Organometallic B<sub>12</sub>–DNA Conjugate: Synthesis, Structure Analysis, and Studies of Binding to Human B<sub>12</sub>‐Transporter Proteins

Hunger, Miriam; Mutti, Elena; Rieder, Alexander; Enders, Barbara; Nexø, Ebba; Kräutler, Bernhard

doi:10.1002/chem.201404359

Cited by 14 publications

(26 citation statements)

References 43 publications

(88 reference statements)

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“…These reagents were prepared by phosphoramidite chemistry, as described in the Experimental Section and ref. . Base‐labile protecting groups were used because the primary 5′‐bromide function was not fully compatible with standard DNA deprotection procedures.…”

Section: Resultsmentioning

confidence: 99%

“…The organometallic DNA–B 12 conjugates Co‐(dN) n ‐Cbl ( n =25 or 39) were prepared through electrochemical reduction, as described recently (Scheme ). Reduction of H 2 OCbl ⋅ Cl at a Hg electrode at −1.10 V versus a 0.1 n calomel electrode (CE) in a deoxygenated solution gave green Co I Cbl.…”

Section: Resultsmentioning

confidence: 99%

“…The use of DNA and RNA oligomers in diagnosis and therapy is strongly hampered by a lack of versatile natural vectors suitable for the in vivo transport of such oligonucleotides and their controlled delivery to cellular or organ targets in humans and animals . We recently started to explore the capacity of the natural cobalamin (Cbl) transport system for this task . In humans and animals, vitamin B 12 (cyanocobalamin (CNCbl)) is absorbed, and delivered by three highly specific Cbl transporters, haptocorrin (HC), intrinsic factor (IF), and transcobalamin (TC), which help to provide all cells with vitamin B 12 and/or other dietary forms of Cbls.…”

Section: Introductionmentioning

confidence: 99%

“… Left: Structural formulas of important B 12 derivatives: vitamin B 12 (L=CN), methylcobalamin (MeCbl; L=CH 3 ), coenzyme B 12 (AdoCbl; L=5′‐deoxyadenosyl), octadecanucleotidylcobalamin (Co‐(dN) 18 ‐Cbl; L=[dT‐(dN) 17 ]Na 17 ), Co‐(dN) 25 ‐Cbl (L=[dT‐(dN) 24 ]Na 24 ), and Co‐(dN) 39 ‐Cbl (L=[dT‐(dN) 38 ]Na 38 ). Top right: symbol for a Cbl as a Trojan Horse with a drug attached as axial ligand; bottom: general symbol for various Cbls.…”

Section: Introductionmentioning

confidence: 99%

“…We recently described exploratory studies with the organometallic B 12 derivative Co‐(dN) 18 ‐Cbl (dN: deoxynucleotide), carrying an 18 nt DNA strand . Remarkably, this DNA–Cbl conjugate appeared to bind well only to TC, but not to IF or HC.…”

Section: Introductionmentioning

confidence: 99%

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Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

et al. 2017

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The synthesis and structural characterization of Co-(dN) -Cbl (Cbl: cobalamin; dN: deoxynucleotide) and Co-(dN) -Cbl, which are organometallic DNA-B conjugates with single DNA strands consisting of 25 and 39 deoxynucleotides, respectively, and binding studies of these two DNA-Cbl conjugates to three homologous human Cbl transporting proteins, transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are reported. This investigation tests the suitability of such DNA-Cbls for the task of eventual in vivo oligonucleotide delivery. The binding of DNA-Cbl to TC, IF, and HC was investigated in competition with either a fluorescent Cbl derivative and Co-(dN) -Cbl, or radiolabeled vitamin B ( Co-CNCbl) and Co-(dN) -Cbl or Co-(dN) -Cbl. Binding of the new DNA-Cbl conjugates was fast and tight with TC, but poorer with HC and IF, which extends a similar original finding with the simpler DNA-Cbl, Co-(dN) -Cbl. The contrasting affinities of TC versus IF and HC for the DNA-Cbl conjugates are rationalized herein by a stepwise mechanism of Cbl binding. Critical contributions to overall affinity result from gradual conformational adaptations of the Cbl-binding proteins to the DNA-Cbl, which is first bound to the respective β domains. This transition is fast with TC, but slow with IF and HC, with which weaker binding results. The invariably tight interaction of the DNA-Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

et al. 2017

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VitaminB₁₂and CofactorF430

Kräutler

Jaun

2022

Fundamentals of Porphyrin Chemistry

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Synthetic Approaches toward Vitamin B₁₂ Conjugates

2018

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The ability to conjugate functional molecules to vitamin B 12 (cobalamin) is an important strategy for the construction of hybrid molecules with various applications in medicinal chemistry, diagnostics, and biological sciences. Cobalamin, as an exogenous compound, reaches mammalian cells via a system of transport proteins and therefore the position of conjugation must be selected in such a way that the recognition process is not disturbed. The complex structure of vitamin B 12 provides many routes for the synthesis of conjugates containing cargos appended at different sites, however, only the e-propionamide chain, βaxial position and R 5' -OH are found to meet the aforementioned criteria. Over the years, a number of synthetic approaches leading to cobalamin conjugates have been developed and, herein, we summarize those leading to conjugates with a cargo tethered at the central cobalt ion, macrocyclic core, ribonucleotide moiety, or a combination thereof. . Synthesis of cobalamin triazoles. Scheme 16. Synthesis of precursor 41 and its subsequent functionalization. Scheme 17. Functionalization of phosphate moiety.[a] Compound 43 c was obtained from 43 b via substitution with NaN 3 .

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Organometallic B₁₂–DNA Conjugate: Synthesis, Structure Analysis, and Studies of Binding to Human B₁₂‐Transporter Proteins

Cited by 14 publications

References 43 publications

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

VitaminB₁₂and CofactorF430

Synthetic Approaches toward Vitamin B₁₂ Conjugates

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Organometallic B12–DNA Conjugate: Synthesis, Structure Analysis, and Studies of Binding to Human B12‐Transporter Proteins

Cited by 14 publications

References 43 publications

Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

VitaminB12and CofactorF430

Synthetic Approaches toward Vitamin B12 Conjugates

Contact Info

Product

Resources

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Organometallic B₁₂–DNA Conjugate: Synthesis, Structure Analysis, and Studies of Binding to Human B₁₂‐Transporter Proteins

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

VitaminB₁₂and CofactorF430

Synthetic Approaches toward Vitamin B₁₂ Conjugates