Project

Discipline

vitamin B12; inhibitor; biomimetic; mechanism; cyanide

Lead
Lay summary
The synthesis of modified vitamin B12 derivatives for medical applications has recently gained considerable attention. Since rapidly proliferating cells demand high amounts of  B12, the development of inhibitors of B12 dependent 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. In a second part of the project, we study biomimetic B12 complexes to gain insights into the mechanism of B12 dependent enzymes. The third objective is to apply these derivatives for improved cyanide detection.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Number	Title	Start	Funding scheme

Cobalamines (Cbl) are essential for the metabolism in mammals and most other forms of life. The interplay between different coordination geometries and redox states triggers cellular uptake as well as reactivity in cofactor-catalysed reactions. We propose to develop imidazole-modified B12 derivatives for two different projects: As biomimetic models of cobalamin-protein complexes and inhibitors of B12-dependant reactions (i) as well as bioinspired catalysts for cyanide detection by signal amplification (ii). In the first project, we intend to investigate modified B12 derivatives as biomimetic models of the “base off-histidine on” binding mode in cobalamin-protein complexes. A postulated proton shuttle mechanism that modulates reactivity in cofactor-catalysed reactions will be tested. New insights into the mode of enzymatic activation are expected. These studies may have implication for the rational design of organometallic catalysts.We also propose a new strategy for the development of inhibitors of B12 dependant reactions. We suggest developing modified B12 derivatives that bind to an important hydrophobic binding pocket and block coincidentally ligation to the protein. Thereby, a required constitutional switch for cofactor activation is suppressed. Cobalamin dependant methione synthase (MetH) is important for DNA and RNA synthesis and inhibition could therefore yield a new class of anti-proliferating agents (i).In biological systems, chemical signals are efficiently converted into biochemical responses by signal transduction and amplification steps. Inspired by these principles, we intend to develop in the second project a catalytic system for cyanide detection in which cyanide (the primary signal) generates an active catalyst from an inactive precursor. The active catalyst triggers the formation of a visually detectable amplified signal. Imidazole-modified B12 derivatives will be applied for this purpose (ii). This could then be used for the detection of cyanide in water in developing countries.