143527-01-9Relevant articles and documents
Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
Dürr, Eva-Maria,McGouran, Joanna F.
, (2021)
SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.
Synthesis of Thymidine Dimers Containing Piperazine in the Internucleoside Linkage and their Incorporation into Oligodeoxynucleotides
Petersen, Gorm Vang,Wengel, Jesper
, p. 2145 - 2154 (2007/10/02)
The synthesis of thymidine dimers in which the natural phosphodiester linkage has been replaced by piperazine (3'-(N(CH2CH2)2N)-5, 9 and 3'-(N(CH2CH2)2N)-CO-4, 10) are described.These new dimers were incorporated into oligodeoxynucleotides on an automated DNA-synthesizer using the phosphoramidite approach.The thermal stability of DNA/DNA duplexes and the enzymatic stability was studied by UV experiments. 17-Mers with 9 incorporated once or twice in the middle exhibited a pronounced decrease in thermal stability (ΔTm -11 degC per modification) while 17-mers with 10 incorporated once or twice in the middle exhibited only a slight decrease in thermal stability (ΔTm -2 degC per modification) when compared to unmodified 17-mers.Furthermore, end-modified oligodeoxynucleotides containing either 9 or 10 displayed five to six fold increased stability towards snake venom phosphodiesterase.