Synthesis and spectral characterization of environmentally responsive fluorescent deoxycytidine analogs

Elmehriki, Adam A. H.; Suchý, Mojmı́r; Chicas, Kirby; Wojciechowski, Filip; Hudson, Robert

doi:10.4161/adna.29174

Cited by 8 publications

(18 citation statements)

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“…Nucleoside analogs 2 – 5 possessing substituted pyrrolocytoside nucleobases have been obtained in one-pot fashion via a reaction cascade involving a Sonogashira cross-coupling with an appropriate alkyne and subsequent 5-endo-dig cyclization . The synthesis of BFpC ( 3 , Scheme ) from protected cytosine 6a and 2-ethynylbenzo[ b ]furan ( 7 , Scheme ) has been described elsewhere …”

Section: Resultsmentioning

confidence: 99%

“…p -NO 2 -PhpC ( 2 , Scheme ), FpC ( 4 , Scheme ), and DABCYLpC ( 5 , Scheme ) have been synthesized in the same manner by reacting suitably protected cytosines 6a or 6b with commercially available p -NO 2 -phenylacetylene ( 10 ), 2-ethynylfuran ( 8 , prepared in two steps from fural using the modified literature protocol), or DABCYL-modified alkyne 9 (Scheme ) developed recently by our laboratory . Subsequent deprotection (Scheme ) led to preparation of nucleobase analogs 2 – 5 (Scheme ) in reasonable overall yield (40–52%), see the Experimental Section for details.…”

Section: Resultsmentioning

confidence: 99%

“…PhpC obeys the Watson–Crick base-pairing rules with guanine (Figure ), is generally stabilizing to hybridization when incorporated into DNA, RNA, or PNA, and possesses useful probe properties . With the aim to tune the fluorescence properties associated with PhpC, we have, among other structural modifications, also prepared 2-benzo[ b ]furyl-substituted (BFpC, 3 , Figure ) and 2-furyl-substituted (FpC, 4 , Figure ) analogs for enhanced fluorescence properties, along with the nucleobase possessing 4-[(4-dimethylaminophenyl)azo]phenyl (DABCYLpC, 5 , Figure ) and 6-( p -nitrophenyl) ( p -NO 2 -PhpC, 2 , Figure ) moieties to serve as fluorescence quenchers …”

Section: Introductionmentioning

confidence: 99%

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Unusual C7- versus Normal 5′-O-Dimethoxytritylation of 6-Arylpyrrolocytidine Analogs

et al. 2016

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Fluorescent deoxynucleosides possessing the modified bases 6-(2-benzo[b]furyl)- and 6-(2-furyl)pyrrolocytosine (BFpC and FpC) have been synthesized along with the quencher nucleosides possessing 6-{4-[(4-dimethylamino)azo]phenyl}pyrrolocytosine (DABCYLpC) and 6-(p-nitrophenyl)pyrrolocytosine (p-NO2-PhpC) nucleobase analogs. Standard treatment of BFpC, FpC, DABCYLpC, and p-NO2-PhpC with dimethoxytrityl chloride (DMT-Cl) led to the unusual substitution on the C7 of the pyrrolocytosine skeleton. The desired 5'-O-DMT-protected nucleoside analogs were synthesized from suitably protected 5'-O-DMT cytidines. Subsequent phosphitylation smoothly afforded BFpC-, FpC-, DABCYLpC-, and p-NO2-PhpC-derived monomers suitable for standard oligonucleotide synthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unusual C7- versus Normal 5′-O-Dimethoxytritylation of 6-Arylpyrrolocytidine Analogs

et al. 2016

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“…In the course of our work with modified bases in peptide nucleic acids, we found that 6‐phenylpyrrolocytosine was much more emissive than the 6‐methyl congener (Hudson et al., ; Hudson, Dambenieks, & Moszynski, ) and this subsequently proved to be the case for the 2′‐deoxyribo‐ and ribonucleosides. The emissivity of the 6‐phenyl‐substituted pyrrolocytidines (ϕ = 0.31 – 0.32) is approximately 10‐fold greater than the methyl‐substituted analog (ϕ = 0.026 – 0.03) (Elmehriki, Suchy, Chicas, Wojciechowski, & Hudson, ; Hardman, Botchway, & Thompson, ; Ming & Seela, ; Yang, Mei, & Seela, ) and this can be critical in applications such as intracellular tracking of oligonucleotides (Wahba et al., ). The protocols reported in this unit may be extended to more diverse 6‐arylpyrrolocytidines (Elmehriki et al., ; Suchy et al., ) with the potential of producing brighter and more responsive fluorescent derivatives.…”

Section: Commentarymentioning

confidence: 99%

6‐Phenylpyrrolocytidine: An Intrinsically Fluorescent, Environmentally Responsive Nucleoside Analogue

Cho

Ghorbani‐Choghamarani

Saitō

et al. 2019

CP Nucleic Acid Chemistry

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The detailed synthetic protocols for the preparation of phosphoramidite reagents compatible with standard, automated oligonucleotide synthesis for the 2 -deoxy-and ribo-6-phenylpyrrolocyitidine are reported. Each protocol starts with the parent nucleoside and prepares the 5 -O-dimethoxytrityl-N 4benzoyl-5-iodocytosine derivative for the nucleobase modification chemistry. The key step is the direct formation of 6-phenylpyrrolocytosine aglycon via a sequential, one-pot Pd-catalyzed Sonogashira-type cross-coupling followed by a 5-endo-dig cyclization. Subsequent standard transformations provide the deoxy-and 2 -O-tert-butyldimethysilyl protected ribo-nucleoside phosphoramidite reagents. C 2019 by John Wiley & Sons, Inc.Keywords: base-discriminating fluorophore r DNA r environmentally responsive r fluorescence r Pyrrolocytidine r RNA

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“…[2,10] Although pyrrolo-C is able to maintain pseudo-Watson-Crick bonding with guanine without perturbing the overall structure of the nucleic acid, [11] it has a modest fluorescence intensity, making it a less sensitive probe. [10,12] Thus, there is a need for a new environmentally sensitive cytosine analog that can report with high sensitivity on nucleic structure and interactions while retaining high quantum yields.…”

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confidence: 99%

6‐phenylpyrrolocytosine as a fluorescent probe to examine nucleotide flipping catalyzed by a DNA repair protein

et al. 2020

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Cellular exposure to tobacco‐specific nitrosamines causes formation of promutagenic O6‐[4‐oxo‐4‐(3‐pyridyl)but‐1‐yl]guanine (O6‐POB‐G) and O6‐methylguanine (O6‐Me‐G) adducts in DNA. These adducts can be directly repaired by O6‐alkylguanine‐DNA alkyltransferase (AGT). Repair begins by flipping the damaged base out of the DNA helix. AGT binding and base‐flipping have been previously studied using pyrrolocytosine as a fluorescent probe paired to the O6‐alkylguanine lesion, but low fluorescence yield limited the resolution of steps in the repair process. Here, we utilize the highly fluorescent 6‐phenylpyrrolo‐2′‐deoxycytidine (6‐phenylpyrrolo‐C) to investigate AGT‐DNA interactions. Synthetic oligodeoxynucleotide duplexes containing O6‐POB‐G and O6‐Me‐G adducts were placed within the CpG sites of codons 158, 245, and 248 of the p53 tumor suppressor gene and base‐paired to 6‐phenylpyrrolo‐C in the opposite strand. Neighboring cytosine was either unmethylated or methylated. Stopped‐flow fluorescence measurements were performed by mixing the DNA duplexes with C145A or R128G AGT variants. We observe a rapid, two‐step, nearly irreversible binding of AGT to DNA followed by two slower steps, one of which is base‐flipping. Placing 5‐methylcytosine immediately 5′ to the alkylated guanosine causes a reduction in rate constant of nucleotide flipping. O6‐POB‐G at codon 158 decreased the base flipping rate constant by 3.5‐fold compared with O6‐Me‐G at the same position. A similar effect was not observed at other codons.

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Synthesis and spectral characterization of environmentally responsive fluorescent deoxycytidine analogs

Cited by 8 publications

References 59 publications

Unusual C7- versus Normal 5′-O-Dimethoxytritylation of 6-Arylpyrrolocytidine Analogs

Unusual C7- versus Normal 5′-O-Dimethoxytritylation of 6-Arylpyrrolocytidine Analogs

6‐Phenylpyrrolocytidine: An Intrinsically Fluorescent, Environmentally Responsive Nucleoside Analogue

6‐phenylpyrrolocytosine as a fluorescent probe to examine nucleotide flipping catalyzed by a DNA repair protein

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