A General Synthesis of C8-Arylpurine Phosphoramidites

Abstract

A general scheme for the synthesis of C8-arylpurine phosphoramidites has been developed. C8-Arylation of C8-bromo-2′-deoxyguanosine is the key step and has been achieved through the use of a Suzuki coupling. Since the coupling reaction is conducted under aqueous conditions, it is unnecessary to protect and then deprotect the hydroxyl groups, thus saving several steps and improving overall yields. Once the C8-arylgroup is introduced, the glycosidic bond becomes very sensitive to acid catalyzed cleavage. Protection of the amino groups as the corresponding N,N-dimethylformamidine derivative improves stability of the derivatives. Synthetic C8-arylpurines were successfully used to prepare synthetic oligonucleotides.

The conformational effect of para-substituted C8-arylguanine adducts on the B/Z-DNA equilibrium

“…CD spectra were measured using a Jasco J-810 spectropolarimeter (Easton, MD). The oligonucleotides CG and CG 8Ph were prepared as previously described [24] as were the protected 8-(4-aryl)-2'-deoxyguanosine phosphoramidites needed for oligonucleotide synthesis [29].…”

Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase

“…It has been described that 8-substituted purine nucleosides are more sensitive to acidic conditions than their non-substituted analogues [1,21] and indeed we have experienced serious difficulties to remove the isopropylidene group by acid treatment without affecting the glycosidic bond. In this scenario, we considered relevant to determine the hydrolytic stability of the synthesised 8substituted inosines at different pH values.…”

C8-Arylguanine Modified Hairpin Oligonucleotides: Synthesis, Conformational Analysis, and Tools for the Investigation of Z-DNA Formation

“…There have been several amine protecting groups that have been used to protect the free amine group on the guanine ring and standard guanine phosphoramidites use an isobutyryl moiety. However the addition of a C8-aryl group onto the 2'deoxyguanosine renders the nucleoside more susceptible to acid cleavage and our group, along with another group, have demonstrated that protection using a N,N-dimethylformamidine 100,125,130 creates a more stable C8-aryl-2'-deoxyguanosine nucleoside, which is important in subsequent nucleosidic functionalization reactions as well as during DNA synthesis. Reaction with C8-aryl- Unlike the previous two reactions in the C8-aryl-2'-deoxyguanine phosphoramidite synthetic scheme, this reaction product requires purification before the phosphitylation reaction.…”

“…[98][99][100] In addition our group has also demonstrated expertise in the synthesis of C8-aryl-2'-deoxyguanine modified nucleoside to produce C8-aryl-2'-deoxyguanine analogs with various para-substituents on the C8-aryl modification that can be incorporated into oligonucleotide sequences. 125 In general, the C8-aryl-2'-deoxyguanine modified nucleoside synthesis begins with 8-bromo-2'-deoxyguanosine synthesis prepared from 2'-deoxyguanosine and NBS which is further used in the Suzuki coupling reaction with an arylboronic acid to make C8-aryl-2'-deoxyguanosine. Subsequently, the exocyclic amine is converted to a dimethylformamidine and then the 5'-hydroxyl is converted to the dimethoxy trityl ether.…”

“…The synthesis of the C8-aryl-2'-deoxyguanine modified nucleoside has been reviewed extensively by Thomsen et al 124 The C8-aryl-2'-deoxyguanine phosphoramidites synthesis begins with 2'-deoxyguanosine and in five steps is converted to the C8-aryl-2'-deoxyguanosine modified phosphoramidite (Scheme 2.1). 125 This product is then incorporated into the hairpin oligonucleotide sequence. The conversion of the 2'-deoxyguanosine to 8-bromo-2'-deoxyguanosine (1) is achieved via reaction with N-bromosuccinimde (NBS).…”