N-Functionalization of β-aminophosphonates: cytotoxic effects of the new derivatives

Abstract

β-Aminophosphonates obtained by the Michael addition of primary amines to the double bond of diethyl vinylphosphonate proved to be suitable starting materials (amine components) in the Kabachnik–Fields reaction with formaldehyde and dialkyl phosphites or secondary phosphine oxides to afford N-phosphonylmethyl- and N-phosphinoylmethyl-β-aminophosphonates. On the other hand, the starting aminophosphonates were modified by N-acylation using acid chlorides. The N-acyl products were found to exist in a dynamic equilibrium of two conformers as suggested by the broad NMR signals. At 26 °C, there may be rotation around the N–C axis of the acylamide function. At the same time, low-temperature NMR measurements at −5 °C revealed the presence of two distinct rotamers that could be characterized by ³¹P, ¹³C and ¹H NMR data. The modified β-aminophosphonic derivatives were subjected to a comparative structure–activity analysis on MDA-MB-231, PC-3, A431 and Ebc-1 tumor cell lines, and in a few cases, significant activity was detected.