Efficient Synthesis of Acylated, Dialkyl alpha-Hydroxy-Benzylphosphonates and Their Anticancer Activity

An efficient method applying acyl chlorides as reagents was developed for the acylation of the hindered hydroxy group of dialkyl alpha-hydroxy-benzylphosphonates. The procedure did not require any catalyst. A few acylations were also performed with the S-C-enantiomer of dimethyl alpha-hydroxy-benzylphosphonate, and the optical purity was retained. A part of the acyloxyphosphonates was tested against eight tumor cell lines of different tissue origin at c = 50 mu M concentration. The compounds elicited moderate cytostatic effect against breast, skin, prostate, colon, and lung carcinomas; a melanoma cell line; and against Kaposi's sarcoma cell lines. Then, dose-dependent cytotoxicity was assayed, and benzoylation of the alpha-hydroxy group was identified as a moiety that increases anticancer cytotoxicity across all cell lines. Surprisingly, a few analogues were more toxic to multidrug resistant cancer cell lines, thus evading P-glycoprotein mediated drug extrusion.