Structure and Transport Properties of a Novel, Heavily Fluorinated Carbohydrate Analogue

Abstract

We are interested in heavily fluorinated analogues of biomolecules to probe the relative importance of static and induced dipolar interactions in molecular recognition. Our hypothesis is that induced dipole interactions have a larger effect on the chemical potential of a solute in aqueous solution compared to that of the same molecule in a translationally static environment, such as when it is bound to a protein receptor or active site. If this hypothesis is correct, decreasing the polarizability of a biologically active compound while maintaining its electrostatic charge distribution and shape should lead to enhanced binding to the physiological receptor. We call this strategy enhancing "polar hydrophobicity". Since the C-F bond is among the most polar and least polarizable in organic chemistry (as evinced by the extremely low refractive indices of fluorocarbons), 1 extensive fluorine substitution is a reasonable approach to increase polar hydrophobicity and to improve transport and recognition of biomolecule analogues.Fluorine substitution is a powerful tool in medicinal and bioorganic chemistry. [2][3][4][5] The chemical inertness, relatively small size, and short C-F bond length 1,6 have made C-F substitution attractive for replacement of a number of functional groups, including C-OH, C-H, and CdO. The aggregate size of the C-F group is substantially larger than that of C-H and smaller than that of C-OH. For total spatial extent, the gem-difluoro group should be an adequate substitution for CHOH. Thus, our initial studies have focused on heavily fluorinated carbohydrate analogues, such as 1-hydroxy-5-hydroxymethyl-2,2,3,3,4,4hexafluorooxane, 1. These analogues retain the overall shape and

Pharmaceuticals and Other Biomedical Applications

“…The heavily fluorinated glucose analog depicted in Scheme 9.24 [94] illustrates the concept of ''polar hydrophobicity'' [95], a term coined by DiMagno and co-workers. The heavily fluorinated glucose analog depicted in Scheme 9.24 [94] illustrates the concept of ''polar hydrophobicity'' [95], a term coined by DiMagno and co-workers.…”

Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

“…More recently in the group, good progress has been made toward transition metal-mediated routes into these densely functionalized β, γ-unsaturated AA’s, with the potential for catalytic control of stereochemistry. This includes both allylic amination [106–108] and formal [3,3]-sigmatropic rearrangement approaches [109]. …”

“…DiMagno has pointed out that this feature of organically-bound fluorine means that fluoroalkyl are less able to engage in dispersion-based interactions with aqueous solvent than simple alkyl groups. He has proposed the term, “polar hydrophobicity” [2] to describe this phenomenon, and points out that this may provide unique opportunities for enhancing ligand binding to a protein target [3]. In terms of specific interactions with functionalities in proteins, while C-F bonds appear to have rather limited H-bond acceptor ability[4–6], in optimally aligned cases F--H-N-amide interactions may make contributions to binding [7–9].…”

Synthesis, characterization and evaluation of antileishmanial activity of copper(II) with fluorinated α-hydroxycarboxylate ligands

“…Fluorine is a small, highly electronegative, atom, with a smaller volume than groups such as CH 3 , NH 2 and OH. The C-F bond is highly polar but only slightly polarizable, accounting in some instances for the low aqueous solvation energies and high lipophilicities of some fluorinated molecules in comparison with their non-fluorinated analogs (Kim 1998;Biffinger et al 2004;Gerebtzoff 2004;Shimizu and Hiyama 2005). Fluorine is already widely present in medicine: currently, there are ca.…”