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Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts

English title Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts
Applicant Zelder Felix
Number 129479
Funding scheme Project funding (Div. I-III)
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.07.2010 - 31.12.2011
Approved amount 90'124.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Nutritional Research, Vitaminology

Keywords (6)

Medicinal Inorganic Chemistry; vitamin B12; peptides; electrochemistry; coordination chemistry; metal based drugs

Lay Summary (English)

Lead
Lay summary
The synthesis of modified B12 derivatives for medical applications has recently gained considerable attention. Since rapidly proliferating cells demand high amounts of vitamin B12, the development of inhibitors of B12 dependant enzymes, so called anti-vitamins seems to be very attractive and has not been explored sufficiently enough. The project aims towards the development of a new class of these compounds that develop cytostatic or cytotoxic activity in vivo. Goals to be achieved: 1) Synthesis of a new class of modified B12 derivatives 2) Optimization of the structure through molecular modelling and chemical synthesis 3) Reactivity studies in model reactions and B12 dependant enzymatic reactions In conclusion, the main objective of this research proposal is the development of a new class of inhibitors based on an essential and natural molecule.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
"Intra base off/inter base on" coordination: self-assembly of a dimeric vitamin B12 derivative with a versatile tail
Zhou K, Zelder F (2011), "Intra base off/inter base on" coordination: self-assembly of a dimeric vitamin B12 derivative with a versatile tail, in CHEMICAL COMMUNICATIONS, 47(43), 11999-12001.
Identification of Diastereomeric Cyano-Aqua Cobinamides with a Backbone-Modified Vitamin B12 Derivative and with H-1 NMR Spectroscopy
Zhou K, Zelder F (2011), Identification of Diastereomeric Cyano-Aqua Cobinamides with a Backbone-Modified Vitamin B12 Derivative and with H-1 NMR Spectroscopy, in EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, (1), 53-57.
One-step synthesis of alpha/beta cyano-aqua cobinamides from vitamin B12 with Zn(II) or Cu(II) salts in methanol
Zhou K, Zelder F (2011), One-step synthesis of alpha/beta cyano-aqua cobinamides from vitamin B12 with Zn(II) or Cu(II) salts in methanol, in JOURNAL OF PORPHYRINS AND PHTHALOCYANINES, 15(7-8), 555-559.
Vitamin B12 mimics having a peptide backbone and tuneable coordination and redox properties.
Zhou Kai, Zelder Felix (2010), Vitamin B12 mimics having a peptide backbone and tuneable coordination and redox properties., in Angewandte Chemie (International ed. in English), 49(30), 5178-80.

Collaboration

Group / person Country
Types of collaboration
Institute of Evolutionary Biology and Environmental Studies Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
MPI Marburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ISABC 11 Poster Modified Vitamin B12 derivatives with tuneable coordination and redox properties 02.12.2011 Barcelona, Spain Zelder Felix;
Herbsttagung SCS Poster Vitamin B12 mimics with novel applications and bioactivities 09.09.2011 Lausanne, Switzerland Zelder Felix; Zhou Kai;
Seminar of the Max-Planck Institute for Terrestrial Microbiology and the Philipps University of Marburg/ Germany Individual talk Synthesis and properties of modified B12 derivatives 13.05.2011 Marburg, Germany Zelder Felix;
Chemiedozententagung, Mainz/ Germany Talk given at a conference Modifizierte Vitamin B12-Derivate mit variablen Koordinations- und Redoxeigenschaften 14.03.2011 Mainz, Germany Zelder Felix;


Awards

Title Year
CMSZH Travel Award from the Graduate School of Chemical and Molecular Sciences Zurich 2011

Associated projects

Number Title Start Funding scheme
117822 Modified B12 derivatives as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.07.2008 Project funding (Div. I-III)
117822 Modified B12 derivatives as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.07.2008 Project funding (Div. I-III)

Abstract

Cobalamines (Cbl) are among the most important biomolecules that modulate their chemical and biological properties by the ability to switch between different coordination states. Based on this ability, we suggest a new strategy for the development of inhibitors of vitamin B12 (B12) dependant reactions. Since it has been demonstrated that the catalytically active species in various B12 dependant transformations is a B12-protein complex in the so called `base-off/histidine-on` form,we intend to interlock the artificial cofactor in his `base-on` constitution through preorganization. As a consequence of this modification, the natural trigger of the reaction is blocked and inhibition is expected while the analogue is still being transported into the cells. Therefore, a novel class of B12 derivatives so called peptide B12 (pB12) has been developed. In these derivatives with the same length of the linker as in its natural counterpart B12, the phosphodiester and the ribofuranotide moiety have been replaced with a peptide mimic. The `base-on/base-off` equilibrium of these compounds has been studied by spectrophotometric pH titration. After only two modifications, a pB12 derivative with improved properties has been synthesized whose `base-on` stability is only 4 times lower than in vitamin B12, but at least 130 times higher than in other B12 derivatives with artificial linker structures. Electrochemical investigations are the focus of the current research and biological studies have been initiated and will be partly performed in collaboration. We intend to carry out structural and conformational analysis that will assist to further preorganize the linker structure for tight binding. This will be supplemented by a combinatorial approach on the solid phase. Besides, the pB12 derivatives can also be considered as model compounds of B12 that enable to study physicochemical properties like the electrostatic attraction between the linker and the metal centre. Numerous further modifications including the alteration of the base as well as the conjugation with biologically active molecules can be envisaged for the future.
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