Synthesis, structure, and biological evaluation of three series of novel 4-C-hydroxymethyl pentopyranosyl nucleosides as anticancer and antiviral agents

The primary goal of this work was to prepare novel series of pentopyranosyl pyrimidine and purine nucleosides to be evaluated as potential anticancer and antiviral agents. These nucleosides were of interest, in part, to study the conformational preference of the nucleosides required for enzymatic recognition by the various cellular (or viral) enzymes responsible for their bioactivation.; The strategy used for the synthesis of these nucleosides involved preparation of appropriately-protected carbohydrate sugar derivatives followed by their subsequent coupling to various trimethylsilylated pyrimidines and purines in the presence of a catalyst (SnCl₄) to yield the α- and β-anomers of the target compounds. The key step in the synthesis of each carbohydrate sugar derivative involved the introduction of a 4-hydroxy-methyl group by hydroboration of a protected 4-methylidene compound. Thermodynamic-controlled isomerization of the α-hydroxymethyl group at C-4 to its β-epimer provided a route to the desired sugar.; For the threo (I) and erythro (II) nucleoside series, the 1-acetates I-9 and II-5 were reacted at 0°C in CH₃CN for 30h under the aforementioned reaction conditions to yield the desired nucleoside products which were deprotected using NaOCH ₃/MeOH or KOH/EtOH, whereas, the xylo (III) nucleoside series were prepared by reaction of III-16 in 1,2-dichloroethane at 50°C for 3–8h, then debenzylated using catalytic (20% Pd(OH) ₂/C, H₂, EtOH, 1 atm) or transfer (20% Pd(OH)₂/C, cyclohexene, MeOH, reflux). The only exception involved the use of BCl ₃ for the preparation of III-29α and III-29β because dechlorination occurs by the other two methods.; The conformation of the nucleosides was deduced from the coupling constants and the splitting patterns found in the 1H NMR spectra of the compounds. The α anomers of series (I) adopted a 1C₄ conformation, which places the base in an equatorial orientation. The β-anomers also had equatorially oriented bases as result of their 4C₁ sugar conformations. Series ( II) nucleosides also adopted conformations (1C ₄: β-anomers; 4C₁: α-anomers) that oriented the base equatorially. The last series (III), even at the expense of three axially oriented substituents, still favored a 1C₄ conformation for the α-anomers and a 4C₁ conformation for the β-anomers. Thus, the base was again equatorial.; All of the final nucleosides were evaluated for anticancer and antiviral activity as well as for their interaction with essential enzymes required for their bioactivation. Compounds I-12α, I-18α, and I-20α were substrates for deoxycytidine kinase. The thymine analogue I-16α exhibited activity (IC₅₀ = 7.73 μM) against HSV-1 virus. The 2-chloroadenine derivative I-20α proved to be moderately inhibitory (IC₅₀ = 28.5 μM) to RSV viral growth. None of the compounds proved to be cytotoxic up to the highest concentration tested (60 μg/ml).