Synthesis of Fluorinated Nitrogen-Containing Compounds Through Superelectrophilic Activation in Superacid HF/SbF5∗∗This work is dedicated to Pr Jean-Claude Jacquesy with great consideration.

Thibaudeau, Sébastien; Carreyre, Hélène; Martin‐Mingot, Agnès

doi:10.1016/b978-0-12-803740-9.00013-5

“…To this end, the alcohol position was locked by generating its fluoro-analogue 5 . Due to the C–F bond properties, [ 55 , 56 ] blocking metabolic position with fluorine atom is a common practice in medicinal chemistry research [ 57 ], and our group has already contributed to this field [ 58 , 59 , 60 , 61 , 62 ]. Compound 5 was then tested as an hCA inhibitor and its inhibition profile was completely different from dodoneine 1 and compound 2 , thus confirming that phenolic bicycle 2 can be considered as a new lead structure in the quest for hCA III selective inhibitors [ 63 ].…”

Section: Resultsmentioning

confidence: 99%

Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery

Carreyre

¹

,

Carré

²

,

Ouédraogo

³

et al. 2017

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Dodoneine (Ddn) is one of the active compounds identified from Agelanthus dodoneifolius, which is a medicinal plant used in African pharmacopeia and traditional medicine for the treatment of hypertension. In the context of a scientific program aiming at discovering new hypotensive agents through the original combination of natural product discovery and superacid chemistry diversification, and after evidencing dodoneine’s vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III) and L-type Ca2+ current inhibition. These derivatives can now be considered as new lead compounds for vasorelaxant therapeutics targeting these two proteins.

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“…61). [100] 3) Fluorination of the aromatic tail also strongly impacts the potencya nd selectivity of the studied inhibitors. This comes mainly from ac ombination of ap K a -lowering effect and finely tuned dispersive interactions.M oreover, insertion of ap erfluroaromatic tail may lead to ab alanced hydro/lipophilic profile for the CAIs,thereby improving their pharmacokinetic properties.T his is the case with the antiglaucoma agent 67,w hich showed av ery high penetrability through the cornea and as low elimination, thus ensuring along-lasting IOP lowering effect.…”

Section: Discussionmentioning

confidence: 99%

Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution

Berrino

¹

,

Michelet

²

,

Martin‐Mingot

³

et al. 2021

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The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this “magic effect” of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give “general guidelines” on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future.

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Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution

Berrino

¹

,

Michelet

²

,

Martin‐Mingot

³

et al. 2021

Angewandte Chemie

1

0

View full text Add to dashboard Cite

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this “magic effect” of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give “general guidelines” on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future.

show abstract

Synthesis of Fluorinated Nitrogen-Containing Compounds Through Superelectrophilic Activation in Superacid HF/SbF5∗∗This work is dedicated to Pr Jean-Claude Jacquesy with great consideration.

Cited by 4 publications

References 203 publications

Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery

Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery

Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution

Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution

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