Cytotoxic Agents by the Phosphinoylation and Thiophosphinoylation of 3-Hydroxy-1,2,3,6-tetrahydrophosphinine 1-Oxides as β-Hydroxyphosphonates and -Phosphine Oxides

A series of hydroxy-1,2,3,6-tetrahydrophosphinine oxides were prepared by the two-step ring enlargement of 1-substituted 3-phospholene 1-oxides via the corresponding dichlorocarbene adducts. The two diastereomers of the P-ethoxy-3-phosphabicyclo[3.1.0]hexane 3-oxides could be identified by single crystal X-ray analysis, hence the isomers could be characterized by NMR methods. Detailed examination of the crystal structures of the two isomers shows weak O & centerdot;& centerdot;& centerdot;H and Cl & centerdot;& centerdot;& centerdot;H interactions, which are different for the two isomers, in accord with the different arrangements of the molecules in the solid state. The less hindered hydroxy-tetrahydrophosphinine oxide isomers were selectively phosphinoylated and thiophosphinoylated. The cytotoxic effect of the P-heterocycles synthesized was tested on U266 myeloma cells and on A2058 melanoma cells. The results are promising, as the viability of the cells was decreased drastically at the higher 100 mu M concentration, especially in respect of one hydroxy-tetrahydrophosphinine oxide and the two P-functionalized derivatives, independently of the substituent's nature.