Directing Quadruplex-Stabilizing Drugs to the Telomere:  Synthesis and Properties of Acridine−Oligonucleotide Conjugates

Casals, Joan; Debéthune, Laurent; Alvarez, Karine; Risitano, Antonina; Fox, Keith R.; Grandas, Anna; Pedroso, Enrique

doi:10.1021/bc060194t

Cited by 16 publications

(20 citation statements)

References 32 publications

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“…Studying G-quadruplex stabilizing drugs [35,36], we have previously shown that DAPER is able to selectively bind to G-quadruplex structures with respect to duplex, on account of G-quadruplex larger aromatic area and higher charge density [37][38][39]. Both these features characterize also triplex structure with respect to duplex, suggesting us to investigate DAPER for its ability to bind and stabilize the anti-parallel triplexes [40].…”

Section: Stabilizing Effect Of the Perylene Derivative Daper On Triplmentioning

confidence: 99%

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

Rossetti

D'Isa

Mauriello

et al. 2007

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Montesano 49, I-80131 Napoli, Italy. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT*corresponding author A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2 ABSTRACTThe promoter of human telomerase reverse transcriptase (hTERT) gene, in the region from -1000 to +1, contains two homopurine-homopyrimidine sequences (-835/-814 and -108/-90), that can be considered as potential targets to triple helix forming oligonucleotides (TFOs) for applying antigene strategy.We have chosen the sequence (-108/-90) on the basis of its unfavorable Since DAPER is a symmetric molecule, the induced Circular Dichroism (CD) spectra in the range 400-600 nm, allows us to obtain information on drug binding to triplex and duplex DNA. The drug induced ellipticity is significantly higher in the case of triplex with respect to duplex and, surprisingly, it increases at decreasing of DNA. A model is proposed where self-stacked DAPER binds to triplex or to duplex narrow grooves.

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Section: Stabilizing Effect Of the Perylene Derivative Daper On Triplmentioning

confidence: 99%

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

Rossetti

D'Isa

Mauriello

et al. 2007

Biophysical Chemistry

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“…This side product has previously been reported, and avoided, either by removing one capping step and include morpholine washing when synthesizing POCs from 5′-aminonucleoside-containing oligonucleotides (8) or use of active esters when conjugating acridine derivatives (36). This is a separate problem, occurring before and not connected to the conjugation method per se , and the acetylated fraction will not react further.…”

Section: Resultsmentioning

confidence: 99%

An activated triple bond linker enables ‘click’ attachment of peptides to oligonucleotides on solid support

Wenska

Alvira

Steunenberg

et al. 2011

Nucleic Acids Research

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A general procedure, based on a new activated alkyne linker, for the preparation of peptide–oligonucleotide conjugates (POCs) on solid support has been developed. With this linker, conjugation is effective at room temperature (RT) in millimolar concentration and submicromolar amounts. This is made possible since the use of a readily attachable activated triple bond linker enhances the Cu(I) catalyzed 1,3-dipolar cycloaddition (‘click’ reaction). The preferred scheme for conjugate preparation involves sequential conjugation to oligonucleotides on solid support of (i) an H-phosphonate-based aminolinker; (ii) the triple bond donor p-(N-propynoylamino)toluic acid (PATA); and (iii) azido-functionalized peptides. The method gives conversion of oligonucleotide to the POC on solid support, and only involves a single purification step after complete assembly. The synthesis is flexible and can be carried out without the need for specific automated synthesizers since it has been designed to utilize commercially available oligonucleotide and peptide derivatives on solid support or in solution. Methodology for the ready conversion of peptides into ‘clickable’ azidopeptides with the possibility of selecting either N-terminus or C-terminus connection also adds to the flexibility and usability of the method. Examples of synthesis of POCs include conjugates of oligonucleotides with peptides known to be membrane penetrating and nuclear localization signals.

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“…Acridine-oligonucleotide conjugates were also designed and found to interact with both single stranded telomeric sequences and G4 structure 148 To address these issues, our group had truncated the quadruplex binding domain of LL37 and made some selective mutations to increase the affinity towards c-MYC G4 developing a peptide molecule, KR12C (Table 2), which is highly specific to previously undruggable c-MYC G4 and stabilize it by 9 ○ C as observed from Circular Dichroism melting experiment. We also observed binding affinity (KD) of the peptide to the c-MYC G4 is 901 nM 151 through Isothermal titration Calorimetry, in the presence of MCF-7 nuclear extract (which mimicked a molecular crowding condition).…”

Section: (C) Ligands Conjugated With Peptides Nucleotides and Glycosmentioning

confidence: 99%

G-Quadruplex targeting ligands: A hope and a new horizon in Cancer Therapeutics

Banerjee¹,

Panda²,

Chatterjee³

2018

Preprint

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G-quadruplex, a unique secondary structure in nucleic acids found throughout human genome elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, G-quadruplex structure regulates transcription, translation, splicing, telomere stability etc. Changes in its structure and stability lead to differential expression of oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small molecules/ other biologics has shown elevated research interest. Covering previous reports, in this review we try to enlighten the facts on the structural diversity in G-quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next generation cancer treatment.

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Directing Quadruplex-Stabilizing Drugs to the Telomere: Synthesis and Properties of Acridine−Oligonucleotide Conjugates

Cited by 16 publications

References 32 publications

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

An activated triple bond linker enables ‘click’ attachment of peptides to oligonucleotides on solid support

G-Quadruplex targeting ligands: A hope and a new horizon in Cancer Therapeutics

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