Overview of Biologically Active Nucleoside Phosphonates

The use of the phosphonate motif featuring a carbon-phosphorous bond as bioisosteric replacement of the labile P–O bond is widely recognized as an attractive structural concept in different areas of medicinal chemistry, since it addresses the very fundamental principles of enzymatic stability and minimized metabolic activation. This review discusses the most influential successes in drug design with special emphasis on nucleoside phosphonates and their prodrugs as antiviral and cancer treatment agents. A description of structurally related analogs able to interfere with the transmission of other infectious diseases caused by pathogens like bacteria and parasites will then follow. Finally, molecules acting as agonists/antagonists of P2X and P2Y receptors along with nucleotidase inhibitors will also be covered. This review aims to guide readers through the fundamentals of nucleoside phosphonate therapeutics in order to inspire the future design of molecules to target infections that are refractory to currently available therapeutic options

Phosphonomethyl Oligonucleotides as Backbone-Modified Artificial Genetic Polymers

Although several synthetic or xenobiotic nucleic acids (XNAs) have been shown to be viable genetic materials in vitro, major hurdles remain for their in vivo applications, particularly orthogonality. The availability of XNAs that do not interact with natural nucleic acids and are not affected by natural DNA processing enzymes, as well as specialized XNA processing enzymes that do not interact with natural nucleic acids, is essential. Here, we report 3′–2′ phosphonomethyl-threosyl nucleic acid (tPhoNA) as a novel XNA genetic material and a prime candidate for in vivo XNA applications. We established routes for the chemical synthesis of phosphonate nucleic acids and phosphorylated monomeric building blocks, and we demonstrated that DNA duplexes were destabilized upon replacement with tPhoNA. We engineered a novel tPhoNA synthetase enzyme and, with a previously reported XNA reverse transcriptase, demonstrated that tPhoNA is a viable genetic material (with an aggregate error rate of approximately 17 × 10–3 per base) compatible with the isolation of functional XNAs. In vivo experiments to test tPhoNA orthogonality showed that the E. coli cellular machinery had only very limited potential to access genetic information in tPhoNA. Our work is the first report of a synthetic genetic material modified in both sugar and phosphate backbone moieties and represents a significant advance in biorthogonality toward the introduction of XNA systems in vivo

Uncommon Three-, Four-, and Six-Membered Nucleosides

Over the past two decades, nucleoside analogues exhibiting uncommon sugar moieties rather than natural ribo‐ and 2′‐deoxyribofuranose rings have received growing attention because of the increased recognition of their various biological roles. In particular, countless reports have been published that describe the value of ring‐contracted analogues based on a three or four‐membered pseudo‐sugar unit in the treatment of viral infections. Within this latest context, the pursuit of carbocyclic nucleosides structurally related to natural furanose units has been driven by their distinguishing stability toward chemical and metabolic degradation, due to the absence of an anomeric center. In an effort to generate more effective therapeutics through modifications of the carbohydrate moiety of nucleosides, many powerful and innovative transformations have been accomplished, which led to the creation of an important structural variety, including three‐, four‐, and six‐membered ring analogues

Synthesis of N-heterocyclic compounds via ene-yne metathesis reactions

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Synthesis of cyclic and macrocyclic ethers using metathesis reactions of alkenes and alkynes

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Alkene and enyne metathesis reactions on allylic and propargylic amines

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