Alkyl Hydrogen Phosphonate Derivatives of the anti-HIV Agent AZT may be Less Toxic than the Parent Nucleoside Analogue

McGuigan, Christopher; Bellevergue, Patrice; Jones, Bryan C. N. M.; Mahmood, Naheed; Hay, Alan J.; Petrík, Juraj; Karpas, Abraham

doi:10.1177/095632029400500409

Cited by 10 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A series of alkyl, i.e., ethyl, isopropyl, and tert-butyl, masked 5′-O-phosphate ester derivatives (7−9) was synthesized to evaluate their effects on the well-characterized cardioprotective effect of 1. 10 In addition, various other modifications on the atoms of the 5′-O-phosphate group of reference compound 1, such as dideutero (10), thioate (11,12), and dithioate (13), have been made in the form of diethyl esters. Finally, we also decided to evaluate the cardioprotective ability of ester analogues 14, 15, and 16 of phosphonate derivatives 2, 6, and 3, respectively.…”

Section: ■ Resultsmentioning

confidence: 99%

“…However, model studies of phosphotriesters and phosphonate diesters have shown that simple esters similar to our uncharged alkyl esters are not readily cleaved in vivo . 11–14 Therefore, we examined the stability of representative nucleotide derivatives under biological conditions. Consistently, we were unable to demonstrate any hydrolysis of phosphonate diesters 14 and 16 under various conditions of pH extremes (1 and 11) and the presence of rat plasma or liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

“…In our case, internalization into the cell is undesirable because the P2X receptors are ion channels on the surface that are stimulated by extracellular ligands. However, model studies of phosphotriesters and phosphonate diesters have shown that simple esters similar to our uncharged alkyl esters are not readily cleaved in vivo. − Therefore, we examined the stability of representative nucleotide derivatives under biological conditions. Consistently, we were unable to demonstrate any hydrolysis of phosphonate diesters 14 and 16 under various conditions of pH extremes (1 and 11) and the presence of rat plasma or liver microsomes. − Thus, we have no evidence that the protected esters are acting in vivo as prodrugs of the charged derivatives, although we have not examined stability in the presence of cardiac and other tissues.…”

Section: Discussionmentioning

confidence: 99%

“…R f = 0. (11). To a solution containing nucleoside 28 (7.0 mg, 13.9 μmol) in MeOH and H 2 O (2 mL, 1:1, v/v) was added Dowex-50 resin (∼50 mg).…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

See 3 more Smart Citations

5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

et al. 2013

View full text Add to dashboard Cite

Activation of a cardiac myocyte P2X4 receptor protects in heart failure. 5’-Phosphonate and 5’-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a mini-osmotic pump in a mouse ischemic heart failure model; most significantly increased intact heart contractile function (echocardiography) compared to vehicle-infusion. Several new thio and deuterated phosphate derivatives were protective in a calsequestrin (CSQ)-overexpressing heart failure model. Diethyl (7, MRS4084) and diisopropyl (8, MRS4074) phosphotriesters were highly protective in the ischemic model. Substitution of 2-Cl with iodo reduced protection in the CSQ model. Diisopropyl ester 16 (MRS2978) of (1’S,2’R,3’S,4’R,5’S)-4’-(6-amino-2-chloropurin-9-yl)-2’,3’-(dihydroxy)-1’-(phosphonoethylene)-bicyclo[3.1.0]hexane was highly efficacious (CSQ), while lower homologue 1’-phosphonomethylene derivative 14 was inactive. Thus, we identified uncharged carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure, suggesting this as a viable and structurally broad approach.

show abstract

Section: ■ Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…R f = 0. (11). To a solution containing nucleoside 28 (7.0 mg, 13.9 μmol) in MeOH and H 2 O (2 mL, 1:1, v/v) was added Dowex-50 resin (∼50 mg).…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

See 2 more Smart Citations

5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

et al. 2013

View full text Add to dashboard Cite

show abstract

“…However, when phosphazide was later tested on three different cell lines (MT-4, CE M-SS and CE M-X 174), its activity was found to be lower than that of AZT by almost an order of magnitude [20]. It was reported in another paper [21] that the anti-HIV activity of compound 1 in the cell cultures C8 and JM was 10–20 times higher vs. that of AZT. Contrariwise, according to [22], the selectivity indices of H-phosphonate 1 were 1.5 and 15 times higher than those of AZT (IIIB and HXB2 strains of HIV in blood mononuclear cells were used).…”

Section: Nikavir (Phosphazide) the First Achievement In Designing Dementioning

confidence: 99%

AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection

Khandazhinskaya

Shirokova

2013

Acta Naturae

View full text Add to dashboard Cite

Despite the numerous drawbacks, 3’-azido-3’-deoxythymidine (AZT, Zidovudine, Retrovir) remains one of the key drugs used in the treatment and prevention of HIV infection in both monotherapy and HAART. A strategy in searching for new effective and safe AZT agents among latent (depot) forms of AZT has yielded its first positive results. In particular, the sodium salt of AZT 5’-H-phosphonate (Nikavir, phosphazide) has demonstrated clinical advantages over parent AZT: first and foremost, lower toxicity and better tolerability. It can be effectively used for the prevention of vertical transmission from mothers to babies and as an alternative drug for HIV-infected patients with low tolerance to Zidovudine. Preclinical studies of another phosphonate, AZT 5’-aminocarbonylphosphonate, have demonstrated that it releases AZT when taken orally. Pharmacokinetic studies have shown a prolonged action potential. Based on the analysis of both toxicological and pharmacological data, AZT 5’-aminocarbonylphosphonate has been recommended for clinical trials.

show abstract

Lipophilic α‐hydroxybenzylphosphonates as prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine (AZT)

et al. 1995

View full text Add to dashboard Cite

The a-hydroxybenzylphosphonates 1 a-l j of the antiviral drug 3'-azido-2',3'-dideoxythymidine 5 (AZT) as potential lipophilic prodrugs were readily accessible in 49% to 87 YO 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 l a -l j 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 l a -l j 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 10 % heat-inactivated fetal calf serum (FCS). The title compounds la-1 j exhibited considerable HIV-1 and HIV-2 activity in wild-type CEM/O cells.Today, the most successful therapy against retroviral infections such as AIDS is based on the use of analogs of natural nucleosides [']. Most of these nucleoside analogs are 2',3'-dideoxynucleosides (e.g. 3'-azido-2',3'-dideoxythymidine (AZT)n). The mode of action of these nucleoside analogs is the inhibition of the replicating enzyme of HIV, reverse transcripta~e [~,~] or the incorporation into the growing DNA chain which results in chain terminati~n [~]. Hence, in order to develop their biological activity, the nucleoside analogs have to be metabolized into their 5'-triphosphate derivatives inside the infected cell. This biotransformation is effected by host cell kinases in three steps via the nucleoside monophosphate and the nucleoside diphosphateI2I. Some nucleoside analogs are known to be suitable inhibitors of the reverse transcriptase in vitro when used as the triphosphates, but are not active in vivo because no phosphorylation occurs [5]. In most cases the first kinase step leading to the monophosphate is the metabolization determining step. So by-passing this kinase by releasing monophosphorylated nucleosides from a prodrug is one attempt to improve the therapeutic potential of the drugsL6I. The advantage of a prodrug is obvious, because also non-active analogs such as 2',3'-dideoxyuridine (ddU) could be used in antiviral chemotherapy. A prodrug for that purpose has to fulfill two requirements: i) it has to be lipophilic for passive membrane diffusion and it has to be transported through the blood brain barrier; ii) furthermore, it should be able to deliver the nucleoside monophosphate spontaneously or enzymatically leaving a non-toxic masking group. Lipophilic nucleoside phosphoric acid triesters were studied with the purpose of releasing bioactive, phosphorylated compounds by hydrolytical or en...

show abstract

Alkyl Hydrogen Phosphonate Derivatives of the anti-HIV Agent AZT may be Less Toxic than the Parent Nucleoside Analogue

Cited by 10 publications

References 25 publications

5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

5′-Phosphate and 5′-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection

Lipophilic α‐hydroxybenzylphosphonates as prodrugs of 3′‐azido‐2′,3′‐dideoxythymidine (AZT)

Contact Info

Product

Resources

About