Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents.

A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of ß-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated ß-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.

A novel one-step synthesis of Gd3+-incorporated mesoporous SiO2 nanoparticles for use as an efficient MRI contrast agent.

Molecular imaging has generated a demand for more sensitive contrast agents for magnetic resonance (MR) imaging. We synthesized, by a novel one-step method, Gd(3+) incorporated mesoporous SiO(2) nanoparticles, Gd(2)O(3)@SiO(2), for use as an efficient contrast agent. The prepared nanoparticles were also coated with poly(lactic-co-glycolic acid) (PLGA). The size, morphology, composition and Brunauer-Emmett-Teller specific surface area of the nanoparticles were evaluated. The Gd(2)O(3)@SiO(2) nanoparticles possess intragranular network morphology with a uniform size distribution and an average size of approximately 20-40 nm. The PLGA-coated nanoparticles were spherical or near-spherical in shape with a diameter of approximately 120 nm, a smooth surface, and neither aggregation nor adhesion tendencies. No free Gd ions were detected to dissociate from Gd(2)O(3)@SiO(2) even up to the limit (<0.03 mg/l) of the ICP equipment (IRIS Advantage). Our theoretical computation based on density functional theory (using DMol3, Materials Studio) revealed that the Gd(2)O(3) molecules are fully absorbed on the interface of mesoporous SiO(2) with a stable state of lower energy. Both Gd(2)O(3)@SiO(2) and PLGA-coated Gd(2)O(3)@SiO(2) samples have a larger T(1) relaxivitiy than commercial gadolinium diethylene triaminepentaacetate (Gd-DTPA). In vitro and in vivo MR images using the Gd(2)O(3)@SiO(2) nanoparticles were observed with a 1.5 T clinical MR scanner and compared with the images using Gd-DTPA. The Gd(2)O(3)@SiO(2) nanoparticles display a better magnetic property than commercial Gd-DTPA. In vivo MR imaging demonstrated that the nanoparticles were mainly distributed in the liver. Strong enhancement was also detected in nasopharyngeal carcinoma CNE-2 xenografted tumors. The Gd(2)O(3)@SiO(2) nanoparticles are not only potential candidates for highly efficient contrast agents for MR imaging, but also might be developed into potent targeted probes for in vivo molecular imaging of cancer.

Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted phenylmethylenethiosemicarbazones as tyrosinase inhibitors.

A series of hydroxy- or methoxy-substituted phenylmethylenethiosemicarbazones were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. The results demonstrated that most of target compounds had remarkable inhibitory activities on mushroom tyrosinase. Interestingly, compound 2h was found to be the most potent tyrosinase inhibitor with IC50 value of 0.18 microM. The possible interaction mode between compound 2h and tyrosinase was proposed. In addition, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of select compounds (IC50<10.0 microM) were also investigated. Compounds 2d, 2e, 2h, 2i and 2l exhibited more potent DPPH radical scavenging activity than well-known antioxidants ascorbic acid (Vc) and tertiary butyl hydroquinone (TBHQ). These results suggested that such compounds might be utilized for the development of new candidate for treatment of dermatological disorders.

A comparative molecular field analysis of cytotoxic beta-carboline analogs.

AIM: To derive a model that could be used in drug design. METHODS: Beta-carbolines are reported to have antitumor activities on cultured cancer cell lines. A comparative molecular field analysis (CoMFA) was undertaken to elucidate the correlation of cytotoxities and structural parameters of 16 beta-carboline analogs (1-16). The compound 12 was finally used as a template for the other compounds in the dataset because of its highest biological activity. RESULTS: The CoMFA applied to the final alignment resulted in a q2(cv) of 0.656 and it showed that the steric fields contributed 43.3% of the model information while the electrostatic fields represented the other 56.7%. CONCLUSION: Three designed compounds, which were predicted to have high, moderate and low activities respectively, were synthesized. The IC50 values of these compounds indicated the significance of the analysis in this study. The model derived from the current study could be further used in design for more active compounds.