Nucleosided derived antibiotics to fight microbial drug resistance: New utilities for an established class of drugs?

Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Nucleoside analogues have also been shown to target many other bacterial and fungal cellular processes although these are not well characterized and may therefore represent opportunities to discover new drugs with unique mechanisms of action. In this Perspective, we demonstrate that nucleoside analogues, cornerstones of anticancer and antiviral treatments, also have great potential to be repurposed as antibiotics so that an old drug can learn new tricks

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

λ5-Phosphorus-Containing α-Diazo Compounds (PCDCs): a valuable tool for accessing phosphorus-functionalized molecules

The compounds characterized by the presence of a λ5-phosphorus functionality at the α-position with respect to the diazo moiety, here referred to as λ5-phosphorus-containing α-diazo compounds (PCDCs), represent a vast class of extremely versatile reagents in organic chemistry and are particularly useful in the preparation of phosphonate- and phosphinoxide-functionalized molecules. Indeed, thanks to the high reactivity of the diazo moiety, PCDCs can be induced to undergo a wide variety of chemical transformations. Among them are carbon–hydrogen, as well as heteroatom–hydrogen insertion reactions, cyclopropanation, ylide formation, Wolff rearrangement, and cycloaddition reactions. PCDCs can be easily prepared from readily accessible precursors by a variety of different methods, such as diazotization, Bamford–Stevens-type elimination, and diazo transfer reactions. This evidence along with their relative stability and manageability make them appealing tools in organic synthesis. This Review aims to demonstrate the ongoing utility of PCDCs in the modern preparation of different classes of phosphorus-containing compounds, phosphonates, in particular. Furthermore, to address the lack of precedent collective papers, this Review also summarizes the methods for PCDCs preparatio

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

Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy

Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC50 =0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK-) VZV strains (EC50 = 0.47 and 0.2 μM, respectively) and HCMV (EC50 = 3.5-7.2 μM) without any cytotoxicity (CC50 >100)

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents

[Review of] Stanley David Lyman. Wounded Knee, 1973: A Personal Account

Wounded Knee, 1973: A Personal Account, by Stanley David Lyman, must be taken for what it is. Written in diary form, Lyman\u27s narrative of the seventy-one day armed siege on the Pine Ridge Reservation in South Dakota offers an insider\u27s view of the events known as Wounded Knee II; albeit an inaccurate account of the facts

Synthesis of atropisomeric 2,2'-disubstituted-3,3'-quinazolin-4,4'-diones and their application in asymmetric synthesis

This thesis reports all the efforts made in the synthesis of 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ), a new class of atropisomeric molecules derived from the 4-quinazolinone scaffold, and their potential application as chiral auxiliaries in asymmetric synthesis. Chapter 1 provides first an overview of axial chirality and atropisomerism and then it reports a review of asymmetric reactions such as Diels-Alder, 1,3-dipolar cycloaddition, epoxydation and cyclopropanation, which have been used in literature as a model for the development of new chiral auxiliaries and chiral ligands. Chapter 2 describes first the synthesis of a series of 2-substituted benzoxazinones and 3-amino-2-substitute-quinazolinones units. Then the successful synthesis of racemic symmetrical and unsymmetrical 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ) by condensation of benzoxazinones and aminoquinazolinones units is presented. Chapter 3 presents the design and synthesis of chiral non racemic unsymmetrical and symmetrical biquinazolinones. Once chirality has been introduced via the functionalization of 3-aminoquinazolinone with non-racemic amino acids, the corresponding unsymmetrical biquinazolines were produced using the same methodology previously adopted for the racemic unsymmetrical biquinazolinones. Chapter 4 highlights the unexpected synthesis of 4-isopropyl-3-oxo-l,9a,10- triazaanthracen-9-ones. Full characterization of this new heterocyclic compound is herein reported together with the development of an efficient methodology (good to high yield, no chromatographic purification) for the synthesis of other members of this novel class of compounds. Chapter 5 first presents all the attempts performed for the functionalization of symmetrical 2, 2'-methyl- and 2,2'-ethyl-biquinazolinones via carbanionic chemistry. Lithiation of 2,2'-dimethyl-3,3'-biquinazolinone, and further reaction with aromatic aldehydes led to the corresponding styryl derivates. These compounds were used as a prochiral starting materials in diastereoselective reactions like epoxydation, Diels-Alder, 1,3-dipolar cycloaddition and cyclopropanations in order to assess the efficiency of the biquinazolinones as chiral auxiliaries.EThOS - Electronic Theses Online ServiceGBUnited Kingdo