Six-membered ring phosphates and phosphonates as model compounds for cyclic phosphate prodrugs: is the anomeric effect involved in the selective and spontaneous cleavage of cyclic phosphate prodrugs?
In recent years, several six-membered ring phosph(on)ates and phosphonamides have been reported as potent prodrugs against liver diseases such as hepatitis B and C and also as antitumor agents. Apparently, the success for their biological activity depends on the selective cleavage of the C4-O3 bond within the respective P-heterocyclic ring. Empirical observations have suggested that the group attached to the C4 position (aryl or pyridyl group) is responsible for the selective cleavage. In this regard, we show in the present work that the configuration at the P-atom, the conformation of the P-heterocyclic ring, and particularly, the anomeric effect are involved in the spontaneous and selective cleavage of the C4-O3 bond in cyclic phosph(on)ates. We arrived at this assumption based on the conformational and configurational study of simple model phosphates and phosphonates, where it was observed that the spontaneous conversion of unstable six-membered ring phosphates to their most stable six-membered ring phosphate (4d, 6d and 7d to 5d), by a selective C4-O3 bond cleavage, depends on both: the stereochemistry of the aryl group at C4 and the electronic nature of the substituent attached to the P-atom. Thus, we postulated that the anomeric effect weakens the C4-O3 bond within the 1,3,2-dioxaphosphorinane ring, favoring thus their selective cleavage and spontaneous conversion, similarly to the proposed mechanistic mode of action of six-membered ring P-heterocyclic prodrugs.
Cruz-Gregorio
Silvano
S
Centro de Investigación de la Facultad de Ciencias Químicas, BUAP, 14 Sur Esq. San Claudio, San Manuel, 72570, Puebla, México.
Rodriguez-Palacios
Vicente
V
Höpfl
Herbert
H
Quintero
Leticia
L
Sartillo-Piscil
Fernando
F
D008958:Models, Molecular; D008968:Molecular Conformation; D063065:Organophosphonates / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D013237:Stereoisomerism
D063065:Organophosphonates; D010710:Phosphates; D011355:Prodrugs