Abstract
Nine modified nucleosides, incorporating zinc-binding pharmacophores, have been synthesised and evaluated as inhibitors of the DNA repair nuclease SNM1A. The series included oxyamides, hydroxamic acids, hydroxamates, a hydrazide, a squarate ester and a squaramide. A hydroxamic acid-derived nucleoside inhibited the enzyme, offering a novel approach for potential therapeutic development through the use of rationally designed nucleoside derived inhibitors.
Highlights
SNM1A is a DNA damage repair enzyme implicated in interstrand crosslink (ICL) repair.[1]
With oxyamides 5 and 6 in hand, we turned our attention to the synthesis of hydroxamic acid-derived nucleosides (Scheme 2)
We have synthesised a range of zinc-binding pharmacophores incorporated at the 5′-position of thymidine and these were tested against the human exonuclease SNM1A for inhibition
Summary
SNM1A is a DNA damage repair enzyme implicated in interstrand crosslink (ICL) repair.[1]. SNM1A interacts with long DNA strands via a positively charged patch on the enzyme’s surface that binds the negatively charged DNA backbone. This leads to processive activity with higher molecular weight substrates, whereas no processivity is observed with small oligonucleotides.[2] The 5′-phosphate group of the oligonucleotide substrate binds through H-bonding in the active site and is required for hydrolytic activity. The scissile phosphodiester is postulated to bind to the zinc metal centre prior to attack by an activated water molecule.[2,7] There are a limited number of inhibitors of SNM1A. To date, there has not been a modified nucleoside inhibitor
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