Fluorine in Medicinal Chemistry

Böhm, Hans‐Joachim; Banner, David W.; Bendels, Stefanie; Kansy, Manfred; Kuhn, Bernd; Müller, Klaus; Obst‐Sander, Ulrike; Ståhl, Martin

doi:10.1002/cbic.200301023

Cited by 1,409 publications

(669 citation statements)

References 36 publications

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“…1 B and C). We chose the difluoromethylene moiety as an electron-withdrawing group because of its synthetic accessibility and its inertness in biological systems (16). Importantly, this group does not create an electrophilic Michael acceptor capable of alkylating biological nucleophiles, as would a -conjugated substituent such as a carbonyl group.…”

Section: Resultsmentioning

confidence: 99%

Copper-free click chemistry for dynamic in vivo imaging

Baskin

Prescher²,

Laughlin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

1,635

1,386

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Dynamic imaging of proteins in live cells is routinely performed by using genetically encoded reporters, an approach that cannot be extended to other classes of biomolecules such as glycans and lipids. Here, we report a Cu-free variant of click chemistry that can label these biomolecules rapidly and selectively in living systems, overcoming the intrinsic toxicity of the canonical Cu-catalyzed reaction. The critical reagent, a substituted cyclooctyne, possesses ring strain and electron-withdrawing fluorine substituents that together promote the [3 ؉ 2] dipolar cycloaddition with azides installed metabolically into biomolecules. This Cu-free click reaction possesses comparable kinetics to the Cu-catalyzed reaction and proceeds within minutes on live cells with no apparent toxicity. With this technique, we studied the dynamics of glycan trafficking and identified a population of sialoglycoconjugates with unexpectedly rapid internalization kinetics.azide ͉ bioorthogonal reaction ͉ cyclooctyne glycan trafficking ͉ molecular imaging

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Section: Resultsmentioning

confidence: 99%

Copper-free click chemistry for dynamic in vivo imaging

Baskin

Prescher²,

Laughlin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

1,635

1,386

View full text Add to dashboard Cite

show abstract

“…change of pK a and thus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 9 protonation state, change of electron distribution in an aromatic ring). 19,20 We analyzed the environment of …”

Section: Structural Modeling and Interactions Of 4-fluoro-phenylalaninementioning

confidence: 99%

Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity

et al. 2017

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Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging.In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (K i = 0.84 ± 0.03 nM). A fluorine atom introduced in the paraposition of phenylalanine enhanced the binding affinity as much as 10-fold. Furthermore, we improved the proteolytic stability by substituting the N-terminal arginine by norarginine. The resulting inhibitor combines high inhibitory affinity and selectivity with a good stability in plasma (K i = 1.63 ± 0.18 nM, >27,000-fold selectivity, t 1/2 plasma = 16 ± 4 h). The inhibitor efficiently blocked activation of the intrinsic coagulation pathway in human blood ex vivo.

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“…Fluorine substitution is commonly used in medicinal chemistry to alter the lipophilicity or metabolic stability of a drug, and its inclusion often has beneficial effects on activity, protein binding, and cell penetration [13]. Flurithromycin, (8S)-8-fluoroerythromycin A, had higher serum and tissue levels than erythromycin at similar doses, demonstrative of the beneficial pharmacological effect of fluorination on the macrolide molecule [14].…”

Section: Resultsmentioning

confidence: 99%

“…The combined organic phases were washed with brine, dried over MgSO 4 , filtered, and evaporated. The residue was purified by silica gel chromatography using ethyl acetate/hexanes, yielding 13 13 …”

Section: -Azido-6-deoxyerythronolide B (14)mentioning

confidence: 99%

Preparation of Erythromycin Analogs Having Functional Groups at C-15

et al. 2006

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Chemobiosynthesis has been used to prepare analogs of erythromycins having unique functional groups at the 15-position. Using diketide thioester feeding to genetically engineered Streptomyces coelicolor, analogs of 6-deoxyerythronolide B were prepared having 15-fluoro, 15-chloro, and 15-azido groups. Bioconversion using a genetically engineered mutant of Saccharopolyspora erythraea was used to produce 15-fluoroerythromycin A and 15-azidoerythromycin A. These new erythromycin analogs provide antibacterial macrolides with unique physicochemical properties and functional groups that allow for selective derivatization.

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Fluorine in Medicinal Chemistry

Cited by 1,409 publications

References 36 publications

Copper-free click chemistry for dynamic in vivo imaging

Copper-free click chemistry for dynamic in vivo imaging

Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity

Preparation of Erythromycin Analogs Having Functional Groups at C-15

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