Di-heterometalation of thiol-functionalized peptide nucleic acids

Abstract

As a proof-of-principle, two hetero-bimetallic PNA oligomers containing a ruthenium(II) polypyridyl and a cyclopentadienyl manganese tricarbonyl complex have been prepared by serial combination of solid-phase peptide coupling and in-solution thiol chemistry. Solid-phase N-terminus attachment of Ru(II)-polypyridyl carboxylic acid derivative, C1, onto the thiol-functionalized PNA backbone (H-a-a-g-t-c-t-g-c-linker-cys-NH 2) has been performed by standard peptide coupling method. As two parallel approaches, the strong affinity of thiols for maleimide and haloacetyl group has been exploited for subsequent post-SPPS addition of cymantrene-based organometallic cores, C2 and C3. Michael-like addition and thioether ligation of thiol functionalized PNA1 (H-gly-a-a-g-t-c-t-g-c-linker-cys-NH 2) and PNA2 (C1-a-a-g-t-c-t-g-c-linker-cys-NH 2) to cymantrene maleimide and chloroacetyl derivatives, C2 and C3, respectively, has been performed. The synthesized ruthenium(II)-cymantrenyl PNA oligomers have been characterized by mass spectrometry (ESI-MS) and IR spectroscopy. The distinct Mn-CO vibrational IR stretches, between 1,924-2,074 cm (-1) , have been used as markers to confirm the presence of cymantrenyl units in the PNA sequences and the purity of the HPLC-purified PNA thioethers assessed using LC-MS.

The development of ruthenium(ii) polypyridyl complexes and conjugates forin vitrocellular andin vivoapplications

“…[329][330][331][332][333][334][335][336][337][338] However, while the synthesis of a number of Ru(II)-PNA conjugates has been reported, evaluation of their application in cells has yet to be investigated. [339][340][341] Please do not adjust margins Please do not adjust margins…”

Template‐Mediated Stabilization of a DNA G‐Quadruplex formed in the HIV‐1 Promoter and Comparative Binding Studies

“…The reaction between thiol-containing biomolecules and chloroacetamide-containing reporters (and vice versa) has been investigated in an umber of independents tudies. [23] The reactionisu sually performed in aqueous/organic mixtures with an excess of 2t o1 0equivalents ao ne reactanto ver the other. The reactioni sa lso performed under reducing conditions (tris(2-carboxyethyl)phosphine (TCEP)) to prevent the formation of disulfides pecies.…”

“…The SN2 reaction betweent hiol containingbiopolymers and reporters bearing iodoacetamide functions has been extensively reported in the past. [23] We hypothesized that such an SN2-thiol coupling reaction (TC) could be used along with OL and CuAAcf or the stepwise assembly of nucleic acid foldamers 2 from bifunctionnalized oligonucleotides and an adequately heterofunctionalized peptides caffold (Scheme 1). In the course of this work, we have found that the stepwise conjugation of oligonucleotide 3,b earing an aldehyde function at its 3' end, and oligonucleotide 4,b earing at hiol functiona ti ts 5' end, ontoc yclopeptide 6,f unctionalized with both an oxyamine and ac hloroacetamide moieties, allowed for the assembly of an intermediate conjugate 8 that may be subjected to intramolecular CuAAC reactions to form 2.A ll functionalities were found to be compatible and all ligations steps were performed with good to excellent yields.…”

Insertion of organometallic moieties into peptides and peptide nucleic acids using alternative “click” strategies

“…In particular, substitution with metal complexes have been of great interest to exploit additional properties of the new PNA-metal complex conjugate. 8,15,16,37,[44][45][46][47][48][49][50][51] In this work, we applied photoclick to achieve the insertion of a ferrocene moiety into a PNA sequence that was previously applied as an antisense agent on hepatitis B virus. 52 This sequence, which was synthesized via solid phase synthesis, 53 was further modified with the insertion of the PNA monomer bearing the modified tetrazole and a cysteine for conjugation via Michael addition (PNA, Fig.…”