Synthesis of a bis-Phosphonic Acid Derivative of Trolox, a New Potential Antioxidant

Abstract

1-Amino-1,1-bis-phosphonates are attracting more and more interest in various areas of chemistry and medicine because of the combination of unique chemical, physical, and biological properties that enable various biologically active compounds that are used as immunomodulators, calcium-exchange regulators, antitumor drugs, etc. to be synthesized [1]. Conjunction of pharmacologically active compounds and bis-phosphonates in order to increase the binding capability or concentration of these biologically active compounds in certain compartments in vivo, e.g., bone, is of separate interest because it would facilitate targeted delivery of the compound [2, 3]. This communication is a continuation of studies in this direction, in particular, modification of folic acid [4] and derivatives of ursolic, betulonic, and betulinic acids [5]. Trolox is a well-known antioxidant and a water-soluble derivative of vitamin E. It is used to relieve oxidative stress. The goal of the present work was to synthesize the conjugate of trolox (1) and bis-phosphonate derivative 2. We prepared previously the diethyl ester of 1-(2-aminoethylamino)-1-(diethylphosphoryl)ethylphosphonic acid (2) [4], which was a convenient structural synthetic block. Reaction of trolox and 2 in the presence of carbodiimidazole (CDI) formed the diethyl ester of 1-diethylphosphoryl-1-{2-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl)amino]ethylamino}ethylphosphonic acid (3). The structure of 3 was confirmed by PMR and 13C and 31P NMR spectroscopy and mass spectrometry. Thus, the bis-phosphonate conjugate based on the antioxidant trolox was synthesized.