124930-59-2Relevant academic research and scientific papers
P-(Alkyl)-nucleoside 5′-hydrogenphosphonates as depot forms of antiviral nucleotide analogues
Khandazhinskaya,Shirokova,Karpenko,Zakirova,Tarussova,Krayevsky
, p. 1795 - 1804 (2000)
P-(Alkyl)esters of AZT 5′-hydrogenphosphonate were synthesized and their stabilities in the phosphate buffer and human serum were evaluated. The esters bearing residues of primary and secondary alcohols were degraded to give AZT, whereas those containing tertiary alkyl groups yielded AZT 5′-hydrogenphosphonate. The corresponding derivatives of d2A and d2T showed the same properties.
Studies on the decomposition pathways of diastereoisomeric mixtures of aryl nucleoside α-hydroxyphosphonates under hydrolytic conditions. Synthesis of α-hydroxyphosphonate monoesters
Szymanska-Michalak, Agnieszka,Stawinski, Jacek,Kraszewski, Adam
experimental part, p. 976 - 983 (2010/08/05)
Decomposition pathways of nucleoside α-hydroxyphosphonates 1 (diastereomeric mixtures) bearing different aryl groups, both in the ester and the hydroxymethine fragment, were investigated under various hydrolytic conditions. We found that in aqueous basic media, the stability and decomposition pathways of these compounds were governed by the electronic features of the aryl group in the hydroxymethine moiety (hydroxyphosphonate ? H-phosphonate diester + aldehyde equilibria) and the nature of attacking nucleophiles (α-nucleophiles, e.g. hypoiodite or peroxide anions). The significant differences observed in the rates of hydrolysis of hydroxyphosphonates 1vs. their O-acylated derivatives point to the importance of an intramolecular acid catalysis exerted by the adjacent hydroxyl function. Based on these findings, an efficient synthetic protocol for otherwise difficult to access hydroxyphosphonate monoesters of type 7 has been developed.
Synthesis of AZT/d4T boranophosphates as anti-HIV prodrug candidates
Lin, Changxue,Fu, Hua,Tu, Guangzhong,Zhao, Yufen
, p. 509 - 516 (2007/10/03)
AZT/d4T phosphonates were synthesized by sequential condensation of AZT/ d4T with the corresponding alcohols or 5′-DMT-thymidine in the presence of pivaloyl chloride. Sequential silylation, boronation, and hydrolysis in ammonium hydroxide of these phosphonates led to anti-HIV prodrug candidates AZT/d4T boranophosphates.
Carbonylbisphosphonate and (diazomethylene)bisphosphonate analogues of AZT 5′-diphosphate
McKenna, Charles E.,Kashemirov, Boris A.,Roze, Christian N.
, p. 383 - 395 (2007/10/03)
A novel nucleotide analogue is described, in which the α,β-phosphoric anhydride oxygen of a nucleoside 5′-diphosphate is replaced by a carbonyl group: the carbonylbisphosphonate analogue 5 of 2′,3′-dideoxy-3′- azidothymidine 5′-diphosphate (AZT 5′-diphosphate). 5 was synthesized from tetramethyl (diazomethylene)bisphosphonate 1 via the trimethyl ester 4 of the corresponding AZT 5′-(diazomethylene)bisphosphonate 6, which is also a new type of nucleotide analogue. The ultimate product 5 was isolated by reverse-phase HPLC, and characterized by 31P, 13C, and 1H NMR; and by high-resolution mass spectrometry. The ketone group of 5 is a visible chromophore (yellow) and reversibly forms a colorless hydrate. The ketone hydrate 'pK' is about 4.2 when excess of magnesium ion is present. The potential of such analogues as novel inhibitors of enzymes mediating nucleotide-dependent biochemical processes is discussed.
Lipophilic &α-Hydroxybenzylphosphonates as Prodrugs of 3'-Azido-2',3'-dideoxythymidine (AZT)
Meier, Chris,Habel, Lothar W.,Balzarini, Jan,Clercq, Eric De
, p. 2195 - 2202 (2007/10/03)
The α-hydroxybenzylphosphonates 1a-1j of the antiviral drug 3'-azido-2',3'-dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49percent to 87percent yield via a four-step synthetic pathway introducing the modifications in the aromatic ring system in the last step by making use of intermediate 6.All compounds 1a-1j exhibited higher partition coefficients in 1-octanol/water than AZT (5).In hydrolysis studies at pH 7.5 we observed that precursors to bioactive compounds were delivered by simple hydrolysis of the lipophilic precursors 1a-1j via two different mechanisms: the phosphonate-phosphate rearrangement leading to the benzylphosphotriesters 2 and/or the direct cleavage into the di-AZT phosphonate 6.Both compounds 2 and 6 were further degraded yielding the potentially antiviral active compounds 4 and 8, respectively.The hydrolysis pathway could be controlled by the substitution pattern in the benzylic moiety.Identical hydrolytic behavior of 1 was detected in "biological" hydrolysis kinetics by using a RPMI culture medium containing 10percent heat-inactivated fetal calf serum (FCS).The title compounds 1a-1j exhibited considerable HIV-1 and HIV-2 activity in wild-type CEM/O cells. - Keywords: AZT; Nucleoside α-hydroxybenzylphosphonates; Phosphonate-phosphate rearrangement; Prodrugs; HIV chemotherapy
