Synthesis of L-scyllo-inositol 1,2,4-trisphosphate, scyllo-inositol 1,2,4,5-tetrakisphosphate and phosphorothioate and DL-2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate: optical resolution of DL-1-O-allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-scyllo-inositol

Lampe, Dethard; Liu, Changsheng; Mahon, Mary F.; Potter, Barry V. L.

doi:10.1039/p19960001717

Cited by 20 publications

(11 citation statements)

References 34 publications

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“…Fluorine‐substituted analogs of naturally occurring and biologically active organic compounds are widely studied 1–18. It has already become a common practice in bioorganic chemistry to replace a hydroxyl group for a fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process 3–7.…”

Section: Introductionmentioning

confidence: 99%

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When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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ABSTRACT:In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorinecontaining aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures.

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Section: Introductionmentioning

confidence: 99%

“…Obviously, a fluorine atom cannot donate hydrogen bonds, but it is electronegative and can accept them. Thus, molecules in which hydroxyl groups were replaced by fluorine atoms are thought to provide insight into the interactions with enzymatic binding sites 1, 2.…”

Section: Introductionmentioning

confidence: 99%

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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“…It can also be thought of as a regioisomer of Ins(1,3,4,5)P 4 , where the phosphate at the 3-position has been transposed onto the adjacent 2-position. To further the elucidation of the structural basis for interaction of Ins(1,4,5)P 3 with its receptor and metabolic enzymes, we also synthesized scyllo -inositol 1,2,4,5-tetrakisphosphate ( scyllo -Ins(1,2,4,5)P 4 , 4 , Figure a), which possesses an equatorial phosphate at C-2 rather than an axial one relative to Ins(1,2,4,5)P 4 . The receptor binding and Ca 2+ release properties of Ins(1,2,4,5)P 4 and scyllo -Ins(1,2,4,5)P 4 as well as their interactions with the metabolic enzymes of Ins(1,4,5)P 3 have been examined. , Both analogues were full agonists with similar potencies to that of Ins(1,4,5)P 3 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Calcium Mobilizing, and Physicochemical Properties of d-chiro-Inositol 1,3,4,6-Tetrakisphosphate, a Novel and Potent Ligand at the d-myo-Inositol 1,4,5-Trisphosphate Receptor

et al. 1999

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The synthesis of a novel and potent ligand at the D-myo-inositol 1,4, 5-trisphosphate receptor (InsP3R) is described. D-chiro-Inositol 1,3, 4,6-tetrakisphosphate (7) and L-chiro-inositol 1,3,4, 6-tetrakisphosphate (ent-7) have been synthesized from D-2, 5-di-O-benzyl-chiro-inositol and L-2,5-di-O-benzyl-chiro-inositol, respectively. The potency of binding and Ca2+ release of 7 and ent-7 were examined in L15 and Lvec cells. 7 was a full agonist at the InsP3R in both cells, and ent-7 was inactive. The results are compared to those from D-myo-inositol 1,4,5-trisphosphate (1), DL-scyllo-inositol 1,2,4-trisphosphate (2), DL-myo-inositol 1,2,4, 5-tetrakisphosphate (3), scyllo-inositol 1,2,4,5-tetrakisphosphate (4), D-myo-inositol 2,4,5-trisphosphate (5), and D-chiro-inositol 1, 3,4-trisphosphate (6). The protonation processes of 7 have also been investigated by 31P NMR titration experiments.

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“…Fluorine-substituted analogues of naturally occurring and biologically active organic compounds have become the focus of increasing interest. − They are thought to provide insight into the interactions between enzymatic binding sites and hydroxyl groups which are replaced by fluorine. , Thus, it has already become a common practice in bioorganic chemistry to replace a hydroxyl group with fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process. − The rationale for such a strategy stems from similarities between the F atom and the OH group, with particular reference to polarity as well as to the close isosteric relationship between fluorine and oxygen. ,, Consequently, the F atom is considered to be a good substitute of the OH group because it introduces a small steric disturbance, which is especially significant in molecules where conformational recognition is important . Once the F atom is introduced, the high carbon−fluorine bond energy renders the substituent relatively resistant to metabolic transformation .…”

Section: Introductionmentioning

confidence: 99%

Effects of Substitution of OH Group by F Atom for Conformational Preferences of Fluorine-Substituted Analogues of (R,R)-Tartaric Acid, Its Dimethyl Diester, Diamide, and N,N,N‘,N‘-Tetramethyl Diamide. Ab Initio Conformational Analysis

Hoffmann¹,

Rychlewski²,

Rychłewska³

1999

J. Am. Chem. Soc.

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High-level ab initio methods up to MP2/6-311++G**//RHF/6-31G* have been used to characterize the conformations of isolated molecules of (2S,3S)-2,3-dideoxy-2,3-difluorotartaric acid (FTA) and its dimethyl diester (FME), diamide (FAM), and N,N,N‘,N‘-tetramethyldiamide (FTMA). A wide range of possible structures (84 for FTA and 63 for FME, FAM, FTMA) has been surveyed at the RHF/3-21G level. At the highest level of theory, 23 conformers were located for FTA, 15 for FME, 9 for FAM, and 11 for FTMA. Electronic correlation has been included with the relatively large basis set 6-311G, augmented with polarization and diffuse functions, to calculate MP2/6-311++G**//RHF/6-31G* single-point energies for all the conformers. Frequency analysis and thermochemical calculations have been performed at the RHF/6-31G* level and the results have been utilized to assess gas-phase populations of conformers at 298 K for the studied molecules. Moreover, SM5.4 solvation model was used to assess Gibbs free energies of conformers both in water and in chloroform. The obtained results are compared to those from previous studies of (R,R)-tartaric acid and its derivatives and analyzed in terms of effects of substitution of the hydroxyl group by the fluorine atom. It seems that substitution of the OH group by an F atom leads to greater conformational diversity of the molecules studied, mainly because the F atom cannot act as a hydrogen bond donor. From our results, it appears that if hydroxyl groups of (R,R)-tartaric acid are involved in intermolecular interactions, like in crystals or polar solvents, then the conformational preferences of these compounds are similar to the conformational preferences of isolated molecules of their dideoxydifluoro analogues.

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Synthesis of L-scyllo-inositol 1,2,4-trisphosphate, scyllo-inositol 1,2,4,5-tetrakisphosphate and phosphorothioate and DL-2-deoxy-2-fluoro-myo-inositol 1,4,5-trisphosphate: optical resolution of DL-1-O-allyl-3,6-di-O-benzyl-4,5-O-isopropylidene-scyllo-inositol

Cited by 20 publications

References 34 publications

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Synthesis, Calcium Mobilizing, and Physicochemical Properties of d-chiro-Inositol 1,3,4,6-Tetrakisphosphate, a Novel and Potent Ligand at the d-myo-Inositol 1,4,5-Trisphosphate Receptor

Effects of Substitution of OH Group by F Atom for Conformational Preferences of Fluorine-Substituted Analogues of (R,R)-Tartaric Acid, Its Dimethyl Diester, Diamide, and N,N,N‘,N‘-Tetramethyl Diamide. Ab Initio Conformational Analysis

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