Selikhova A. Synthesis, structure and properties of calixarene dimethylphosphine oxides and sulfamidophosphonic acids.

The dissertation is devoted to the development of convenient preparative methods for the functionalization of the upper rim of calix[4]arenes and thiacalix[4]arenes with dimethylphosphine oxide, α-hydroxymethyl-dimethylphosphine oxide, and sulfamidophosphonic acid fragments, with the aim of imparting useful physicochemical and biological properties to the resulting compounds. The reaction of tetrachloromethyl-tetrahydroxycalix[4]arene and tetrachloromethyl-tetrahydroxythiacalix[4]arene with (trimethylsilyl)dimethyl phosphinite afforded water-soluble tetrahydroxy(thia)calixarenes bearing four hydrophilic dimethylphosphine oxide groups at the upper rim of the macrocycle. Preparative methods for the phosphorylation of alkoxy-formylcalixarenes with (trimethylsilyl)dimethyl phosphinite were developed, providing calixarenes functionalized with α-hydroxymethyldimethylphosphine oxide groups. It was established that the degree of alkylation of the lower rim of diformylcalixarenes significantly affects the stereochemical outcome of the reaction with (trimethylsilyl)dimethyl phosphinite. Thus, phosphorylation of dipropoxy-diformylcalixarene proceeds stereospecifically to afford exclusively the (RR + SS) racemic form of calixarene-α-hydroxymethyldimethylphosphine oxide. In contrast, phosphorylation of tetrapropoxy-diformylcalixarene yields equimolar mixtures of the racemic and meso forms of calixarene-α-hydroxymethyldimethylphosphine oxide. The structure, stereochemistry, and ability of calixarene-α-hydroxymethyldimethylphosphine oxides to form intermolecular P=O•••H–O hydrogen bonds were investigated by X-ray crystallographic analysis. It was found that a dipropoxycalixarene containing one α-hydroxymethyldimethylphosphine oxide group forms a one-dimensional linear polymeric chain linked by P=O•••H–O hydrogen bonds. In contrast, a dipropoxycalixarene bearing two α-hydroxymethyldimethylphosphine oxide groups forms a stereoregular helical polymeric chain connected through ten-membered P=O•••H–O hydrogen-bonded rings. It was demonstrated that the self-assembly of calixarene-α-hydroxymethyldimethylphosphine oxides depends on the conformational mobility of the macrocyclic framework and is governed by the degree of substitution at the lower rim of the macrocycle. The reaction of mono- and diformylcalixarenes with excess sulfonamides in tetraethoxysilane solution at 190 °C afforded mono- and disulfonylimino calixarenes in high yields. Conditions for the diastereospecific addition of diethyl phosphite to the C=N bond of mono- and disulfonylimino calixarenes were developed. This reaction leads to the formation of meso forms of the ethyl esters of calixarene-sulfamidophosphonic acids. Subsequent treatment of the obtained compounds with bromotrimethylsilane followed by methanol afforded calixarene-sulfamidophosphonic acids. It was established that amphiphilic dialkoxycalixarene-bis-α-hydroxymethyldimethylphosphine oxides form micelles and thermoreversible gels in aqueous media, making them promising candidates for drug delivery systems. The stability constants (KA = 1100–12000 M-1) of host–guest supramolecular complexes formed by water-soluble calixarene phosphonic acids and calixarene dimethylphosphine oxides with active pharmaceutical ingredients (APIs) of antiviral drugs from different classes, determined by RP-HPLC, indicate their potential application as vectors in drug delivery systems. It was found that calixarene-sulfamidophosphonic acids selectively inhibit Na+,K+-ATPases of the plasma membrane of uterine myocytes (IC50 = 36–61 nM) and therefore represent promising candidates as regulators of calcium homeostasis and myometrial contractile activity.