Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media

Liu, Jie; Barrio, Jorge R.; Satyamurthy, Nagichettiar

doi:10.1016/j.jfluchem.2006.06.006

Cited by 10 publications

(10 citation statements)

References 49 publications

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“…By analogy with adenine derivatives, the primary sites of protonation of the purines are expected to be N‐1 and N‐7, and possibly N‐3 14. 37, 38 Protonation of a purine at N‐1 (or N‐3) followed by attack of an aniline leads to the Meisenheimer–Jackson intermediate. The basic mechanistic scheme is illustrated in Scheme for the S N Ar reaction of anilines with 6‐cyclohexylmethoxy‐2‐fluoropurine.…”

Section: Discussionmentioning

confidence: 99%

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Carbain

Coxon

Lebraud

et al. 2014

Chemistry A European J

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Small-molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) is as an effective combination for achieving SN Ar reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro-, chloro-, bromo- or alkylsulfonyl). This method provides a variety of compounds containing a "kinase-privileged fragment" associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer-Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N-protonation without deactivating the aniline by conversion into an anilinium species. The TFA-TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA-TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2-, 3- and 4-substituted anilines giving product yields that are normally in the range 50-90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields.

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Section: Discussionmentioning

confidence: 99%

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Carbain

Coxon

Lebraud

et al. 2014

Chemistry A European J

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“…No experimental data is available for this compound, as difficulties concerning its synthesis were only recently resolved (Liu et al. 2006 ; Ghosh et al. 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

2010

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The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution.

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“…Many studies involving 8-substituted analogs of cyclic adenosine and guanosine are reviewed in ref . Much less is known about the biological effects of 8-F-guanosines, probably because of the fact that these became synthetically feasible only very recently. , …”

Section: Introductionmentioning

confidence: 99%

Efficient Free Energy Calculations for Compounds with Multiple Stable Conformations Separated by High Energy Barriers

Hritz¹,

Oostenbrink²

2009

J. Phys. Chem. B

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Compounds with high intramolecular energy barriers represent challenging targets for free energy calculations because of the difficulty to obtain sufficient conformational sampling. Existing approaches are therefore computationally very demanding, thus preventing practical applications for such compounds. We present an enhanced sampling-one step perturbation method (ES-OS) to tackle this problem in a highly efficient way. A single molecular dynamics simulation of a judiciously chosen reference state (using two sets of soft-core interactions) is sufficient to determine conformational distributions of chemically similar compounds and the free energy differences between them. The ES-OS method is applied to a set of five biologically relevant 8-substituted GTP analogs having high energy barriers between the anti and the syn conformations of the base with respect to the ribose part. The reliability of ES-OS is verified by comparing the results to Hamiltonian replica exchange simulations of GTP and 8-Br-GTP and the experimentally determined 3J(C4,H1') coupling constant for GMP in water. Additional simulations in vacuum and octanol allow us to calculate differences in the solvation free energies and in lipophilicities (log P). Free energy contributions from individual conformational regions are also calculated, and their relationship with the overall free energy is derived leading to a set of multiconformational free energy formulas. These relationships are of general applicability and can be used in free energy calculations for a more diverse set of compounds.

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Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media

Cited by 10 publications

References 49 publications

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

Efficient Free Energy Calculations for Compounds with Multiple Stable Conformations Separated by High Energy Barriers

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Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media

Cited by 10 publications

References 49 publications

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

Efficient Free Energy Calculations for Compounds with Multiple Stable Conformations Separated by High Energy Barriers

Contact Info

Product

Resources

About

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines