Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 µM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg-1 · d-1, ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 µM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

Synthesis and antifungal activity of novel s-substituted 6-fluoro-4-alkyl(aryl)thioquinazoline derivatives.

6-Fluoro-4-quinazolinol is prepared by the cyclization reaction of 2-amino-5-fluorobenzoic acid and formamide. The resulting thiol obtained by treatment of hydroxyl group with phosphorus (V) sulfide is converted under phase transfer condition to 4-substituted 4-alkylthio-6-fluoroquinazoline derivatives by reaction with halide. The structures of the compounds are confirmed by elemental analysis, IR, and (1)H NMR. Title compounds 3a, 3g, and 3h are found to possess good antifungal activities. Using the mycelial growth rate method in the laboratory, the mechanism of action of 3g against Fusarium oxysporum in vitro is studied. The results indicate that 3a, 3g, and 3h have high inhibitory effect on the growth of most of the fungi with EC(50) values ranging from 8.3 to 64.2 microg/mL. After treating F. oxysporum with compound 3g at 100 microg/mL, only 6.5% of its spore bourgeoned. The permeability of the cell membrane increases along with the malformation of the hypha and condensation of its endosome. After treatment with compound 3g at 100 microg/mL within 12h, the mycelial reducing sugar, D-GlcNAc, content and chitinase activity decline, but the soluble protein content shows no obvious change.