Syntheses and characterization of vitamin B12-Pt(II) conjugates and their adenosylation in an enzymatic assay

Pilar Ruiz-Sánchez; Stefan Mundwiler; Bernhard Spingler; Nicole R. Buan; Jorge C. Escalante-Semerena; Roger Alberto

doi:10.1007/s00775-007-0329-4

Syntheses and characterization of vitamin B₁₂-Pt(II) conjugates and their adenosylation in an enzymatic assay

Pilar Ruiz-Sánchez, Stefan Mundwiler, Bernhard Spingler, Nicole R. Buan, Jorge C. Escalante-Semerena, Roger Alberto

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Aiming at the use of vitamin B₁₂ as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B₁₂ with trans-[PtCl(NH₃)₂(H₂O)]⁺, [PtCl ₃(NH₃)]^- and [PtCl₄]^2-. These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [{Co}-CN-{trans-PtCl(NH₃)₂}] ⁺ (5), [{Co}-CN-{trans-PtCl₂(NH₃)}] (6), [{Co}-CN-{cis-PtCl₂(NH₃)}] (7) and [{Co}-CN-{PtCl ₃}]^- (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central "Co-CN-Pt" motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B₁₂ conjugates. Release of the platinum complexes from vitamin B₁₂ is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the β-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B ₁₂ can potentially be used for delivering metal-containing compounds into cells.

Original language	English (US)
Pages (from-to)	335-347
Number of pages	13
Journal	Journal of Biological Inorganic Chemistry
Volume	13
Issue number	3
DOIs	https://doi.org/10.1007/s00775-007-0329-4
State	Published - Mar 2008
Externally published	Yes

Keywords

Adenosyltransferase
Cisplatin
Targeting
Vitamin B

ASJC Scopus subject areas

Biochemistry
Inorganic Chemistry

Access to Document

10.1007/s00775-007-0329-4

Cite this

@article{f5245add09d44ab3a5cd2377f75644e8,

title = "Syntheses and characterization of vitamin B12-Pt(II) conjugates and their adenosylation in an enzymatic assay",

abstract = "Aiming at the use of vitamin B12 as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B12 with trans-[PtCl(NH3)2(H2O)]+, [PtCl 3(NH3)]- and [PtCl4]2-. These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [{Co}-CN-{trans-PtCl(NH3)2}] + (5), [{Co}-CN-{trans-PtCl2(NH3)}] (6), [{Co}-CN-{cis-PtCl2(NH3)}] (7) and [{Co}-CN-{PtCl 3}]- (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central {"}Co-CN-Pt{"} motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B12 conjugates. Release of the platinum complexes from vitamin B12 is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the β-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B 12 can potentially be used for delivering metal-containing compounds into cells.",

keywords = "Adenosyltransferase, Cisplatin, Targeting, Vitamin B",

author = "Pilar Ruiz-S{\'a}nchez and Stefan Mundwiler and Bernhard Spingler and Buan, {Nicole R.} and Escalante-Semerena, {Jorge C.} and Roger Alberto",

note = "Funding Information: Acknowledgements This project was supported financially by Swiss National Science Foundation grant 117658 (P.S.-R.); N.B. and J.C.E.-S. were supported by PHS grant R01-GM40313 to J.C.E.-S. Thanks to Laurent Bigler, Institute of Organic Chemistry at the University of Zurich, for careful MS measurements.",

year = "2008",

month = mar,

doi = "10.1007/s00775-007-0329-4",

language = "English (US)",

volume = "13",

pages = "335--347",

journal = "Journal of Biological Inorganic Chemistry",

issn = "0949-8257",

publisher = "Springer Verlag",

number = "3",

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TY - JOUR

T1 - Syntheses and characterization of vitamin B12-Pt(II) conjugates and their adenosylation in an enzymatic assay

AU - Ruiz-Sánchez, Pilar

AU - Mundwiler, Stefan

AU - Spingler, Bernhard

AU - Buan, Nicole R.

AU - Escalante-Semerena, Jorge C.

AU - Alberto, Roger

N1 - Funding Information: Acknowledgements This project was supported financially by Swiss National Science Foundation grant 117658 (P.S.-R.); N.B. and J.C.E.-S. were supported by PHS grant R01-GM40313 to J.C.E.-S. Thanks to Laurent Bigler, Institute of Organic Chemistry at the University of Zurich, for careful MS measurements.

PY - 2008/3

Y1 - 2008/3

N2 - Aiming at the use of vitamin B12 as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B12 with trans-[PtCl(NH3)2(H2O)]+, [PtCl 3(NH3)]- and [PtCl4]2-. These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [{Co}-CN-{trans-PtCl(NH3)2}] + (5), [{Co}-CN-{trans-PtCl2(NH3)}] (6), [{Co}-CN-{cis-PtCl2(NH3)}] (7) and [{Co}-CN-{PtCl 3}]- (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central "Co-CN-Pt" motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B12 conjugates. Release of the platinum complexes from vitamin B12 is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the β-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B 12 can potentially be used for delivering metal-containing compounds into cells.

AB - Aiming at the use of vitamin B12 as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B12 with trans-[PtCl(NH3)2(H2O)]+, [PtCl 3(NH3)]- and [PtCl4]2-. These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [{Co}-CN-{trans-PtCl(NH3)2}] + (5), [{Co}-CN-{trans-PtCl2(NH3)}] (6), [{Co}-CN-{cis-PtCl2(NH3)}] (7) and [{Co}-CN-{PtCl 3}]- (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central "Co-CN-Pt" motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B12 conjugates. Release of the platinum complexes from vitamin B12 is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the β-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B 12 can potentially be used for delivering metal-containing compounds into cells.

KW - Adenosyltransferase

KW - Cisplatin

KW - Targeting

KW - Vitamin B

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