Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors

Llona‐Minguez, Sabin; Höglund, Andreas; Ghassemian, Artin; Desroses, Matthieu; Calderón-Montaño, José Manuel; Burgos-Morón, Estefanía; Valerie, Nicholas C.K.; Wiita, Elisée; Almlöf, Ingrid; Koolmeister, Tobias; Mateus, André; Cázares-Körner, Cindy; Sanjiv, Kumar; Homan, Evert; Loseva, Olga; Baranczewski, Paweł; Darabi, Masoud; Mehdizadeh, Amir; Fayezi, Shabnam; Jemth, Ann-Sofie; Berglund, Ulrika Warpman; Sigmundsson, Kristmundur; Lundbäck, Thomas; Jensen, Annika Jenmalm; Artursson, Per; Scobie, Martin; Helleday, Thomas

doi:10.1021/acs.jmedchem.7b00182

Cited by 19 publications

(7 citation statements)

References 25 publications

(68 reference statements)

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“…Its role in mutations arising during processes such as neurodegeneration or aging may also be considered. In addition, previous work has shown that inhibition of DCTPP1 may improve the action of certain pyrimidine nucleoside analogs used as anticancer drugs [11,12,48,49]. Finally, its role in the maintenance of mtDNA integrity may provide a new avenue for therapies of diseases related to nucleotide supply and balance in this organelle.…”

Section: Discussionmentioning

confidence: 99%

DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools

Martínez-Arribas

Requena

Pérez-Moreno

et al. 2019

Cell. Mol. Life Sci.

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To maintain dNTP pool homeostasis and preserve genetic integrity of nuclear and mitochondrial genomes, the synthesis and degradation of DNA precursors must be precisely regulated. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is a dNTP pyrophosphatase with high affinity for dCTP and 5′-modified dCTP derivatives, but its contribution to overall nucleotide metabolism is controversial. Here, we identify a central role for DCTPP1 in the homeostasis of dCTP, dTTP and dUTP. Nucleotide pools and the dUTP/dTTP ratio are severely altered in DCTPP1-deficient cells, which exhibit an accumulation of uracil in genomic DNA, the activation of the DNA damage response and both a mitochondrial and nuclear hypermutator phenotype. Notably, DNA damage can be reverted by incubation with thymidine, dUTPase overexpression or uracil-DNA glycosylase suppression. Moreover, DCTPP1-deficient cells are highly sensitive to down-regulation of nucleoside salvage. Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity.

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Section: Discussionmentioning

confidence: 99%

DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools

Martínez-Arribas

Requena

Pérez-Moreno

et al. 2019

Cell. Mol. Life Sci.

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“…Pyridazine derivatives can be found also in the backbones of several organic light-emitting diodes (OLEDs) (Liu et al, 2017), organic solar cells (OSCs) (Knall et al, 2021), chemosensors (Peng et al, 2020), trifluoroacetic acid (TFA) sensors (Li et al, 2018), bioconjugates (Bahou et al, 2021), low carbon steel corrosion inhibitors (Khadiria et al, 2016), and several other materials. They have also been used as starting materials in organic synthesis (Llona-Minguez et al, 2017), acylating agents (Kung et al, 2002), precursors for N-heterocyclic carbenes (NHCs) (Liu et al, 2012) and metallocarbene precursors. An overview of arylglyoxal monohydrates-based one-pot multi-component synthesis of potentially biologically active pyridazines is given by Mousavi (2022).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (E)-3-({6-[2-(4-chlorophenyl)ethenyl]-3-oxo-2,3-dihydropyridazin-4-yl}methyl)pyridin-1-ium chloride dihydrate

Daoui¹,

Çınar²,

Dege³

et al. 2022

Acta Cryst E

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In the title compound, C18H15ClN3O+·Cl−·2H2O, three intramolecular hydrogen bonds are observed, N—H...O, O—H...Cl and O—H...O. In the crystal, molecules are connected by C—H...Cl and N—H...O hydrogen bonds. Strong C—H...Cl, N—H...O, O—H...Cl and O—H...O hydrogen-bonding interactions are implied by the Hirshfeld surface analysis, which indicate that H...H contacts make the largest contribution to the overall crystal packing at 33.0%.

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“…As a result of the occurrence of two chiral centers, 2,5-diazabicyclo[2.2.1]heptanes are utilized as chiral scaffolds in asymmetric catalysis (Jordis et al, 1999;Gonzá lez-Olvera et al, 2008;Castillo et al, 2013;Díaz-de-Villegas et al, 2014;Avila-Ortiz et al, 2015). The diamine system of 2,5-diazabicyclo[2.2.1]heptane is traditionally included in screening libraries as a rigid counterpart of the flexible piperazine ring (Siebeneicher et al, 2016;Dam et al, 2016;Cernak et al, 2017;Llona-Minguez et al, 2017;Wei et al, 2017). As a consequence, numerous synthetic routes for the preparation of 2,5-diazabicyclo[2.2.1]heptane derivatives have been introduced (see: Portoghese & Mikhail, 1966;Jordis et al, 1990;Yakovlev et al, 2000;Fiorelli et al, 2005;Beinat et al, 2013;Cui et al, 2015;Choi et al, 2016 and the references cited therein).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Britvin

Rumyantsev

2017

Acta Cryst E

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The cage of 2,5-diazabicyclo[2.2.1]heptane is frequently employed in synthetic chemistry as a rigid bicyclic counterpart of the piperazine ring. The 2,5-diazabicyclo[2.2.1]heptane scaffold is incorporated into a variety of compounds having pharmacological and catalytic applications. The unsubstituted parent ring of the system, 2,5-diazabicyclo[2.2.1]heptane itself, has not been structurally characterized. We herein report on the molecular structure of the parent ring in (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide, C 5 H 12 N 2 2+ Á2Br À . The asymmetric unit contains two crystallographically independent cages of 2,5-diazabicyclo[2.2.1]heptane. Each cage is protonated at the two nitrogen sites. The overall charge balance is maintained by four crystallographically independent bromide ions. In the crystal, the components of the structure are linked via a complex three-dimensional network of N-HÁ Á ÁBr hydrogen bonds.

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Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors

Cited by 19 publications

References 25 publications

DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools

DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools

Crystal structure of (E)-3-({6-[2-(4-chlorophenyl)ethenyl]-3-oxo-2,3-dihydropyridazin-4-yl}methyl)pyridin-1-ium chloride dihydrate

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

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