Resumen de Síntesi estereoselectiva d'análegs de nucleósids ciclohexánics conformacionalment restringids
In the last decades, the use of nucleoside analogues (NAs) has garnered extensive research interest for antiviral and anticancer therapy. The conformation and puckering of the sugar moiety of nucleosides play a critical role in modulating their biological activity. In this context, new conformationally restricted carbanucleosides analogues (CNAs) have been designed and synthesised in order to mimic the conformational behaviour of the natural furanose ring. Cyclohexenyl nucleosides are a promising type of antiviral compounds, wherein replacement of the oxygen atom of the furanose ring by a double bond induces annular flexibility, similar to that of regular nucleosides. Recently, it has been described that both enantiomers of cyclohexenyl G (DCG and LCG) display potent and selective anti-herpes virus activity. Considering the interesting anti-HSV activity of cyclohexenyl G, new series of enantiopure bicyclo[4.1.0]heptanyl NAs were proposed in our research group, in which the double bond was replaced by a fused cyclopropane. The present Ph.D Thesis is focused on the enantioselective synthesis of a novel series of six-membered carbocyclic NAs based on the skeleton of cyclohexenyl G containing bicyclo[4.1.0]heptane structure from a common key intermediate. Specifically, it is described the achievement of the following objectives: - Firstly, two synthetic strategies developed in our research group have been optimized in order to prepare the key ketone 36, which is the common intermediate for the preparation of bicyclo[4.1.0]heptane NAs. Ketone 36 has been obtained in a robust, reproducible, and efficient 6-steps approach on a multigram scale in 49% overall yield from commercially available 1,4-cyclohexadione. -Secondly, since the 5’-hydroxymethylbicyclo[4.1.0]heptane analogues BCH-(A, G, T and U) NAs, previously obtained in the research group, did not show significant antiviral activity, in order to complete the 5’-hydroxymethylbicyclo[4.1.0]heptanyl family, the cytosine analogue has been synthesised in 4% overall yield in 17 steps. However, it does not show antiviral activity or cytotoxicity. All of this family of NAs have been evaluated in enzymatic assays in order to determine the virus-TK affinity. The thymidine-based compound BCH-T has an interesting great affinity towards HSV-TK (EC50 = 1.6 ± 0.1 µg/mL) which is consistent with our computational model performed for the first stage of phosphorylation. -Thirdly, a novel family of 5’-hydroxymethyl-4’-hydroxybicyclo[4.1.0]heptan-2’-yl NAs has been prepared. In particular, thymine and guanine NAs have been obtained in 17 and 18 steps and 18% and 10% overall yield, respectively. The thymine C4-epimer and the thymine alk-4,5-ene have been synthesised in 19 steps and 6% and 3% overall yield, respectively. These four NAs have been screened for antiviral activity, although none of them show significant activity. -Finally, a new family of 1,2,3-triazolo-bicyclo[4.1.0]heptanyl CNAs has also been obtained. This approach has allowed the preparation of the four 4-substituted-1,2,3-triazolo-CNAS via CuAAc in 19-16% overall yield in 15 steps. Furthermore, the 4,5-substituted-1,2,3-triazolo-CNAS has been synthesised via cycloaddition and 12% yield in 14 steps. The biological activity of these analogues against several viruses has been evaluated, although only the propylbenzene-1,2,3-triazolo-CNAs 151 shows a considerable activity against Coxsackie B4 virus (EC50 = 13.5-9.4 µg/mL).
