Selective Platination of Modified Oligonucleotides and Duplex Cross‐Links

Algueró, Berta; Osa, Jaime López de la; González, Carlos; Pedroso, Enrique; Marchán, Vicente; Grandas, Anna

doi:10.1002/anie.200603128

“…Ligand exchange by transition metals provides an alternative basis for bipedal diffusion along DNA but few examples have yet been published. To date, Pt(II) migration has only been observed over a single bipedal transfer 54,62,63 . A related system utilizing Pd(II) with a track of pyridine ligands alternatively required addition of heat and a pH change to drive bipedal walking 64 .…”

Section: Resultsmentioning

confidence: 99%

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Fakhari

¹

,

Rokita

²

2014

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DNA has previously served as an excellent scaffold for molecular transport based on its noncovalent base pairing to assemble both stationary and mobile elements. Use of DNA can now be extended to transport systems based on reversible covalent chemistry. Autonomous and bipedal-like migration of crosslinking within helical DNA is made possible by tandem exchange of a quinone methide intermediate. In this report, net transport is illustrated to proceed over 10 base pairs. This process is driven towards its equilibrium distribution of crosslinks and consumes neither the walker nor the track irreversibly. Successful migration requires an electron-rich quinone methide to promote its regeneration and a continuous array of nucleophilic sites along its DNA track. Accordingly, net migration can be dramatically influenced by the presence of noncanonical structures within duplex DNA as demonstrated with a backbone nick and extrahelical bulge.

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“…In studies aimed at understanding how transplatin distorts nucleic acid structure differently than its cis counterpart, it was discovered that pre-formed 1,3 G*pNpG* transplatin-derived adducts on DNA readily rearrange into intermolecular cross-links when annealed to complementary oligonucleotides [88][89][90]. Subsequent mechanistic studies have shown that isomerization reactions between these 1,3 G*pNpG* transplatin adducts and complementary oligonucleotides are sequence-specific [91], can result in unusual G-N7* to C-N3* crosslinks [89], and are also observed using 2'-OMe [92] and chemically modified RNAs [93]. Further work has shown that transplatin-modified 2'-OMe RNAs [94] and cisplatinmodified RNAs [95,96] can be used as antisense oligos for attenuating gene expression in cell lysates and in living cells.…”

Section: Transplatin Cross-linking and Pt(ii) Drug Conjugatesmentioning

confidence: 99%

Binding of Kinetically Inert Metal Ions to RNA: The Case of Platinum(II)

Chapman

¹

,

Hostetter

²

,

Osborn

³

et al. 2011

Structural and Catalytic Roles of Metal Ions in RNA

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In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution of Pt(II) complexes results in significant platination of RNA, and localization studies find Pt(II) in the nucleus, nucleolus, and a distribution of other sites in cells. Treatment with Pt(II) compounds disrupts RNA-based processes including enzymatic processing, splicing, and translation, and this disruption may be indicative of structural changes to RNA or RNA-protein complexes. Several RNA-Pt(II) adducts have been characterized in vitro by biochemical and other methods. Evidence for Pt(II) binding in non-helical regions and for Pt(II) cross-linking of internal loops has been found. Although platinated sites have been identified, there currently exists very little in the way of detailed structural characterization of RNA-Pt(II) adducts. Some insight into the details of Pt(II) coordination to RNA, especially RNA helices, can be gained from DNA model systems. Many RNA structures, however, contain complex tertiary folds and common, purine-rich structural elements that present suitable Pt(II) nucleophiles in unique arrangements which may hold the potential for novel types of platinum-RNA adducts. Future research aimed at structural characterization of platinum-RNA adducts may provide further insights into platinum-nucleic acid binding motifs, and perhaps provide a rationale for the observed inhibition by Pt(II) complexes of splicing, translation, and enzymatic processing.

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“…Subsequent mechanistic studies have shown that isomerization reactions between these 1,3 G*pNpG* transplatin adducts and complementary oligonucleotides are sequence-specific [91], can result in unusual G-N7* to C-N3* cross-links [89], and are also observed using 2’-OMe [92] and chemically modified RNAs [93]. Further work has shown that transplatin-modified 2’-OMe RNAs [94] and cisplatin-modified RNAs [95,96] can be used as antisense oligos for attenuating gene expression in cell lysates and in living cells.…”

Section: In Vitro Studies Of Rna-pt(ii) Adductsmentioning

confidence: 99%

12 Binding of Kinetically Inert Metal Ions to RNA: The Case of Platinum(II)

Chapman¹,

Hostetter²,

Osborn³

et al. 2015

Structural and Catalytic Roles of Metal Ions in RNA

0

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In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution of Pt(II) complexes results in significant platination of RNA, and localization studies find Pt(II) in the nucleus, nucleolus, and a distribution of other sites in cells. Treatment with Pt(II) compounds disrupts RNA-based processes including enzymatic processing, splicing, and translation, and this disruption may be indicative of structural changes to RNA or RNA-protein complexes. Several RNA-Pt(II) adducts have been characterized in vitro by biochemical and other methods. Evidence for Pt(II) binding in non-helical regions and for Pt(II) cross-linking of internal loops has been found. Although platinated sites have been identified, there currently exists very little in the way of detailed structural characterization of RNA-Pt(II) adducts. Some insight into the details of Pt(II) coordination to RNA, especially RNA helices, can be gained from DNA model systems. Many RNA structures, however, contain complex tertiary folds and common, purine-rich structural elements that present suitable Pt(II) nucleophiles in unique arrangements which may hold the potential for novel types of platinum-RNA adducts. Future research aimed at structural characterization of platinum-RNA adducts may provide further insights into platinum-nucleic acid binding motifs, and perhaps provide a rationale for the observed inhibition by Pt(II) complexes of splicing, translation, and enzymatic processing.

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Selective Platination of Modified Oligonucleotides and Duplex Cross‐Links

Cited by 18 publications

References 20 publications

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Binding of Kinetically Inert Metal Ions to RNA: The Case of Platinum(II)

12 Binding of Kinetically Inert Metal Ions to RNA: The Case of Platinum(II)

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