Synthesis of new nucleoside phosphoraziridines as potential site-directed antineoplastic agents

Abstract

With the aim of increasing the selectivity of the 2,2-dimethylphosphoraziridine type antitumor agents toward the intracellular site of DNA synthesis, a series of new compounds was synthesized in which the reactive bis(2,2-dimethyl-1-aziridinyl)phosphinyl (2,2-DMAP) group was linked through a carbamate or amide linkage to thymidine or cytosine nucleoside moieties. The 3'- and 5'-(2,2-DMAP)carbamates of thymidine (1 and 2) were found to be highly unstable, therefore the corresponding O-acetyl derivatives 5 and 6 were prepared by reacting 5'- and 3'-acetylthymidine, respectively, with dichloroisocyanatophosphine oxide followed by the addition of 2,2-dimethylaziridine and triethylamine. The 3'- and 5'-(2,2-DMAP)amides of thymidine 14 and 15 were prepared by reacting the appropriate thymidinylamines with bis(2,2-dimethyl-1-aziridinyl)phosphinyl chloride (17). The N4-(2,2-DMAP)amides of cytidine, 2'-deoxycytidine, and cytosine arabinoside (18, 19, and 20, respectively) were prepared by reacting the hydrochlorides of the O-peracetylated cytosine nucleosides with triethylamine and POCl3 and, subsequently, with 2,2-dimethylaziridine and triethylamine, to give the corresponding N4-(2,2-DMAP)cytosine nucleoside peracetates 21, 22, and 23, respectively, which were then deacetylated by aminolysis. However, the peacetate intermediates were found to be more stable and, probably for the same reason, also more active against P388 leukemia in mice than the deacetylated products. Particularly, 22 and 23 showed sufficient activity in this in vivo assay system to warrant further evaluation. The relationships between the antitumor activities, the chemical alkylating activities, and the cholinesterase inhibitory activities of these agents are discussed.

Synthesis, Physicochemical and Pharmacokinetic Studies of Potential Prodrugs of β-L-2′-Deoxycytidine, a Selective and Specific Anti-HBV Agent

“…The desired compound was recrystallized from ethanol (0.91 g, 78%); mp 192-193°C [lit. 187-189°C for the D-enantiomer (Breiner et al, 1990) . Acetic anhydride (0.20 ml, 2.20 mmol) was added to a suspension of β-L-dC (Pierra et al, 2000) (0.41 g, 1.83 mmol) in dry N,Ndimethylformamide (DMF, 9.2 ml) and the mixture was stirred at room temperature for 24 h (Bhat et al, 1989).…”

“…Selective N-or O-acylations of β-L-dC and preparation of the N 4 -substituted imine derivative were accomplished following similar procedures as those previously developed for the preparation of the corresponding D-enantiomer counterparts (Figure 2) (Bhat et al, 1989;Breiner et al, 1990;Kerr & Kalman, 1994).…”

“…Selective N-or O-acylations of β-L-dC and preparation of the N 4 -substituted imine derivative were accomplished following similar procedures as those previously developed for the preparation of the corresponding D-enantiomer counterparts (Figure 2) (Bhat et al, 1989;Breiner et al, 1990;Kerr & Kalman, 1994). When evaluated against human immunodeficiency virus (HIV), yellow fever virus (YFV) and bovine viral diarrhoea virus (BVDV) replication in cell-based assays (La Colla, manuscript in preparation), none of them showed cytotoxicity or antiviral activity at the highest concentration tested (100 µM, data not shown).…”

“…13.48 mmol) in glacial acetic acid (4.8 ml) was stirred at room temperature for 10 min, then dry chloroform (3.5 ml) was added and the stirring continued for 24 h (Breiner et al, 1990). The solution was evaporated under reduced pressure and coevaporated with ethanol.…”

“…The desired compound was recrystallized from ethanol (0.91 g, 78%); mp 192-193°C [lit. 187-189°C for the D-enantiomer (Breiner et al, 1990)…”