RNAs Containing Carbocyclic Ribonucleotides

Abstract

Toward the goal of evaluation of carbocyclic ribonucleoside-containing oligonucleotide therapeutics, we developed convenient, scalable syntheses of all four carbocyclic ribonucleotide phosphoramidites and the uridine solid-support building block. Crystallographic analysis confirmed configuration and stereochemistry of these building blocks. Duplexes with carbocyclic RNA (car-RNA) modifications in one strand were less thermodynamically stable than duplexes with unmodified RNA. However, circular dichroism spectroscopy indicated that global conformations of the duplexes containing car-RNAs were similar to those in the unmodified duplexes.

Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues

“…14,15,34 The sizable 3 J H1′–H2′ coupling constants observed here for 22 and 23 are indicative of H 1 –C 1 –C 2 –H 2 torsion angles tending to 150°, and tentatively support this 1 E conformational assignment in solution-phase. However, these couplings are larger than related values observed for non-fluorinated carbanucleosides ( 3 J H1′–H2′ = 5.6 Hz for carbauridine in DMSO-d 6 , 16 and 3 J H1′–H2′ = 8.5 Hz for aristeromycin and carbaguanosine in D 2 O). 35…”

“…However, these couplings are larger than related values observed for non-fluorinated carbanucleosides ( 3 J H1'-H2' = 5. 6 Hz for carbauridine in DMSO-d6, 16 and 3 J H1'-H2' = 8.5 Hz for aristeromycin and carbaguanosine in D 2 O). 35 1 J coupling constants can serve as convenient identifiers for the anomeric carbon within nucleoside rings, alongside supporting patterns of stereochemical identity ( and  anomers).…”

“…This led to the formation of 17 (Scheme 3, box) as the major product, following redcution. By lowering the reaction temperature to 0 °C and increasing the equivalents of NaIO 4 five-fold, the unwanted elimination was suppressed and the desired material (16) was obtained. Following this optimisation, concomitant reduction and deprotection delivered 15 and 16, with 16 isolated in 60% yield over the three steps.…”

“…14,15 The carbocylic structural motif has successfully underpinned development of the therapeutics abacavir and entecavir and has recently been included within synthetic RNA oligonucleotides. 16 In addition to using CH 2 to replace the furanose ring oxygen, there are a limited number of reports that concomitantly build fluorine into this carbocylic modification, effectively introducing CF 2 (Figure 1c). For example, 6'6'difluorinated purines have been developed to target RNA virus activity.…”

“…14,15 The carbocylic structural motif has successfully underpinned development of the therapeutics abacavir and entecavir and has recently been included within synthetic RNA oligonucleotides. 16…”