novel therapeutic strategy for the treatment of HCC.

以靛红酸酐(2)为起始原料,经氮上烷基化、开环、关环以及酯的氨解生成异羟肟酸等多步简单反应合成了目标化合物选择性HDAC6抑制剂4-((2,4-二氧基-3-苯乙基-3,4-二氢喹唑啉-1(2H)-基)-甲基)-N-羟基苯甲酰胺(1).产物结构经1 H NMR、13 C NMR以及MS确证.新的合成路线具有反应条件温和、后处理简单等优点,总收率83.8％.