Biologically Important Flourine Interactions

Karipides, Anastas

Abstract

Fluorinated compounds have long been known to influence the course of biological reactions and have been extensively used as metabolic inhibitors of enzyme actions. In particular, fluorocarboxylates form a broad class of compounds which appear to have unusual biochemical activity. For example, fluorocitrate is a very effective inhibitor of the enzyme aconitase and there has been considerable interest and research activity concerning the structural nature of this inhibition. Fluorinated carboxylates clearly behave differently in biochemical systems than their hydrogen analogues, but despite the significant biological importance of these fluoro-derivatives, relatively little is known about the nature of intermolecular carbon-bound fluorine interactions. The central objective of this research project is to determine the manner in which fluorine atoms influence their environments so that we may understand why such extraordinary behavior in biological action arises. To achieve this objective we propose to determine and critically analyze the structural characteristics of fluorine atom interactions in fluorocarboxylic acids and their multivalent salts using x-ray diffraction methods. A large number of fluorine-substituted aromatic and aliphatic carboxylic acids will be used. The 2-fluorocarboxylic acids will be synthesized from corresponding alpha-amino acids using established procedures. Salts of these acids will be prepared with a broad of cations selected from alkali and alkaline earth metal ions, substituted ammonium ions, divalent and trivalent transition metal ions and rare-earth ions. For those combinations of fluoroacid anion cation that produce suitable single crystals, detailed x-ray crystal structure determinations will be carried out. In those instances where a parent fluoroacid is crystalline at room temperature, its crystal structure will also be investigated. Whenever possible, comparisons will be made of the structural features of the fluorinated species with the corresponding """"""""hydrogen"""""""" derivative to document the differences arising from fluorine substitution. Particular interest will be focused on the extent and nature of direct metal ion-fluorine, C-F...M and indirect water-mediated hydrogen-bonded, C-F...H2O-M, interactions, which serve as possible models for the interactions of fluorosubstrates with macromolecules such as fluorocitrate inhibition of aconitase.