Synthesis and Pharmacological Evaluation of Modified Sugars and Nucleosides

Abstract

Modified sugar derivatives and nucleoside have been in clinical use for decades and there is still need of new therapeutics to fight against pandemic outbreak. Synthesizing new molecules and repurposing known compounds can be a cost-effective solution to develop new drugs. Starting with commercially available α-D-glucose as the lead compound, and by chemically modifying it several known and new sugar derivatives and nucleosides have been synthesized in this study. These structural modifications include conversion of six membered glucose to five membered ribose sugar, inversion and benzylating of 3-OH, deprotecting isopropylidene rings, periodate oxidation, reduction of aldehyde, protecting some sensitive groups and breaking others, acylation of sugar moiety followed by glycosylation to synthesis nucleoside derivatives. This 20 steps long reaction scheme resulted 13 sugar derivatives and 7 nucleosides including 3 locked nucleic acid monomers with the first time report of a 2',4'-bridged nucleosides named ((1R,3R,4R,7S)-7-hydroxy-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dioxabicyclo[2.2.1]heptan-1-yl)methyl isobutyrate [21]. Though LNA monomers are typically used to increase the thermal stability and strong binding affinity in oligonucleotide duplexes, here these agents have been tested along with some other selected sugar derivatives for potential antimicrobial effects, cytotoxicity in human HeLa cells, peripheral analgesia producing and inflammation reducing capacity in animal models for the first time. Two nucleoside derivatives, [12] and [15] showed excellent cytotoxic effects where compound [15] induced the death of 95% cells tested at 500 μg/ml concentration resulting the IC50 of 54 μg/ml. The new compound [21] has also showed a good level of cytotoxicity to the same cells. Unfortunately, the tested compounds didn’t show antimicrobial effect against the tested 13 bacteria and 3 fungi. Among the tested compounds, [04], [20] and [21] showed promising analgesic activity (p<0.01) at a dose of 50 mg/kg in mice model. The compounds, [08] and [20] showed moderate anti-inflammatory activity in rat model. In a nutshell, advanced investigation of cytotoxicity of the synthesized nucleosides may discover a great lead for future chemotherapy. This medicinal chemistry focused study may encourage other fellow researchers to engage in organic synthesis utilizing limited resources and eventually may attract pharmaceutical industries to come forward to invest in new molecule discovery.