Regioisomeric Synthesis and Characteristics of the α-Hydroxy-1,N²-propanodeoxyguanosine

Abstract

Acrolein, a known mutagen, undergoes reaction in vitro under physiological conditions with both 2'-deoxyguanosine and native DNA to give rise to exocyclic adducts of the 5,6,7,8-tetrahydropyrimido[1,2-a]purine-10(3H)-one class having a hydroxyl group at either the 6 or the 8 position (these positions are respectively designated alpha and gamma when referring to the 1,N(2)-(propano-bridge). Previously, we have shown that the 8-hydroxy derivative has very low mutagenicity probably because, in double-stranded DNA, this residue exists in the open-chain aldehydic form [N(2)-(3-oxopropyl)-2'-deoxyguanosine] (5). To continue our investigation in this area, we needed ample supplies of the 6-hydroxy isomers. This current paper describes high-yield simple methods for the synthesis in bulk of the 6-hydroxy and the 6-methoxy exocyclic adducts 1 and 3 and a new efficient synthesis of 1,N(2)()-(prop-1,3-diyl)-2'-deoxyguanosine (4), previously used as a chemically stable model in studying the physico-biological implications of 1,N(2) exocyclic adduction to dG.

Impact of α‐hydroxy‐propanodeoxyguanine adducts on DNA duplex energetics: Opposite base modulation and implications for mutagenicity and genotoxicity

“…Our energetic data are generally consistent with in vivo studies15 demonstrating that the α‐OH‐PdG adduct is genotoxic rather than mutagenic. Specifically, α‐OH‐PdG extensively blocks DNA replication, yet primarily codes for dC incorporation with a low frequency of base substitution mutations when bypassed in translesion synthesis.…”

“…Recent advances in nucleic acid synthetic techniques have resulted in the successful production of chemically stable γ‐OH‐PdG and α‐OH‐PdG11–16 adducts. Availability of the natural acrolein adduct has generated renewed interest in characterizing the lesion‐specific biophysical properties of both regioisomers 17–21.…”

Site Specific Synthesis and Polymerase Bypass of Oligonucleotides Containing a 6-Hydroxy-3,5,6,7-tetrahydro-9H-imidazo[1,2-a]purin-9-one Base, an Intermediate in the Formation of 1,N2-Etheno-2‘-deoxyguanosine

“…Periodate oxidation of a vicinal diol is a common strategy for the incorporation of aldehyde functionality into oligonucleotides under mild and neutral conditions (35)(36)(37)(43)(44)(45)(46)(47)(48)(49)(50)(51). dGuo was alkylated at the N1-position with allyl bromide under alkaline conditions to give the N1-propenyl derivative (13) in 66% yield (Scheme 3) (34,43,52,53). HPLC analysis of the reaction mixture showed minor byproducts whose UV spectra were consistent with O 6 -and N 2 -alkylation; these minor products were not isolated.…”

Alkylation of 9‐substituted guanine derivatives with α,ω‐dihaloalkanes

“…[14] Similarly, the route to 3a includes the synthesis of its 6-hydroxy or 6-methoxy derivatives followed by the reduction step. [8,15,16] 2 of 13 | FRAMSKI et Al.…”

“…Later studies have led to the preparation of 2a by reduction of its 6‐hydroxy congener with NaBH 4 or NaCNBH 3 . Similarly, the route to 3a includes the synthesis of its 6‐hydroxy or 6‐methoxy derivatives followed by the reduction step …”