Synthesis and evaluation of squaramide and thiosquaramide inhibitors of the DNA repair enzyme SNM1A

Berney, Mark; Doherty, William; Jauslin, Werner Theodor; Manoj, Manav T; Dürr, Eva-Maria; McGouran, Joanna F.

doi:10.1016/j.bmc.2021.116369

Cited by 11 publications

(22 citation statements)

References 35 publications

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“…In vitro studies have shown that SNM1A can hydrolyse RNA as well as DNA, albeit with lower efficiency, [1,2] and we have previously shown that a uridine derivative bearing an N-hydroxysquaramide at the 3'-position inhibited SNM1A. [17] In an effort to develop SNM1A inhibitors with increased efficacy, we prepared a series of uridine derivatives bearing ZBGs previously untested against this enzyme at the 3'-position. Under-studied ZBGs including oxime, hydroxylamine, and 2-thiophene carboxamide moieties were investigated, as well as a sulfonamide, well established as a ZBG in inhibitors for other enzymes.…”

Section: Resultsmentioning

confidence: 99%

“…To enable addition of a ZBG at the 3'-position, uridine derivative 5 containing a 3'-amino group was prepared (Scheme 1). [17,18] Oxime-bearing uridine derivatives 1 and 2 were prepared from uridine as previously described. [17] A mixture of the E/Z oxime isomers 1 and 2 was reduced in 84 % yield using sodium triacetoxyborohydride formed in situ from sodium borohydride and acetic acid.…”

Section: Resultsmentioning

confidence: 99%

“…[17,18] Oxime-bearing uridine derivatives 1 and 2 were prepared from uridine as previously described. [17] A mixture of the E/Z oxime isomers 1 and 2 was reduced in 84 % yield using sodium triacetoxyborohydride formed in situ from sodium borohydride and acetic acid. Formation of an alkylated product 3 was also observed, presumably due to acetylation of hydroxylamine product 4 by boron triacetate followed by reduction of the resulting amide.…”

Section: Resultsmentioning

confidence: 99%

“…[2,11] Phosphorylated uridine derivatives bearing 2-thiophene carboxamide and sulfonamide ZBGs were prepared (Scheme 4). Thiophene-bearing uridine derivative 9 was treated with As nucleoside derivatives bearing squaramide ZBGs were previously found to show promise as SNM1A inhibitors, [17] a uridine derivative 25 bearing a 5'-phosphate as well as a 3'squaramide was synthesised (Scheme 4). Squaryl monoamide 21 was prepared as previously described by reaction of 3'aminouridine derivative 5 with diethyl squarate.…”

Section: Resultsmentioning

confidence: 99%

“…Substrate-mimic inhibitors are modified nucleosides, appended with a zinc-binding group (ZBG) to enhance binding to the active site. Inhibitors of this type which have demonstrated efficacy when tested in vitro include nucleoside derivatives bearing hydroxamic acid, [15] malonate, [16] squaramide [17] and thiosquaramide [17] ZBGs. A broad range of potential ZBGs has yet to be explored for this enzyme however, and the need remains to develop SNM1A inhibitors with greater efficacy.…”

Section: Introductionmentioning

confidence: 99%

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5’‐Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A

et al. 2022

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Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5'-3' exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5'-position, as well as zinc-binding groups at the 3'-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5'-phosphate dramatically increased the potency of the inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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5’‐Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A

et al. 2022

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Two‐Step Validation Approach for Tools To Study the DNA Repair Enzyme SNM1A

et al. 2023

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We report a two‐step validation approach to evaluate the suitability of metal‐binding groups for targeting DNA damage‐repair metalloenzymes using model enzyme SNM1A. A fragment‐based screening approach was first used to identify metal‐binding fragments suitable for targeting the enzyme. Effective fragments were then incorporated into oligonucleotides using the copper‐catalysed azide–alkyne cycloaddition reaction. These modified oligonucleotides were recognised by SNM1A at >1000‐fold lower concentrations than their fragment counterparts. The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage. However, SNM1A and other enzymes of this class are poorly understood, as there is a lack of tools available to facilitate their study. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generating modified oligonucleotide structures with high affinity for DNA damage‐repair enzymes.

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