Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Beta-1,3-glucuronosyltransferase (B3GAT3), overexpressed in hepatocellular carcinoma (HCC) and negatively correlated to prognosis, is a promising target for cancer therapy. Currently, no studies have reported small molecule inhibitors of B3GAT3. In this study, we designed and synthesized a series of small-molecule inhibitors of B3GAT3 through virtual screening and structure optimization. The lead compound TMLB-C16 exhibited potent B3GAT3 inhibitory activity (KD = 3.962 µM) by effectively suppressing proliferation and migration, and inducing cell cycle arrest and apoptosis in MHCC-97H (IC50= 6.53 ± 0.18 µM) and HCCLM3 (IC50= 6.22 ± 0.23 µM) cells. Furthermore, compound TMLB-C16 demonstrated favorable pharmacokinetic properties with a relatively high bioavailability of 68.37%. It significantly inhibited tumor growth in both MHCC-97H and HCCLM3 xenograft tumor models without causing obvious toxicity. These results indicate that compound TMLB-C16 is an effective small molecule inhibitor of B3GAT3, providing a basis for the future development of B3GAT3-targeted drugs.

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma.

Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Molecular characterization of the genome-wide BOR transporter family and their responses to boron conditions in common wheat (Triticum aestivum L.).

Boron (B) deficiency is an agricultural problem that causes significant yield losses in many countries. B transporters (BORs) are responsible for B uptake and distribution and play important roles in yield formation. A comprehensive analysis of the BOR family members in common wheat is still lacking. In the present study, to clarify the molecular characterization and response to B status, genome-wide TaBOR genes and expression patterns were investigated. Fourteen TaBOR genes were identified in common wheat by a homology search. The corresponding phylogenetic tree indicated that 14 TaBOR genes were separately classified into subfamilies of TaBOR1, TaBOR3, and TaBOR4. All TaBOR genes had 12-14 extrons and 11-13 introns. Most TaBOR proteins contained 10 conserved motifs, and motifs 1, 2, 3, 4, and 6 constituted the conserved bicarbonate (HCO3 -) domain. Fourteen TaBOR genes were mapped on 13 chromosomes mainly distributed in the first, third, fifth, and seventh homologous groups. The promoters of TaBOR genes consisted of phytohormones, light responses, and stress-related cis-elements. GO analysis indicated that TaBOR genes were enriched in terms of transmembrane transport and ion homeostasis. TaBOR genes showed diverse expression profiles in different tissues. The members of the TaBOR1 subfamily showed high expression in grains, leaves, roots, stems, and spikes, but members of the TaBOR4 subfamily were highly expressed only in spikes and grains. RT-qPCR indicated that TaBOR1-5A, TaBOR1-5B, and TaBOR1-5D were induced by low B concentrations and had much higher expression in roots than in shoots. TaBOR3-3A, TaBOR3-3B, TaBOR3-3D, TaBOR4-1A, TaBOR4-1B, TaBOR4-1D, and TaBOR3-4B were induced by low and high B concentrations and had high expression in roots and shoots. TaBOR3-4D and TaBOR3-7B were upregulated by low and high B concentrations, respectively, but had expression only in roots. Our results provide basic information on the TaBOR family, which is beneficial for elucidating the functions of TaBOR genes to overcome the problem of B deficiency.