SYNTHESIS OF NEW TYPES OF CHLORINE-CONTAINING NUCLEOSIDES AND 2',6-DISUBSTITUTED URIDINES FOR ANTIVIRAL/ANTICANCER SCREENING

Research Topic

Nucleoside analogues call attention due to their ability to mimic the naturally occurring counterparts and to interfere with the processes of biosynthesis of DNA or RNA, and therefore to act as antiviral/anticancer drugs.1-6 Success of derivatives like Ribavirin, AZT, D4T, DDI, Tenofovir or Acyclovir to mention only some of the approved drugs, strongly confirms that the field of nucleoside analogues has been very promising in medicinal chemistry. This interest is also spurred by viral mutations with concomitant development of resistance towards the existing drugs. This implies a necessity to constantly search for potential new leads. Numbers of viruses attacking humans is known, like Zika, Chikungunya, Ebola, SARS corona virus and Dengue virus (all RNA viruses), against which no treatment at present has been developed. Even though the incidence of human infections by the first three viruses are rather limited geographically, a realistic situation of spreading them creates a serious health problem considering high mortality rates approaching 90% in the case of Ebola epidemics. These factors are of great interest to medicinal chemistry to obtain new nucleoside analogues for antiviral and anticancer screening.

Some halogenated derivatives are known in the literature, such as Gemcitabine that was approved as anticancer drug and also demonstrated to be a potent inhibitor of RNA transcription and replication against influenza A virus.7, 8 One promising strategy to obtain new nucleoside analogues is the introduction of halogen substituents into the sugar ring. This type of modification can result into some nucleosides in a remarkable improvement in the bioactivity and stability of the correspondent compounds.9 Halogens can effect inter and intramolecular forces, that affect binding of ligands, structural conformation and thus induce selective inhibition to the specific target.10

This project aims at the synthesis of compounds chlorinated nucleosides (no shown here), as well as their phosphoramidates derivatives as pro-drugs with a (potentially) better pharmacological profile, for biological evaluation against RNA or DNA viruses and neoplastic strains.

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