Nucleobase-Functionalized 7-Deazaisoguanine and 7-Deazapurin-2,6-diamine Nucleosides: Halogenation, Cross-Coupling, and Cycloaddition

Abstract

The functionalization in position-7 of 7-deazaisoguanine and 7-deazapurin-2,6-diamine ribo-and 2′-deoxyribonucleosides by halogen atoms (chloro, bromo, iodo), and clickable alkynyl and vinyl side chains for copper-catalyzed and copper-free cycloadditions is described. Problems arising during the synthesis of the 7-iodinated isoguanine ribo-and 2′-deoxyribonucleosides were solved by the action of acetone. The impact of side chains and halogen atoms on the pK a values and hydrophobicity of nucleosides was investigated. Halogenated substituents increase the lipophilic character of nucleosides in the order Cl < Br < I and decrease the pK values of protonation. Photophysical properties (fluorescence, solvatochromism, and quantum yields) of azide−alkyne click adducts bearing pyrene as sensor groups were determined. Pyrene fluorescence was solvent-dependent and changed according to the linker lengths. Excimer emission was observed in dioxane for the long linker adduct. Bioorthogonal inverse-electrondemanding Diels−Alder cycloadditions (iEDDA) were conducted on the electron-rich vinyl groups of 7-deazaisoguanine and 7deazapurin-2,6-diamine nucleosides as dienophiles and 3,6-dipyridyl-1,2,4,5-tetrazine as diene. The initially formed complex reaction mixture of isomers could be easily oxidized with iodine in tetrahydrofuran (THF)/pyridine leading to single aromatic tetrazine adducts within a short time and in excellent yields.

7-Deazapurine and Pyrimidine Nucleoside and Oligonucleotide Cycloadducts Formed by Inverse Diels–Alder Reactions with 3,6-Di(pyrid-2-yl)-1,2,4,5-tetrazine: Ethynylated and Vinylated Nucleobases for Functionalization and Impact of Pyridazine Adducts on DNA Base Pair Stability and Mismatch Discrimination

“…As shown in Figure , the iEDDA reaction of vinyl nucleosides 1a - 5a ,− (Figure ) as dienophiles was carried out with 3,6-di(pyrid-2-yl)-1,2,4,5-tetrazine 6 as diene without oxidizing reagent (routes A). In route B, iodine was used as oxidizing reagent to obtain the pyridazine nucleoside cycloadducts.…”

7-Deaza-2′-deoxyisoguanosine, a Noncanonical Nucleoside for Nucleic Acid Code Expansion and New DNA Constructs: Nucleobase Functionalization of Inverse Watson–Crick and Purine–Purine Base Pairs

“…One series contains bromo or iodo substituents at the 7-position of the nucleobase, the second series contains clickable side chains with terminal triple bonds for the azide–alkyne cycloaddition (Scheme ). Starting materials for the functionalized building blocks were the nucleosides 3b – d and 3f , g . , For the synthesis of the 7-bromo building block 4b , the amino group of 3b was protected with a butylamidine residue. As described earlier, for the 7-iodo compound 3c , the acetamidine protecting group was chosen for amino protection .…”

“…Starting materials for the functionalized building blocks were the nucleosides 3b – d and 3f , g . , For the synthesis of the 7-bromo building block 4b , the amino group of 3b was protected with a butylamidine residue. As described earlier, for the 7-iodo compound 3c , the acetamidine protecting group was chosen for amino protection . The acetamidine protecting group was also selected for the alkynyl and alkenyl nucleosides 3d , 3f and 3g .…”

“…Recently, we reported on the functionalization of monomeric 7-deaza-2′-deoxyisoguanosine with a series of halogen, alkenyl and alkynyl residues at the 7-position of the 7-deazapurine base . This work incorporates the base functionalized nucleosides into two types of base pairs: purine–purine base pairs and inverse Watson–Crick pairs.…”

“…Recently, we used functionalized 8-aza-7-deazaisoguanine (pyrazolo[3,4- d ]pyrimidine) nucleosides for a functionalization study . This investigation documented the positional impact of isoguanine functionalization at position-8 of purine nucleosides with respect to position-7 of 8-aza-7-deazaisoguanine (pyrazolo[3,4- d ]pyrimidine) nucleosides.…”