Synthesis and Anticancer and Antiviral Activities of C-2′-Branched Arabinonucleosides

Abstract

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2’ position were prepared from the corresponding 3’,5’-O-silylene acetal-protected nucleoside 2’-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2’-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2’ substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2’-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.

In vitro and in vivo antiplasmodial evaluation of sugar-modified nucleoside analogues

“…A specific feature of the thio-substituted nucleoside analogues 7 – 20 is that they contain a configurationally modified furanose unit instead of natural d -ribose. Using our recently established photoinduced thiol-ene coupling method 21 , the l - lyxo ( 7 – 9 ), d - xylo ( 10 –1 9 ), and d - arabino ( 20 ) configured nucleoside analogues could be obtained with high stereoselectivity by radical mediated addition reactions between C4’-, C3’- or C2’-exomethylene nucleosides and various thiols including amino acid derivatives, 1-thiosugars or alkyl mercaptans 16 – 19 . In addition to the furanose-modified nucleoside analogues 7 – 20 , some simple, protected or partially protected nucleoside derivatives 21 – 26 were included in the antimalarial studies as reference compounds.…”

“…To produce a 2’-modified nucleoside analogue for the antimalarial assay, the 2’- C -exomethylene-3',5'- O -silylene-acetal derivative of uridine ( 29 ) was prepared and subjected to a photoinduced hydrothiolation reaction with butyl mercaptane 27b 19 . The reaction proceeded with good yield and almost complete stereoselectivity providing the expected d - arabino configured 2’- C -butylsulfanylmethyl nucleoside 20 with 69% yield and an isomeric purity of 91% (20:1 d - arabino : d - ribo ratio of 20 ).…”

“…The reactions were performed in various solvents selected based on the solubility of the reactants and cooling was used to achieve high diastereoselectivity. Based on our previous results, the thiol-ene couplings were carried out at low temperature (− 40/− 80 °C) in order to achieve high conversion and high stereoselectivity 16 – 19 , 21 . Using such conditions, the hydrothiolated products ( 11 – 18 ) with the expected d - xylo configuration were indeed obtained efficiently and with excellent diastereomeric excesses.…”

“…The first group includes morpholino-nucleoside hybrids composed of morpholino unit(s) at the 5’-end and a nucleoside or 2’-deoxyribonucleoside at the 3’-end 15 . The second group consists of configurationally altered, l - lyxo , d - xylo or d - arabino configured nucleoside derivatives bearing a sulfanylmethyl-linked substituent at different positions of the furanose ring, which can be prepared by photoinitiated radical addition of various thiols onto C4’, C3’ or C2’ exomethylene moiety of nucleosides 16 – 19 . Regarding the great potential of nucleoside analogues 11 , 12 as well as morpholine-containing derivatives 13 , 14 in antimalarial therapy, we decided to test the antiplasmodial activity of the newly developed types of nucleoside analogues.…”

Selenization of Small Molecule Drugs: A New Player on the Board

“…It is well-known that the carbohydrate moieties of nucleosides have attracted widespread attention over the past years, as it is a promising approximation in the design of novel chemotherapeutic and antiviral agents. − Even though a great number of nucleoside analogues have been synthesized and applied for the treatment of several cancers, they are usually hindered by their physicochemical properties and the development of resistance to them. , Thereby, novel molecules have been designed by incorporating a Se moiety into the framework of cytarabine (1-β- d -arabinofuranosylcytosine, AraC), a nucleoside analogue that has remained the mainstay chemotherapy for acute myeloid leukemia (AML) for over 40 years. ,, …”