Abstract
A concise synthesis of 2’-deoxyisoguanosine is achieved whereby 2,6-dichloropurine is glycosylated using the Hoffer sugar to give a pair of beta-configured nucleoside N9/N7 regioisomers that are aminated using methanolic ammonia with concomitant deprotection of the sugar. Following chromatographic separation, pure 2-chloro-2’-deoxyadenosine was isolated as a single isomer. Displacement of the C2 chlorine atom using sodium benzyloxide, followed by hydrogenolysis of the benzyl group, gives 2’-deoxyisoguanosine. Isoguanine was incorporated into DNA by solid supported synthesis using the suitably protected 2-allyloxy-2’-deoxyadenosine phosphoramidite with the allyl group being removed post-oligomerisation under Noyori conditions. DNA melting studies showed isoguanine to exhibit adenine-like triplex formation.
Highlights
We sought to examine whether isoguanine could exhibit adenine (A)-like triplex formation in its N3-H tautomeric form when incorporated into DNA, extending the triplex-forming capabilities of this intriguing purine heterocycle (Figure 2 right)
Isoguanine was incorporated into DNA and shown to participate in adenine-like triplex formation, most likely in its N3-H tautomeric form
The DNA melting studies and semi-empirical heats of formation calculated for representative N9methylated isoguanine tautomers, support the viability of isoguanine as its N3-H tautomer in DNA triplex formation furthering the elucidation of the molecular recognition characteristics of this intriguing purine heterocycle
Summary
Not a DNA base, isoguanine (isoG) occurs naturally and various methods have been reported for the preparation of derivatives[1,2,3,4] including its riboside,5 2’-deoxyriboside[6,7,8,9] and other analogues.[10,11] Isoguanine has been widely studied and when incorporated into nucleic acids,[12,13,14,15,16,17,18,19,20,21,22,23] has been shown to form stable base pair[7,24,25,26,27,28] (Figure 1 left) and triplex motifs[29] (Figure 1 middle) as its N1-H tautomer.
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