Fluoro-olefin Isosteres as Peptidomimetics

Welch, John T.; Lin, J. T.; Boros, L. G.; DeCorte, Bart L.; Bergmann, Kathryn E.; Gimi, Raomond

doi:10.1021/bk-1996-0639.ch010

Cited by 20 publications

(6 citation statements)

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“…The development of efficient and mild methods for the synthesis of organofluorine compounds represents a broad area in organic chemistry, because the incorporation of a fluorine-containing group into an organic molecule dramatically alters its physical, chemical, and biological properties . Among them, monofluorinated olefins have attracted a great deal of attention because of their wide range of applications. , Especially, fluoroolefins (CFCH) can act as ideal amide bond mimics (CONH) as a result of steric and electronic similarities .…”

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confidence: 99%

First Stereospecific Synthesis of (E)- or (Z)-α-Fluoroenones via a Kinetically Controlled Negishi Coupling Reaction

et al. 2006

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A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).

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confidence: 99%

First Stereospecific Synthesis of (E)- or (Z)-α-Fluoroenones via a Kinetically Controlled Negishi Coupling Reaction

et al. 2006

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“…169 The disruptive nature of the CH 3 -substituted alkene moiety can be attributed to its poorer mimicry of the electrostatic potential surface of the parent amide. 170 3.3.3. Reduced Amides.…”

Section: N-methylationmentioning

confidence: 99%

“…Wipf and co-workers found that a CF 3 -substituted alkene moiety could be incorporated within the gramicidin scaffold in a “conformationally conservative” manner ( 55 , Figure ), whereas a CH 3 -substituted alkene moiety disrupted the gramicidin conformation ( 56 ) . The disruptive nature of the CH 3 -substituted alkene moiety can be attributed to its poorer mimicry of the electrostatic potential surface of the parent amide …”

Section: The Effect Of Structural Modification On the Conformations O...mentioning

confidence: 99%

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

2020

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Cyclic peptides are promising scaffolds for drug development, attributable in part to their increased conformational order compared to linear peptides. However, when optimizing the target-binding or pharmacokinetic properties of cyclic peptides, it is frequently necessary to “fine-tune” their conformations, e.g., by imposing greater rigidity, by subtly altering certain side chain vectors, or by adjusting the global shape of the macrocycle. This review systematically examines the various types of structural modifications that can be made to cyclic peptides in order to achieve such conformational control.

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“…The concept of conformationally constrained (Z)fluoro-olefin dipeptide isosteres that mimic the active "trans" conformation of the dipeptidyl peptidase inhibitors was already exploited by Welch et al [26][27][28] in synthesizing fluoro-olefin analogues of two known inhibitors with alanyl-Ψ[CFdC]-proline structure (8). Although no general and unambiguous conclusions considering the effect on inhibitory potency of introducing the fluoro-olefin group in these compounds can be drawn from only two examples, Welch could experimentally verify that there is indeed enzyme affinity for these peptidomimetics.…”

Section: Introductionmentioning

confidence: 99%

Fluoro-Olefins as Peptidomimetic Inhibitors of Dipeptidyl Peptidases

et al. 2004

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The feasibility of the fluoro-olefin function as a peptidomimetic group in inhibitors for dipeptidyl peptidase IV and II (DPP IV and DPP II) is investigated by evaluation of N-substituted Gly-Psi[CF=C]pyrrolidines, Gly-Psi[CF=C]piperidines, and Gly-Psi[CF=C](2-cyano)pyrrolidines. Of this later class, the (Z)- and (E)-fluoro-olefin analogues were prepared and chemical stability in comparison with the parent amide was checked. Most of these compounds exhibited a strong binding preference toward DPP II with IC(50) values in the low micromolar range, while only low DPP IV inhibitory potential is seen.

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Fluoro-olefin Isosteres as Peptidomimetics

Cited by 20 publications

References 0 publications

First Stereospecific Synthesis of (E)- or (Z)-α-Fluoroenones via a Kinetically Controlled Negishi Coupling Reaction

First Stereospecific Synthesis of (E)- or (Z)-α-Fluoroenones via a Kinetically Controlled Negishi Coupling Reaction

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

Fluoro-Olefins as Peptidomimetic Inhibitors of Dipeptidyl Peptidases

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