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Synthesis and in vitro esterase‐mediated metabolism of phosphoserine aryloxy triester phosphoramidates. A. Synthesis of a phosphoserine aryloxy triester phosphoramidate (8). B. Mechanism of aryloxy triester phosphoramidates metabolism. C. ³¹P NMR in vitro enzymatic assay of the breakdown of the phosphoserine phosphoramidate by carboxypeptidase Y.
Source publication
The specific targeting of protein‐protein interactions by phosphoserine‐containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as...
Citations
... The spectroscopic analyses confirmed the structures of the newly synthesized compounds, which were subsequently evaluated in vitro for their ability to inhibit the pancreatic α-amylase enzyme. [58] Miccoli et al. [59] developed a method in 2020 for the synthesis of phosphoserine with aryloxy triester phosphoramidate masking groups. The synthetic approach involved protecting the N-and C-terminals of phosphoserine to enable selective addition of the aryloxy triester phosphoramidate group to the hydroxyl side chain. ...
Organophosphorus compounds (OPs) are a diverse group of chemical compounds that contain organic moieties directly bonded to phosphorus or through a heteroatom like oxygen, nitrogen, or sulfur. They are ubiquitous in the human environment due to their unique properties and high biological activity. OPs have been widely used in various fields such as agriculture (as pesticides), industry (for producing lubricants, hydraulic fluids, and plastics), medicine (as drugs against osteoporosis, anticancer, and antiviral compounds), and veterinary (as anthelmintics). As an important class of organophosphorus compounds, this review provides an overview of phosphoramidate compounds covering their synthetic pathways, a brief explanation of their mechanisms, and their various applications.
... Our objective was to study the impact of the overall charge of the trackable therapeutic agent (or theranostic) on its biological properties. Indeed, it has been shown that it can have an impact on the cellular uptake [47], the mode of transport in the cells [48], etc. At physiological pH, azaBODI-Au-1 possesses two positive charges (two ammonium arms), azaBODI-Au-2 can be charged 4þ (two ammonium arms and protonation of the two NMe 2 groups brought by the thiolato ligand), and azaBODI-Au-3 is neutral (two ammonium arms and two negative charges brought by the two sulfonates). ...
Three near-infrared (NIR-I) optical theranostic systems were synthesized, characterized and studied in vitro and in vivo. These original homo-bimetallic gold(I)-based aza-BODIPY complexes proved to be trackable through near-infrared optical imaging in cells and in mice. They display anti-proliferative properties in micromolar range against human and murine cancer cell lines (4T1, MDA-MB-231, CT26, and SW480). Moreover, the injection of the most promising theranostic agent in CT26 tumor-bearing BALB/c mice induced a significant anti-cancer activity.
This annual review of the literature provides a comprehensive and critical survey of a vast field of study involving organophosphorus compounds, ranging from phosphines, their chalcogenide derivatives and phosphonium salts, phosphorus (III) acid derivatives, phosphorus (V) acids, penta- and hexa-coordinated phosphorus compounds, phosphazenes and related phosphorus-nitrogen bonded compounds. Coverage in applications as reagents in green synthetic procedures is also given. With an emphasis on interdisciplinary content, this book will appeal to the worldwide organic chemistry and engineering research communities.
Phosphorus‐based self‐immolative (SI) linkers offer a wide range of applications, such as smart materials and drug‐delivery systems. Phosphorus SI linkers are ideal candidates for double‐cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1 day to 2 hours or 5 minutes, as shown for linkers containing p‐fluoro phenol. In turn, double cargo linkers bearing p‐methyl phenol released their cargo more slowly (4 days, 4 hours, and 15 minutes) than their p‐fluoro analogues. The α‐hydroxyisobutyrate linker released both cargos in 25 minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.
Introduction
The ProTide technology is a phosphate (or phosphonate) prodrug method devised to deliver nucleoside monophosphate (or monophosphonate) intracellularly bypassing the key challenges of antiviral and anticancer nucleoside analogues. Three new antiviral drugs, exploiting this technology, have been approved by the FDA while others are in clinical studies as anticancer agents.
Areas covered
The authors describe the origin and development of this technology and its incredible success in transforming the drug discovery of antiviral and anticancer nucleoside analogues. As evidence, discussion on the antiviral ProTides on the market, and those currently in clinical development is included. The authors focus on how the proven capacity of this technology to generate new drug candidates has stimulated its application to non-nucleoside-based molecules.
Expert opinion
The ProTide approach has been extremely successful in delivering blockbuster antiviral medicines and it seems promising in oncology. Its application to non-nucleoside-based small molecules is recently emerging and proving effective in other therapeutic areas. However, investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies to identify the appropriate phosphoramidate motifs depending on the parent molecule are in our opinion mandatory for the future development of these compounds.
