Abstract
New 1′-homocarbanucleoside analogs with an optically active substituted bicyclo[2.2.1]heptane skeleton as sugar moiety were synthesized. The pyrimidine analogs with uracil, 5-fluorouracil, thymine and cytosine and key intermediate with 6-chloropurine (5) as nucleobases were synthesized by a selective Mitsunobu reaction on the primary hydroxymethyl group in the presence of 5-endo-hydroxyl group. Adenine and 6-substituted adenine homonucleosides were obtained by the substitution of the 6-chlorine atom of the key intermediate 5 with ammonia and selected amines, and 6-methoxy- and 6-ethoxy substituted purine homonucleosides by reaction with the corresponding alkoxides. No derivatives appeared active against entero, yellow fever, chikungunya, and adeno type 1viruses. Two compounds (6j and 6d) had lower IC50 (15 ± 2 and 21 ± 4 µM) and compound 6f had an identical value of IC50 (28 ± 4 µM) to that of acyclovir, suggesting that the bicyclo[2.2.1]heptane skeleton could be further studied to find a candidate for sugar moiety of the nucleosides.
Highlights
Nucleosides are a chemical class of active substances used as efficient antitumor [1,2,3] or antiviral drugs [4,5,6,7]
By low pressure chromatography (LPC) purification of the mother liquors, the total yield was increased to 91% (Scheme 1)
Our findings suggest that the bicyclo[2.2.1]heptane skeleton could be a candidate for sugar moiety of the nucleosides with potential virus-inhibiting properties
Summary
Nucleosides are a chemical class of active substances used as efficient antitumor [1,2,3] or antiviral drugs [4,5,6,7]. An impressive number of modifications of the sugar moiety or replacements with carbocyclic fragment, replacement of the base or both have been done and some of the corresponding molecules had antiviral or anticancer activity and became useful drugs [2,3,6,7]. Some changes in the sugar moiety have led to carbocyclic compounds with potent antiviral or anticancer activity. All new ligands (1′-homocarbanucleosides) were found to have the same orientation as AC2 (Figure S4a), as it can be observed in Table S1 for linking to a group of interaction with the amino acids. The molecular design should be taken with caution, because the results are prediction values, not experimental ones
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