8‐Oxo‐7,8‐dihydroadenine and 8‐Oxo‐7,8‐dihydroadenosine—Chemistry, Structure, and Function in RNA and Their Presence in Natural Products and Potential Drug Derivatives

Abstract

A description and history of the role that 8-oxo-7,8-dihydroadenine (8-oxoAde) and 8-oxo-7,8-dihydroadenosine (8-oxoA) have in various fields has been compiled. This Review focusses on 1) the formation of this oxidatively generated modification in RNA, its interactions with other biopolymers, and its potential role in the development/progression of disease; 2) the independent synthesis and incorporation of this modified nucleoside into oligonucleotides of RNA to display the progress that has been made in establishing its behavior in biologically relevant systems; 3) reported synthetic routes, which date back to 1890, along with the progress that has been made in the total synthesis of the nucleobase, nucleoside, and their corresponding derivatives; and 4) the isolation, total synthesis, and biological activity of natural products containing these moieties as the backbone. The current state of research regarding this oxidatively generated lesion as well as its importance in the context of RNA, natural products, and potential as drug derivatives is illustrated using all available examples reported to date.

Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA

“…In addition, 8-oxo-adenosine in a template leads to slow primer extension with U, whereas 8-oxo-guanosine in a template results in highly error prone primer extension. It is known that the 8-oxo-modified purine nucleotides have different proportions of glycosidic conformations ( syn vs. anti ) relative to their canonical counterparts (30). We believe that the poor primer extension observed for the 8-oxo purines may be a direct result of this conformational state.…”

“…The 8-oxo-purines, which arise from oxidative damage, tend to adopt a syn conformation and form Hoogsteen base pairs, which may also decrease copying fidelity (Fig. 1) (23, 24). It is reasonable to assume that prebiotic synthetic pathways that generate nucleotides may also yield intermediates and byproducts, or damage and decay products, that give rise to non-Watson–Crick base pairs.…”

Oxidative Modifications of RNA and Its Potential Roles in Biosystem

“…The 8-oxo-A is known to be an intermediate of adenosine oxidation by xanthine oxidase ( Wyngaarden and Dunn, 1957 ), however, it was also identified by mass spectrometry in polyA after oxidative reactions ( Figure 2 ) ( Alexander et al, 1987 ). 8-oxo-A has been assumed to be a minor oxidized ribonucleoside relative to 8-oxo-G, since 8-oxo-dA was reported to be generated approximately one-tenth of 8-oxo-dG in DNA ( Frelon et al, 2000 ; Choi et al, 2017 ). However, it was reported that 8-oxo-A adduct was increased in the most affected brain regions of late stage AD compared to the age-matched control subjects while 8-oxo-G adduct was decreased ( Weidner et al, 2011 ).…”

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

“…The Dimroth rearrangement has been applied to the synthesis of N 6 -alkyladenines as several 8-oxoadenines [ 121 , 122 , 123 ], including simple purines as caissarone, 28 [ 34 , 120 , 123 ], and aplidiamine, 113 ( Scheme 3 ) [ 83 ]. The introduction of the carbonyl group at C8 to give 8-oxo derivatives, has been achieved by different oxidation procedures, as very well summarised recently by Resendiz et al [ 124 ] either on simple methylpurines or directly on nucleosides.…”