Symmetrical diamidate prodrugs of nucleotide analogues for drug delivery

The use of pronucleotides to circumvent the well-known drawbacks of nucleotide analogs has played a significant role in the area of antiviral and anticancer drug delivery. Several motifs have been designed to mask the negative charges on the phosphorus moiety of either nucleoside monophosphates or nucleoside phosphonates, in order to increase their hydrophobicity and allow entry of the compound into the cell. Among them the bis-amidate analogs, having two identical amino acids as masking groups through a P–N bond, represent a more recent approach for the delivery of nucleotide analogs, endowed with antiviral or anticancer activity. Different synthetic strategies are commonly used for preparing phosphorodiamidates of nucleosides. In this protocol, we would like to focus on the description of the synthetic methodology that in our hand gave the best results using 2′-3′-didehydro-2′-3′-dideoxythymidine (d4T, Stavudine) as model nucleoside. A second strategy for preparing diamidates of nucleoside phosphonates will be reported using {[2-(6-amino-9 H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA, adefovir) as model substrate

Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives

Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents

Phosphate derivatives of AZT display enhanced selectivity of action against HIV1 by comparison to the parent nucleoside

AbstractNovel phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. In particular, phosphates carrying ester-containing side-chains are described. These materials are designed to act as membrane-soluble pro-drugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective antiviral activity. In several cases the phosphate derivatives are more selective in their action than the parent nucleoside AZT. In particular, this arises from the low toxicity of the phosphate pro-drugs by comparison to AZT. These data support the suggestion that the phosphate derivatives exert their biological effects via intracellular release of the nucleotide forms, and suggests that such pro-drug, forms may be worthy of further study

Diastereoselective synthesis of P-chirogenic phosphoramidate prodrugs of nucleoside analogues (ProTides) via copper catalysed reaction

The first copper-catalysed diastereoselective synthesis of P-chiral phosphoramidate prodrugs (ProTides) is reported. This procedure allows the synthesis of diastereomeric-enriched mixtures of ProTides. Application of this methodology to the asymmetric phosphorylation of purine and pyrimidine nucleoside analogues is presented

Maternal Vitamin D levels and the risk of perinatal death

Objective: To determine the association between maternal vitamin D levels and perinatal death. Methods: A retrospective cross-sectional study of all non-anomalous, singleton births (≥24 weeks) with perinatal death compared to a matched control group. Only pregnancies with a recorded vitamin D level at booking (8–19 weeks gestation) were included for analysis. Maternal vitamin D levels were categorized into normal, deficient and insufficient cohorts and variables compared between the three groups. Results: There were 31 perinatal deaths which were compared to 111 controls. Median vitamin D levels were lower in the perinatal death cohort compared to the control group (55 nmol/L versus 64 nmol/L, p = 0.43). There was no significant increase in deaths between the normal and deficient (p = 0.33) or insufficient (p = 0.09) groups. Conclusions: Low maternal vitamin D levels at booking were not associated with an increased risk of perinatal demise

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

Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides).

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3'- and 2'-fluorinated ProTides following different radiosynthetic approaches. The 3'-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15-30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2'-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1-5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min)

Interventions for preventing falls in people with multiple sclerosis.

This is a protocol for a Cochrane Review (Intervention). The aim of this review is to evaluate the effectiveness of interventions designed to reduce the rate of falls in people with multiple sclerosis (MS). Specific objectives include comparing the effectiveness of single, multiple and multifactorial interventions designed to reduce the rate of falls in people with MS

Synthesis and biological evaluation of bicalutamide analogues for the potential treatment of prostate cancer

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and O-acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue (16) was the most active compound with IC50 = 6.59–10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts