Novel substituted 5-methyl-4-acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells.

A series of novel antimitotic agents was designed using the replacement of heterocyclic cores in two tubulin-targeting lead molecules with the acylated 4-aminoisoxazole moiety. Target compounds were synthesized via heterocyclization of ß-aryl-substituted vinylketones by tert-butyl nitrite in the presence of water as a key step. 4-Methyl-N-[5-methyl-3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]benzamide (1aa) was found to stimulate partial depolymerization of microtubules of human lung carcinoma A549 cells at a high concentration of 100 µM and to totally inhibit cell growth (IC50 = 0.99 µM) and cell viability (IC50 = 0.271 µM) in the nanomolar to submicromolar concentration range. These data provide evidence of the multitarget profile of the cytotoxic action of compound 1aa. The SAR study demonstrated that the 3,4,5-trimethoxyphenyl residue is the key structural parameter determining the efficiency both towards tubulin and other molecular targets. The cytotoxicity of 3-methyl-N-[5-methyl-3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]benzamide (1ab) to the androgen-sensitive human prostate adenocarcinoma cancer cell line LNCaP (IC50 = 0.301 µM) was approximately one order of magnitude higher than that to the conditionally normal cells lines WI-26 VA4 (IC50 = 2.26 µM) and human umbilical vein endothelial cells (IC50 = 5.58 µM) and significantly higher than that to primary fibroblasts (IC50 > 75 µM).

Effects of Metal Oxide Nanoparticles on Toll-Like Receptor mRNAs in Human Monocytes.

For the widespread application of nanotechnology in biomedicine, it is necessary to obtain information about their safety. A critical problem is presented by the host immune responses to nanomaterials. It is assumed that the innate immune system plays a crucial role in the interaction of nanomaterials with the host organism. However, there are only fragmented data on the activation of innate immune system factors, such as toll-like receptors (TLRs), by some nanoparticles (NPs). In this study, we investigated TLRs' activation by clinically relevant and promising NPs, such as Fe3O4, TiO2, ZnO, CuO, Ag2O, and AlOOH. Cytotoxicity and effects on innate immunity factors were studied in THP-1(Tohoku Hospital Pediatrics-1) cell culture. NPs caused an increase of TLR-4 and -6 expression, which was comparable with the LPS-induced level. This suggests that the studied NPs can stimulate the innate immune system response inside the host. The data obtained should be taken into account in future research and to create safe-by-design biomedical nanomaterials.