Synthesis, bioactivation and anti-HIV activity of the bis(4-acyloxybenzyl) and mono(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT

Abstract

To investigate the design of prodrugs of antiviral nucleosides for targeting t o the central nervous system, the bis(4-acyloxybenzyl) esters of the 5'-monophosphate of AZT 5 (R = Me, Et, Pr' or Bur) have been prepared. The reaction of the appropriate bis(4-acyloxybenzyl) N,N-diisopropylphosphoramidite 10 (R = Me, Et, Pri or Bur) with AZT in the presence of 1 H-tetrazole, followed by oxidation of the PI'' intermediate with 3-chloroperoxybenzoic acid gave the required triesters 5 in good yield. The lithium salts of the mono(4-acyloxybenzyl) esters of the 5'-phosphate of AZT 7 (R = Me, Et, Pr' or Bur) were prepared by treatment of the triesters 5 with lithium iodide. In the presence of porcine liver carboxyesterase the triesters 5 and diesters 7 decomposed readily t o the 5'-monophosphate of AZT 9. The anti-HIV activities of the triesters 5 and diesters 7 were, with one exception, comparable t o that of AZT, but the greater cytotoxicity of certain compounds in particular types of cell significantly reduced their selectivity indices.

Comparative Study of Bis(Benzyl)Phosphate Triesters of 2′,3′-Dideoxy-2′,3′-Didehydrothymidine (d4T) andCycloSal-d4TMP — Hydrolysis, Mechanistic Insights and Anti-HIV Activity

“…The 7-ethoxycarbonylmethyl group was introduced by reaction of salicyl aldehyde, α-bromoethylacetat and indium in a Reformatsky-type reaction (Araki et al, 1988). The synthesis of bis(4acetoxybenzyl)-d4TMP 7 was done according to a procedure published before except that acetonitrile has been used in all reactions (Thomson et al, 1993) and triester 8 was prepared using the phosphoramidite/1H-tetrazole strategy. The amidites 11, 12, 19 were prepared from the dichloro-N,N-dialkylaminophosphane and the benzyl alcohols 9, 10, 17.…”

Calcium release activity and metabolism of inositol 1,4,5‐trisphosphate in T cells

“…So, for these inositol polyphosphate analogues to represent potential modulators of T cell activation and growth, they must first be taken up into the cell. Indeed, we are currently examining potential chemical modifications of these compounds which have successfully rendered other cell-impermeable compounds permeable such as 3'-azido-3'-deoxythymidine (AZT) [41]. Thus, these compounds provide a starting point for development of cell-permeable analogues which may be able to modulate cell function in intact cells and be used as manipulative tools with which to further elucidate the function of Ins(1 ,4,5)P3 and Ins(1 ,3,4,5)P4 in T-cell-activation processes.…”

Pro-Nucleotides - Recent Advances in the Design of Efficient Tools for the Delivery of Biologically Active Nucleoside Monophosphates

“…Consequently, they are using bis(4'-acyloxybenzyl)-[bis(AB)] nucleotides 24 and 25, respectively (shown as their AZTMP derivatives) instead of the O-acyloxymethyl or the S-acyl-2-thioethyl residue, respectively. As Freeman calculated a separation of about 4 Å, which she states is enough to avoid electrostatic disturbance of the anionic phosphate and the carboxyester residue (41) . The degradation mechanism of the bis(AB) nucleotides of type 24 is the following: the enzyme cleaves the ester moiety in the 4'-position of the aromatic ring to give This document was downloaded for personal use only.…”

“…Freeman et al applied their approach to the delivery of AZTMP (39,41) and obtained in vitro antiviral activity against HIV-1 and SIV that was comparable to AZT 2. Unfortunately, she has not tested the compounds in thymidine kinase-deficient cells which could prove the direct intracellular delivery of AZTMP 9.…”