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).

A Facile Approach to Bis(isoxazoles), Promising Ligands of the AMPA Receptor.

A convenient synthetic approach to novel functionalized bis(isoxazoles), the promising bivalent ligands of the AMPA receptor, was elaborated. It was based on the heterocyclization reactions of readily available electrophilic alkenes with the tetranitromethane-triethylamine complex. The structural diversity of the synthesized compounds was demonstrated. In the electrophysiological experiments using the patch clamp technique on Purkinje neurons, the compound 1,4-phenylenedi(methylene)bis(5-aminoisoxazole-3-carboxylate) was shown to be highly potent positive modulator of the AMPA receptor, potentiating kainate-induced currents up to 70% at 10-11 M.

5-Nitroisoxazoles in SNAr reactions: access to polysubstituted isoxazole derivatives.

An efficient protocol for the straightforward functionalization of the isoxazole ring via the reactions of aromatic nucleophilic substitution of the nitro group with various nucleophiles has been elaborated. The method features excellent chemical yields, easy operability of the reaction, mild reaction conditions and a broad scope of both 5-nitroisoxazoles and nucleophiles. A synthetic approach to 3,5- and 3,4,5-substituted isoxazoles via the sequential functionalization of the isoxazole ring has been developed based on the excellent regioselectivity of the reaction of 3,5-dinitroisoxazoles with nucleophiles.