Biochemistry of Halogenated Carbohydrates

Kirk, Kenneth L.

doi:10.1007/978-1-4757-4605-1_6

Cited by 2 publications

(3 citation statements)

References 90 publications

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“…Much of this performance enhancement is directly attributable stabilization of the drug candidate against metabolism and/or by an increase in drug lipophilicity upon fluorination [3][4][5][6][7]. It is striking that fluorination often imparts these desirable characteristics without compromising a molecule's specificity for its target receptor [8][9][10]. The fact that the association constants for molecular recognition are often unchanged or improved upon fluorination has spurred experimental and theoretical studies aimed at quantifying noncovalent interaction energies of organic fluorine with biologically relevant functional groups [11].…”

Section: Introductionmentioning

confidence: 99%

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

DiMagno

Sun

2006

CTMC

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Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-pi...X and C-F...X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F...X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.

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Section: Introductionmentioning

confidence: 99%

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

DiMagno

Sun

2006

CTMC

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“…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.…”

mentioning

confidence: 99%

“…Fluorine substitution is a powerful tool in medicinal and bioorganic chemistry. − The chemical inertness, relatively small size, and short C−F bond length , have made C−F substitution attractive for replacement of a number of functional groups, including C−OH, C−H, and CO. The aggregate size of the C−F group is substantially larger than that of C−H and smaller than that of C−OH.…”

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confidence: 99%

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

et al. 1998

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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

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Biochemistry of Halogenated Carbohydrates

Cited by 2 publications

References 90 publications

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

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

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