Phosphonate Analogues Research Articles

ChemInform Abstract: Synthesis of Novel Difluoro‐Cyclopropyl Guanine Nucleosides and Their Phosphonate Analogues as Potent Antiviral Agents.

AbstractNovel phosphonate (XIII) demonstrates promising anti‐HIV‐1 activity in vitro, whilst new nucleoside analogue (XIV) displays moderate antiviral activity against human cytomegalovirus in MRC cells.

ChemInform Abstract: Synthesis of Novel 6′‐Spirocyclopropyl‐5′‐norcarbocyclic Adenosine Phosphonic Acid Analogues as Potent anti‐HIV Agents.

AbstractThe new spirocyclopropyl nucleoside analogue (XI) and its SATE thioester prodrug (XIII) show promising anti‐HIV activity.

ChemInform Abstract: Design and Synthesis of Carbocyclic Versions of Furanoid Nucleoside Phosphonic Acid Analogues as Potential anti‐HIV Agents.

AbstractNucleoside phosphonate analogue (VIII) and its SATE prodrug (X) display significant antiviral activity against HIV in vitro.

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

Considerable attention has been focused on the development of phosphonate-containing drugs for application in many therapeutic areas. However, phosphonate diacids are deprotonated at physiological pH and thus phosphonate-containing drugs are not ideal for oral administration, an extremely desirable requisite for the treatment of chronic diseases. To overcome this limitation several prodrug structures of biologically active phosphonate analogues have been developed. The rationale behind the design of such agents is to achieve temporary blockade of the free phosphonic functional group until their systemic absorption and delivery, allowing the release of the active drug only once at the target. In this paper, an overview of acyclic and cyclic nucleoside phosphonate prodrugs, designed as antiviral agents, is presented.

Synthesis of 5-Substituted 2′-Deoxyuridine-5′- Phosphonate Analogues and Evaluation of their Antiviral Activity

A small series of 5-(hetero)aryl-modified nucleoside phosphonates was synthesized via an 8-step procedure including a Wittig reaction and Suzuki–Miyaura coupling. An unanticipated anomerization during phosphonate deprotection allowed us to isolate both anomers of the 5-substituted 2′-deoxy-uridine phosphonates and assess their antiviral activity against a broad panel of viruses.

Synthesis and P2Y2 receptor agonist activities of uridine 5′-phosphonate analogues

We explored the influence of modifications of uridine 5′-methylenephosphonate on biological activity at the human P2Y2 receptor. Key steps in the synthesis of a series of 5-substituted uridine 5′-methylenephosphonates were the reaction of a suitably protected uridine 5′-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki–Miyaura coupling. These analogues behaved as selective agonists at the P2Y2 receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y2 receptor.

Design and Synthesis of Novel 1′,3′-Dioxolane 5′-Deoxyphosphonic Acid Purine Analogues as Potent Antiviral Agents

Electronic parameters of 1′,3 ′-oxygen play significant roles in steering the conformation of nucleoside phosphonic acid analogues. To investigate the relationship of two oxygen atoms with antiviral enhancement, novel 1′,3 ′-dioxolane 5 ′-deoxyphosphonic acid purine analogues were synthesized via de novo acyclic stereoselective route from acrolein and glycolic acid. The synthesized nucleoside phosphonic acid analogues 14 and 19 were subjected to antiviral screening against several viruses, such as HIV-1, HSV-1, HSV-2, and HCMV. The guanine analogue 19 exhibits in vitro anti-HIV-1 activity similar to that of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) in MT-4 cells.

Synthesis and P2Y2 receptor agonist activities of uridine 5′-phosphonate analogues

Synthesis and P2Y2 receptor agonist activities of uridine 5′-phosphonate analogues

Triazole phosphohistidine analogues compatible with the Fmoc-strategy

Phosphorylation of histidine is essential for bacterial two-component signalling; its importance to modulation of eukaryotic protein function remains undefined. Until recently, no immunochemical probes of this post-translational modification existed, however triazole phosphonate analogues of this modified amino acid have now been applied to the generation of site-specific antibodies. The protecting group strategy used in the original report is incompatible with standard protocols for Fmoc-solid phase peptide synthesis. In this paper, we report the application of P(III) chemistry to generate the complementary dibenzyl and di-tert-butyl phosphonate esters. These forms of the triazole analogue are fully compatible with standard Fmoc-SPPS and are therefore ideal for wider application by the chemical and biochemical community.

Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

Although the role of the 2-oxoglutarate dehydrogenase complex (2-OGDHC) has previously been demonstrated in plant heterotrophic tissues its role in photosynthetically active tissues remains poorly understood. By using a combination of metabolite and transcript profiles we here investigated the function of 2-OGDHC in leaves of Arabidopsis thaliana via use of specific phosphonate inhibitors of the enzyme. Incubation of leaf disks with the inhibitors revealed that they produced the anticipated effects on the in situ enzyme activity. In vitro experiments revealed that succinyl phosphonate (SP) and a carboxy ethyl ester of SP are slow-binding inhibitors of the 2-OGDHC. Our results indicate that the reduced respiration rates are associated with changes in the regulation of metabolic and signaling pathways leading to an imbalance in carbon-nitrogen metabolism and cell homeostasis. The inducible alteration of primary metabolism was associated with altered expression of genes belonging to networks of amino acids, plant respiration, and sugar metabolism. In addition, by using isothermal titration calorimetry we excluded the possibility that the changes in gene expression resulted from an effect on 2-oxoglutarate (2OG) binding to the carbon/ATP sensing protein PII. We also demonstrated that the 2OG degradation by the 2-oxoglutarate dehydrogenase strongly influences the distribution of intermediates of the tricarboxylic acid (TCA) cycle and the GABA shunt. Our results indicate that the TCA cycle activity is clearly working in a non-cyclic manner upon 2-OGDHC inhibition during the light period.

Synthesis and antitumour activity of inositol phosphonate analogues

Inositol phosphates regulate important biological functions in intracellular signal transduction events. Phosphonates, because of the stability towards the action of phosphatases, were extensively used to replace phosphates. We herein reported the synthesis of inositol phosphonate analogues using myo-inositol as the starting material, and found that two of phosphonate analogues exhibited relative good cytotoxic activity against non-small cell lung cancer (NSCLC) cell line A549.

Structural Insights into the Inhibition of Cytosolic 5′-Nucleotidase II (cN-II) by Ribonucleoside 5′-Monophosphate Analogues

Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5′-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues.

Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX

VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC(50) of 0.48-8.21mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.

Synthesis of Novel Difluoro-Cyclopropyl Guanine Nucleosides and Their Phosphonate Analogues as Potent Antiviral Agents

The synthesis of new rigid guanine analogues with anti-HIV-1 and anti-herpes viral activities is described. The phosphonate of difluorocyclopropane nucleoside analogue 26 exhibits in vitro anti-HIV-1 activity similar to that of PMEA in MT-4 cells. Further, analogue 20 shows moderate anti-HCMV activity in MRC cells.

A Novel Synthesis of Anionic Heterogemini Surfactants Containing COOH, SO3H and PO(OH)2 Headgroups from Corynomicolic Acid and its Derivatives

Abstract Anionic heterogemini surfactants with –COOH, –SO3H and –PO(OH)2 headgroups in combination were synthesized from Corynomicolic acid derivatives having R = C11H23. The –SO3H headgroup was obtained by the successive conversion of OH → OMs → SCN → SH → –SO3H. The PO(OH)2 headgroup was introduced by the conjugate-addition to E-isomer of α,β-unsaturated ester derived from Corynomycolic acid ester. Heterogemini surfactant with –SO3H and –PO(OH)2 headgroups was also synthesized from phosphonate analog of Corynomycolic acid. The stereoisomers (syn- and anti-isomers) of heterogemini surfactants were separately prepared except for heterogemini surfactants with –COOH and –PO(OH)2 headgroups. Effects of variation and stereochemistry of two anionic headgroups on their surfactant properties were also studied on the basis of surface tension measurements.

Design and Synthesis of Carbocyclic Versions of Furanoid Nucleoside Phosphonic Acid Analogues as Potential Anti-Hiv Agents

Novel 5′-norcarbocyclic adenine and guanine phosphonic acid analogues with 6′,6′-difluorine moiety were designed and synthesized from commercially available epichlorohydrin 5. A regioselective Mitsunobu reaction successfully proceeded from an allylic functional group 16b at low reaction temperature in polar cosolvent to give purine phosphonate analogues 17 and 24, respectively. The purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening against HIV-1. Adenine analogue 21 and its SATE prodrug 29 show significant anti-HIV activity in MT-4 cell lines.

Synthesis of Novel 6′-Spirocyclopropyl-5′-Norcarbocyclic Adenosine Phosphonic Acid Analogues as Potent Anti-Hiv Agents

Novel 5′-norcarbocyclic adenosine phosphonic acid analogues with 6′-electropositive moiety such as spirocyclopropane were designed and synthesized from the commercially available diethylmalonate 5. Regioselective Mitsunobu reaction proceeded in the presence of an allylic functional group at a low reaction temperature in polar cosolvent [dimethylformamide (DMF)/1,4-dioxane] to give purine analogue 15. To improve cellular permeability and enhance the anti-human immunodeficiency virus (HIV) activity of this phosphonic acid, a SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 18–21 and 23 were subjected to antiviral screening against HIV-1.

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Racemic Synthesis of Novel 6'-Methylene-5'-norcarbocyclic Purine Phosphonic Acid Analogues via Mitsunobu Reaction

E-mail: hongjh@chosun.ac.krReceived June 2, 2011, Accepted June 29, 2011Novel 5'-norcarbocyclic adenine and guanine phosphonic acid analogues with 6'-electronegative moiety suchas unsaturated C-C bond were designed and synthesized from commercially available 2-methylene-propane-1,3-diol (4). Regioselective Mitsunobu reaction successfully proceeded from an allylic functional group (±)-12b at low reaction temperature in polar cosolvent (DMF/1,4-dioxane) to give purine phosphonate analogues(±)-13 and (±)-20. The purine nucleoside phosphonate and phosphonic acid analogues were subjected toantiviral screening against HIV-1. Guanine analogue (±)-23 shows significant anti-HIV activity in PBM celllines (EC

Synthesis of Methylenebis(Phosphonate) Analogues of 2-, 4-, and 6-Pyridones of Nicotinamide Adenine Dinucleotide

The synthesis of metabolically stable methylenebis(phosphonate) analogues of 2-, 4-, and 6-pyridones of nicotinamide adenine dinucleotide (NAD) is reported. In contrast to natural pyrophosphates, these NAD analogues are able to penetrate the cell membrane and can be used as probes in cellular assays.