In order to make available new derivatives, diethyl α-amino-α-aryl-methylphosphonates were subjected to phosphorylation, phosphinoylation and even thiophosphinoylation by reaction with phosphoryl chlorides, diphenylphosphinoyl chloride, and with the mixture of diphenylchlorophosphine and elemental sulfur, respectively. The X-ray crystal structures of the diphenylphosphinoyl and the diphenylthiophosphinoyl derivatives revealed molecular and supramolecular similarities, as well as a few differences too. An essential conformation change, along with packing differences are attributable to a change of one heteroatom: an oxygen for a sulfur in one of the P=X function. The diethyl diethylphosphoryl-aminobenzylphosphonates showed the highest antiproliferative effects on multiple myeloma cells, while the thiophosphinoylated diethyl aminobenzylphosphonate was the most effective on pancreatic ductal adenocarcinoma cells.