40615-39-2Relevant articles and documents
Cytotoxic and mutagenic properties of alkyl phosphotriester lesions in Escherichia coli cells
Wu, Jiabin,Wang, Pengcheng,Wang, Yinsheng
, p. 4013 - 4021 (2018)
Exposure to many endogenous and exogenous agents can give rise to DNA alkylation, which constitutes a major type of DNA damage. Among the DNA alkylation products, alkyl phosphotriesters have relatively high frequencies of occurrence and are resistant to repair in mammalian tissues. However, little is known about how these lesions affect the efficiency and fidelity of DNA replication in cells or how the replicative bypass of these lesions is modulated by translesion synthesis DNA polymerases. In this study, we synthesized oligodeoxyribonucleotides containing four pairs (Sp and Rp) of alkyl phosphotriester lesions at a defined site, and examined how these lesions are recognized by DNA replication machinery in Escherichia coli cells. We found that the Sp diastereomer of the alkyl phosphotriester lesions could be efficiently bypassed, whereas the Rp counterparts moderately blocked DNA replication. Moreover, the Sp-methyl phosphotriester induced TT→GT and TT→GC mutations at the flanking TT dinucleotide site, and the induction of these mutations required Ada protein, which is known to remove efficiently the methyl group from the Sp-methyl phosphotriester. Together, our study provided a comprehensive understanding about the recognition of alkyl phosphotriester lesions by DNA replication machinery in cells, and revealed for the first time the Ada-dependent induction of mutations at the Sp-methyl phosphotriester site.
Tetrabutylammonium bromide: An efficient media for dimethoxytritylation of the 5'-hydroxyl function of nucleosides
Khalafi-Nezhad, Ali,Mokhtari, Babak
, p. 6737 - 6739 (2004)
An efficient procedure for selective dimethoxytritylation of the 5'-hydroxyl function of nucleosides in the presence of DABCO in molten tetrabutylammonium bromide is described. The methodology is very practical, environmentally benign and produced the desired product in less than 5 min by grinding in a hot mortar. In addition, the effects of the room temperature ionic liquid (1-butyl-3-methylimidazolium chloride) and microwave irradiation on this system were also studied and the results showed that depurination of the nucleosides occurred under microwave irradiation.
Selective uncaging of DNA through reaction rate selectivity
Rodrigues-Correia, Alexandre,Knapp-Bühle, Diana,Engels, Joachim W.,Heckel, Alexander
, p. 5128 - 5131 (2014)
The synthesis and use of the new nucleobase-caged nucleotides dTpHP and dTNDEACM is reported. Through a combination of time and wavelength selectivity four levels of selective uncaging with only two cages, and only two wavelengths, were obtained. The new residue dTpHP can be uncaged at 313 nm without the formation of unwanted cyclic pyridine dimers.
Synthesis of a convenient thymidine glycol phosphoramidite monomer and its site-specific incorporation into DNA fragments
Gasparutto, Didier,Cognet, Sonia,Roussel, Solveig,Cadet, Jean
, p. 1831 - 1842 (2005)
□ An original phosphoramidite building block of the thymidine glycol lesion has been prepared taking into account the additional diol function and the high lability of this oxidatively induced nucleobase damage. Then the modified nucleoside was site-specifically inserted into DNA fragments by solid support assembling followed by a "one-step" mild final deprotection treatment. Copyright Taylor & Francis Group, LLC.
Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
Dürr, Eva-Maria,McGouran, Joanna F.
, (2021/06/21)
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 DNAs with succinamide internucleoside linkages and its application in discrimination of T-C mismatch
Sun, Yawei,Lü, Huanfang,Sun, Limei,Wang, Dong,Wang, Jiqian
, (2020/11/12)
Peptide nucleic acid (PNA) has many applications in molecular biology and biotechnology, and research continues on modifying the PNA backbone to improve its functionality. We synthesized PNA in our case, artificial DNA that contains neutral succimamide as internucleoside linkages and applied it to mismatch recognition. We embedded the succinamide linkages into DNA by incorporating thymidine–succinamide–thymidine (TST) phosphoramidite at specific sites via standard DNA synthesis. Ultraviolet spectroscopy and melting temperature experiments suggested that such mixed-backbone DNA forms a B-type duplex with natural DNA. We observed a 20 kJ/mol decrease in enthalpy when we incorporated a succinamide linkage into a DNA–PNA duplex. We examined mismatch recognition of the mixed-backbone DNA, and observed that TST embedded DNA recognizes T-C mismatches.
Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate
Brickute,Beckley,Allott,Braga,Barnes,Thorley,Aboagye
, p. 12423 - 12433 (2021/04/07)
The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3′-[18F]fluorothymidine-5′-squaryl ([18F]SqFLT) as a bioisostere to 3′-[18F]fluorothymidine-5′-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluationin vitroshowed low tracer uptake (?1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK?. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK?xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.
3' PROTECTED NUCLEOTIDES
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Paragraph 0484-0487, (2020/07/14)
The present disclosure provides 3' protected nucleotides, including those 3' protected nucleotides having a detectable tag. Systems and methods of sequencing nucleic acids using the 3' protected nucleotides are also disclosed, such as the sequencing of a nucleic acid using a nanopore or the sequencing of a nucleic acid via sequencing-by-synthesis.
RETRACTED ARTICLE: Divergent synthesis of 5-substituted pyrimidine 2′-deoxynucleosides and their incorporation into oligodeoxynucleotides for the survey of uracil DNA glycosylases
Tran, Ai,Zheng, Song,White, Dawanna S.,Curry, Alyson M.,Cen, Yana
, p. 11818 - 11826 (2020/11/18)
Recent studies have indicated that 5-methylcytosine (5mC) residues in DNA can be oxidized and potentially deaminated to the corresponding thymine analogs. Some of these oxidative DNA damages have been implicated as new epigenetic markers that could have profound influences on chromatin function as well as disease pathology. In response to oxidative damage, the cells have a complex network of repair systems that recognize, remove and rebuild the lesions. However, how the modified nucleobases are detected and repaired remains elusive, largely due to the limited availability of synthetic oligodeoxynucleotides (ODNs) containing these novel DNA modifications. A concise and divergent synthetic strategy to 5mC derivatives has been developed. These derivatives were further elaborated to the corresponding phosphoramidites to enable the site-specific incorporation of modified nucleobases into ODNs using standard solid-phase DNA synthesis. The synthetic methodology, along with the panel of ODNs, is of great value to investigate the biological functions of epigenetically important nucleobases, and to elucidate the diversity in chemical lesion repair.
MODIFIED NUCLEOTIDES FOR SYNTHESIS OF NUCLEIC ACIDS, A KIT CONTAINING SUCH NUCLEOTIDES AND THEIR USE FOR THE PRODUCTION OF SYNTHETIC NUCLEIC ACID SEQUENCES OR GENES
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Paragraph 0105, (2020/08/05)
A modified nucleotide, intended for the synthesis of long chain nucleic acids by enzymatic processes, comprising a “natural” nitrogenous base or a natural nitrogenous base analogue, a ribose or deoxyribose carbohydrate, and at least one phosphate group, characterized in that said nucleotide comprises at least one R group, termed the modifier group, carried by said nitrogenous base or analogue and/or by the oxygen in position 3′ of the ribose or deoxyribose molecule, making it possible to block the polymerization of said nucleotide and/or to allow the interaction of said nucleotide with another molecule, such as a protein, during the nucleic acid synthesis, R comprising at least one functional terminal group.
