85597-60-0Relevant academic research and scientific papers
5’-Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A
Berney, Mark,Fay, Ellen M.,Manoj, Manav T,McGouran, Joanna F.
supporting information, (2022/01/13)
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.
Synthesis of 3'O-(2-cyanoethyl)-2'-deoxythymidine-5'-phosphate as a model compound for evaluation of Cyanoethyl Cleavage
Keller, Angelika C.,Serva, Saulius,Knapp, Diana C.,Kwiatkowski, Marek,Engels, Joachim W.
experimental part, p. 515 - 534 (2010/02/28)
An essential and challenging task during the development of our sequencing-by-synthesis (SBS) technique is the evaluation of efficient cyanoethyl (CE) cleavage conditions. For this purpose 3'-O-(2-cyanoethyl)-2'- deoxythymidine-5'-phosphate as a model compound as well as a short DNA oligomer bearing the CE function as terminal group were synthesized and used for various deprotection experiments. As it is already known for 2'-O-CE-protected RNA oligonucleotides, the CE function can be cleaved with tetrabutylammonium fluoride (TBAF) in THF. Indeed, by using 3'-O-(2-cyanoethyl)-2'-deoxythymidine- 5'-phosphate as a simple model compound for cleavage tests, we found out that the 3'-O-CE function is quantitatively cleaved with 1 m TBAF in THF. However, the CE group is also cleaved by other small bases like hydroxy groups under alkaline conditions. The CE cleavage with TBAF in THF gives the fastest and quantitative removal of the CE group under mild conditions for our sequencing-by-synthesis (SBS) application. The efficient removal of the 3'-CE group is crucial for the proof-of-principle of our SBS approach using dye-labeled 3'-CE-blocked dNTPs, which is currently under investigation. Herein we describe the application of 3'-O-(2-cyanoethyl)-2'-deoxythymidine-5'- phosphate as model compound for the development of reversible terminators for the SBS technique. Furthermore we suggest that nucleoside phosphates bearing any removable 3'-modification might be suitable model compounds for cleavage studies in a heterogeneous environment comparable to an oligonucleotide/aprotic solvent system.
