Oligonucleotide Duplexes with Tethered Photoreactive Ruthenium(II) Complexes: Influence of the Ligands and Their Linker on the Photoinduced Electron Transfer and Crosslinking Processes of the Two Strands

Deroo, Stéphanie; Gac, Stéphane Le; Ghosh, Sumana; Villien, Mathilde; Gerbaux, Pascal; Defrancq, Éric; Moucheron, Cécile; Dumy, Pascal; Mesmaeker, Andrée Kirsch‐De

doi:10.1002/ejic.200801083

Cited by 21 publications

(21 citation statements)

References 31 publications

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“…Rather than the common metalation at the N‐7 position of guanine, the ligand is covalently attached to the exocyclic 2‐amino group of the base, suggesting disruption in the duplex structure before reaction with the metal complex. The addition of the ruthenium complex to DNA was used to induce crosslinks between two DNA strands,8e,47 creating potential photo‐reactive “gene silencing” agents 48. In the absence of the complementary sense strand, the anti‐sense oligonucleotide acts as a “seppuku” agent and undergoes self‐crosslinking.…”

Section: Metal Complexes As Dna Damaging Agentsmentioning

confidence: 99%

Light‐Activated Metal Complexes that Covalently Modify DNA

Glazer

2013

Israel Journal of Chemistry

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Many drugs in current clinical use rely on mechanisms of action that involve damage to nucleic acids. While this has been a successful therapeutic approach for many years, the major limitation of these agents is systemic cytotoxicity, resulting from damage caused to healthy cells. Photoactive metal complexes offer the possibility of combining two successful treatment modalities for cancer and other diseases by providing DNA damage similar to that obtained with cisplatin, but in a spatially and temporally controlled manner, as with phototherapy. Recent progress in the field has provided metal complexes that can be triggered to create covalent adducts with nucleic acids both in vitro and in cells. Furthermore, several of these agents have been shown to induce cytotoxicity in cancer cell lines, in vitro tumor models, and in vivo animal models. In the last year, new compounds have been reported that can be activated with low energy light within the “therapeutic window,” where light penetration through tissue is sufficient to access larger volume tumors. This review highlights the advances that demonstrate the potential of light‐activated metal complexes as therapeutics and research tools for biomedical applications.

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Section: Metal Complexes As Dna Damaging Agentsmentioning

confidence: 99%

Light‐Activated Metal Complexes that Covalently Modify DNA

Glazer

2013

Israel Journal of Chemistry

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“…The synthesis and purification of [Ru(TAP) 2 (phen")] 2 þ (Figure 2) (TAP, 1,4,5,8-tetraazaphenanthrene; phen, 1,10-phenanthroline) the preparation of the modified oligonucleotides and the procedure for the coupling of the Ru complex to the 3 0 end of the ODNs were previously reported. [70][71][72] The Ru-ASO conjugates were purified by PAGE and characterized by electrospray mass spectrometry. The complementary sequences (non-modified), namely C-6 and C-4 ( Figure 2) were synthesized with a DNA automatic synthesizer and characterized by electro-spray mass spectrometry.…”

Section: Synthesis Of Ru-asosmentioning

confidence: 99%

Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53

et al. 2012

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High-risk Human Papillomaviruses (HPV) has been found to be associated with carcinomas of the cervix, penis, vulva/vagina, anus, mouth and oro-pharynx. As the main tumorigenic effects of the HPV have been attributed to the expression of E6 and E7 genes, different gene therapy approaches have been directed to block their expression such as antisense oligonucleotides (ASO), ribozymes and small interfering RNAs. In order to develop a gene-specific therapy for HPV-related cancers, we investigated a potential therapeutic strategy of gene silencing activated under illumination. Our aim according to this antisense therapy consisted in regulating the HPV16 E6 oncogene by using an E6-ASO derivatized with a polyazaaromatic ruthenium (Ru II) complex (E6-Ru-ASO) able, under visible illumination, to crosslink irreversibly the targeted sequence. We examined the effects of E6-Ru-ASO on the expression of E6 and on the cell growth of cervical cancer cells. We demonstrated using HPV16 þ SiHa cervical cancer cells that E6-Ru-ASO induces after illumination, a reactivation of p53, the most important target of E6, as well as the inhibition of cell proliferation with a selective repression of E6 at the protein level. These results suggest that E6-Ru ASOs, activated under illumination and specifically targeting E6, are capable of inhibiting HPV16 þ cervical cancer cell proliferation.

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“…As mentioned in the introduction, the importance of photoadduct formation was rst demonstrated with guanine residues in DNA and oligonucleotides. [25][26][27]51 The formation of a photoadduct between biological molecules, or in the present study small peptides, and an organometallic complex, has a dramatic inuence on the activity of the considered biomolecules. The formation of a covalent bond and also the structure of the photoproducts and their three-dimensional organization can open the door to different biomedical applications.…”

Section: Multiple Photo-adducts Formationmentioning

confidence: 85%

Parameters influencing the photo-induced electron transfer from tryptophan-containing peptides to a Ru^II complex: a systematic study

et al. 2015

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Ruthenium(II) polyazaaromatic complexes have gained interest in recent decades as biomolecular tools, especially in the development of new phototherapeutic agents. These light emissive Ru complexes based on π-deficient ligands were first designed to allow a photo-induced electron transfer (PET) with the guanine base in DNA since their (3)MLCT state is highly photo-oxidizing. Later the field of research was extended to proteins with the highlighting of a PET process with the tryptophan residue. This paper reports the kinetics of the luminescence quenching of [Ru(TAP)2phen](2+) by several selected peptide sequences containing at least one tryptophan residue. By using a peptide library we highlight the important parameters influencing the kinetics of the photo-electron transfer process, such as the net electrostatic charge and the number of tryptophan residues. The best peptide candidates were selected to study the formation of photo-products by MALDI-ToF mass spectrometry. A high photoreactivity of the [Ru(TAP)2phen](2+) complex was observed and multiple photoadducts were characterized, among them inter-peptidic adducts as well as intra-peptidic adducts.

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Oligonucleotide Duplexes with Tethered Photoreactive Ruthenium(II) Complexes: Influence of the Ligands and Their Linker on the Photoinduced Electron Transfer and Crosslinking Processes of the Two Strands

Abstract: International audienc

Cited by 21 publications

References 31 publications

Light‐Activated Metal Complexes that Covalently Modify DNA

Light‐Activated Metal Complexes that Covalently Modify DNA

Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53

Parameters influencing the photo-induced electron transfer from tryptophan-containing peptides to a Ru^II complex: a systematic study

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Oligonucleotide Duplexes with Tethered Photoreactive Ruthenium(II) Complexes: Influence of the Ligands and Their Linker on the Photoinduced Electron Transfer and Crosslinking Processes of the Two Strands

Abstract: International audienc

Cited by 21 publications

References 31 publications

Light‐Activated Metal Complexes that Covalently Modify DNA

Light‐Activated Metal Complexes that Covalently Modify DNA

Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53

Parameters influencing the photo-induced electron transfer from tryptophan-containing peptides to a RuII complex: a systematic study

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Parameters influencing the photo-induced electron transfer from tryptophan-containing peptides to a Ru^II complex: a systematic study