ABSTRACT
Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 µM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Thiadiazines/therapeutic use , Triazoles/therapeutic use , Tubulin Modulators/therapeutic use , Tubulin/metabolism , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Binding Sites , Cell Proliferation/drug effects , Female , G2 Phase Cell Cycle Checkpoints/drug effects , HEK293 Cells , Humans , Mice, Inbred BALB C , Molecular Structure , Protein Binding , Structure-Activity Relationship , Thiadiazines/chemical synthesis , Thiadiazines/metabolism , Triazoles/chemical synthesis , Triazoles/metabolism , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Li-excess cation-disordered rock-salts Li1+x/100Ni1/2-x/100Ti1/2-x/100Nbx/100O2 (x = 0, 5, 10, 15, 20) were synthesized in this study, and effects of Nb doping on their electrochemical performance were also investigated. X-ray diffraction (XRD) indicated that the rock-salt structure was maintained, but with lower crystallization. The scanning electron microscopy (SEM) displayed Nb-doped samples' morphology and particles were uniformly distributed within 100 nm. The transmission electron microscopy (TEM) analysis also confirmed that these Nb-doped samples still maintained the cationdisordered rock-salt structure. Charge-discharge test showed that the electrochemical performance was greatly improved after Nb-doping. The Li1.2Ni0.3Ti0.3Nb0.2O2 sample delivered highest capacity of up to 226.5 mAh·g-1, at 20 mA·g-1 density. Moreover, the sample still delivered 130 mAh·g-1 capacity of even 400 mA·g-1 density. This result indicates that the Nb-doping improved the cycling performance and rate capacity. In addition, electrochemical impedance spectroscopy (EIS) test showed that the Nb-doping further enhanced mobility of Li-ions when forming the 0-TM channel.