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I. Synthesis and enzymatic evaluation of fluorinated phosphonate mimics of sugar phosphates. II. A new approach to catalyst screening
Abstract
Development of fluorinated phosphonates as phosphatase-inert surrogates of biological phosphates is an area of long standing interest in the field of phosphate mimics. A complete ‘fluorinated phosphonate scan’ (includes varying both the degree of α-fluorination and phosphonate stereochemistry) of the active site of glucose 6-phosphate dehydrogenase has been carried out. Surprisingly, both the highest and lowest affinity substrate mimics are α-monofluorinated phosphonates. In order to understand our kinetic results, attempts have been made to manually dock the S-diastereomer of the CHF phosphonate, the best substrate analogue, into the active site of glucose 6-phosphate dehydrogenase (G6PDH). The interesting kinetic behavior of the (α-monofluoroalkyl)phosphonates seen in the above study led to the development of a new synthetic methodology that now provides for a practical entry into this under-explored class of phosphate mimics. The lithiated diethyl (α-fluoro-α-phenylsulfony)methyl phosphonate, can be used to displace primary alkyl halides or sugar triflates. The resultant synthetic intermediates then undergo reductive desulfonylation to afford the α-monofluoroalkyl phosphonates. The entire set of phosphonate analogues of fructose 6-phosphate (F6P) have been examined in a very different phosphate binding pocket, that is, in the active site of the tautomerase/amidotransferase enzyme, glucosamine 6-phosphate synthase. This is a collaborative venture with Prof. Bernard Badet, CNRS-Gif-sur-Yvette, France. Results in this active site contrast with those obtained for the G6PDH active site in two ways. The family of fructose 6-phosphonate substrate mimics synthesized here displays slow-binding inhibition. The best inhibitor is now of the α-difluorinated phosphonate variety, with a Ki* value well below Km for F6P itself. On a very different note, a new screening method for catalyst discovery that has potential combinatorial implications has been developed. The screen involves an entirely new approach to monitoring organic reactions in parallel. This screen has been used to identify new catalysts and to optimize reaction conditions for a potentially generalizable synthesis of α, β-unsaturated amino acids. A streamlined synthesis of two PLP enzyme inhibitors of this sub-structural class has been achieved using this chemistry.
Subject Area
Organic chemistry|Biochemistry
Recommended Citation
Bose, Mohua, "I. Synthesis and enzymatic evaluation of fluorinated phosphonate mimics of sugar phosphates. II. A new approach to catalyst screening" (2002). ETD collection for University of Nebraska-Lincoln. AAI3055261.
https://digitalcommons.unl.edu/dissertations/AAI3055261