Silenko O. Synthesis, structure, and properties of (thia)calix[4]arene phosphoric acids and phosphonic acids.

The thesis is devoted to the development of methods for functionalization of calix[4]arene and thiacalix[4]arene at the upper and lower rim with phosphoric or phosphonic acid fragments in order to provide useful biological and physicochemical properties. Convenient methods for regioselective functionalization of the lower rim of tetrahydroxythiacalix[4]arenes with dialkoxylphosphoryl groups have been developed. The obtained esters were converted with quantitative yields into the corresponding thiacalix[4]arene-monophosphonic and diphosphonic acids by sequentially treated with trimethylbromosilane and methanol (the method put forward by McKenna et al.). The cone-shaped spatial structure of the synthesized compounds was determined by NMR spectroscopy and X-ray structure analysis. Recent studies have demonstrated the efficacy of thiacalixaren-phosphoric acids as potent inhibitors of glutathione-S-transferase, exhibiting an IC50 range of 0.2 - 11.7 μM. A method for functionalization of the upper rim of calixarene with N,N-di(octylsulfonamide) substituents has been developed. By interaction of tetra-N,N-di(octylsulfonamide)-tetrahydroxycalix[4]arene with diethylchlorophosphate in the presence of triethylamine or potassium carbonate as a base leads to formation octaethyl ester of tetra-N,N-di(octylsulfonamide)-calix[4]arene-tetraphosphonic acid in the 1,3-alternate conformation. In the case of using lithium carbonate as a base, the tetraethyl ether of tetra-N,N-di(octylsulfonamide)-calix[4]arene-diphosphonic acid was formed in the cone conformation. The obtained ester of diphosphonic acid was converted into an amphiphilic calixarene-diphosphonic acid using the McKenna method. The critical aggregation concentration (CAC) of the amphiphilic N,N-di(octylsulfonamide)-calixarene-diphosphonic acid determination by using the ANS fluorescence in water and phosphate-based saline was 8.24 µM at 25 °C. Interaction of di-O-alkylated calix[4]arenes-1,3-dialdehyde with sodium salts of dialkylphosphites leads to formation of alkyl esters of calixarene-dimethylene-bisphosphonic acid which were transformed into amphiphilic calix[4]arene-di(methylene-bisphosphonic acids) with different alkyl substituents on the lower rim of the macrocycle. The solubilizing effect of the amphiphilic di(dodecyloxy)-calix[4]arene-di(methylene-bisphosphonic acid) was established for the poorly water-soluble active pharmaceutical ingredients of Ibuprofen, Naproxen. A method for introducing propargylic residues onto the upper rim of calixarenes was developed to give calixarenes the ability to enter into click reactions of azide-alkyne cycloaddition. The octapropargyl ester of calix[4]arene-di(methylene-bisphosphonic acid) was obtained through the reaction of di(dodecyloxy)-calix[4]arene-1,3-dialdehyde with dipropargyl phosphite in the presence of triethylamine. By subsequent interaction with lithium bromide, the corresponding ester was transformed into an amphiphilic tetralithium salt of tetrapropargyl ester calixarene-di(methylene-bisphosphonic acid). Amphiphilic dialkoxy-calixarene-di(hydroxymethylene-bisphosphonic acids) were obtained from chloranhydrides of dialkoxy-calix[4]arene-carboxylic acid by sequentially treated with tris(trimethylsilyl)phosphite and methanol. Amphiphilic calixarene-α-ketophosphonic acids with different lengths of alkyl substituents on the lower rim of the macrocycle were synthesized through the Arbuzov reaction of сhloroanhydride of dialkoxy-calixarene-1,3-di(carboxylic acids) with trialkylphosphites and following dealkylation by the McKenna method. Studies of the properties of a series of amphiphilic calixarene-α-ketophosphonic acids show that they can effectively inhibit glutathione-S-transferases with the action of UV-irradiation (wavelength 365 nm) with IC50 values up to 0.12 µM. A method of regioselective distal alkylation of the lower rim of tetrahydroxy-calixarene-methylene-bisphosphonates with 3-methylsulfidopropoxy substituents by the Mitsunobu reaction has been developed. A bifunctional calixarene with 3-methylsulfidopropoxy groups on the lower rim capable of adhesion to the gold surface of conductometric sensor microchips and with receptor groups of methylene bisphosphonic acid on the upper rim capable of binding amino acids was obtained. The stability constants of the complexes of 3 methylsulfidopropoxy-calixarene-methylene-bisphosphonic acid with seventeen amino acids of different nature (KΑ = 10221 - 41504 М-1) were determined by HPLC. Based on the obtained calixarene developed an electrochemical sensor capable of determining arginine in aqueous solutions.