Expanding Catch and Release DNA Decoy (CRDD) Technology with Pyrimidine Mimics

Samantha A. Kennelly; Ramkumar Moorthy; Ruben Silva Otero; Daniel A. Harki

doi:10.1002/chem.202201355

Expanding Catch and Release DNA Decoy (CRDD) Technology with Pyrimidine Mimics

Samantha A. Kennelly, Ramkumar Moorthy, Ruben Silva Otero, Daniel A. Harki

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole (2-NI), 2-nitrobenzene (2-NB), 2-nitropyrrole (2-NP) and 3-nitropyrrole (3-NP). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.

Original language	English (US)
Article number	e202201355
Journal	Chemistry - A European Journal
Volume	28
Issue number	58
DOIs	https://doi.org/10.1002/chem.202201355
State	Published - Oct 18 2022

Bibliographical note

Funding Information:
We gratefully acknowledge the NIH (R01‐GM110129) and the University of Minnesota for financial support. Mass spectrometry was performed at the University of Minnesota Masonic Cancer Center Analytical Biochemistry Core Facility, which is supported by the NIH (P30‐CA77598). NMR spectrometry was performed at the University of Minnesota NMR Center.

Publisher Copyright:
© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Keywords

DNA decoys
DNA hybridization
nucleosides
oligonucleotides
photolysis

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abstract = "Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole (2-NI), 2-nitrobenzene (2-NB), 2-nitropyrrole (2-NP) and 3-nitropyrrole (3-NP). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.",

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author = "Kennelly, {Samantha A.} and Ramkumar Moorthy and Otero, {Ruben Silva} and Harki, {Daniel A.}",

note = "Funding Information: We gratefully acknowledge the NIH (R01‐GM110129) and the University of Minnesota for financial support. Mass spectrometry was performed at the University of Minnesota Masonic Cancer Center Analytical Biochemistry Core Facility, which is supported by the NIH (P30‐CA77598). NMR spectrometry was performed at the University of Minnesota NMR Center. Publisher Copyright: {\textcopyright} 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.",

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AU - Moorthy, Ramkumar

AU - Otero, Ruben Silva

AU - Harki, Daniel A.

N1 - Funding Information: We gratefully acknowledge the NIH (R01‐GM110129) and the University of Minnesota for financial support. Mass spectrometry was performed at the University of Minnesota Masonic Cancer Center Analytical Biochemistry Core Facility, which is supported by the NIH (P30‐CA77598). NMR spectrometry was performed at the University of Minnesota NMR Center. Publisher Copyright: © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

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N2 - Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole (2-NI), 2-nitrobenzene (2-NB), 2-nitropyrrole (2-NP) and 3-nitropyrrole (3-NP). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.

AB - Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole (2-NI), 2-nitrobenzene (2-NB), 2-nitropyrrole (2-NP) and 3-nitropyrrole (3-NP). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.

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Expanding Catch and Release DNA Decoy (CRDD) Technology with Pyrimidine Mimics

Abstract

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