The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin -N6- YL) Alkanes1

Prescott, Mark; McLennan, Alexander G.; Agathocleous, D. C.; Page, Philip C. Bulman; Cosstick, Richard; Galpin, I.J.

doi:10.1080/07328318908054174

Cited by 7 publications

(4 citation statements)

References 13 publications

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“…The adenosine kinase from bovine liver has been highly purified by using a purification procedure described by Merkler and Schramm (1987), which has also been used for adenosine kinases from other mammalian sources (Rotllan and Miras Portugal, 1985;Prescott et al, 1989;Bontcmps et al, 1993). Bovine liver adenosine kinase is monomeric with an apparent molecular mass of about 45 kDa.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Elalaoui

Divita

Maury

et al. 1994

European Journal of Biochemistry

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Bovine liver adenosine kinase is a 45-kDa monomeric protein which exhibits a characteristic intrinsic tryptophan fluorescence with a maximal excitation at 284 nm and an emission peak centered at 335 nm. A total of three tryptophan residues/molecule has been estimated by using a fluorescence titration method. Low values of Stern-Volmer quenching constants in the presence of either acrylamide or iodide (4.2 M-' or 1.5 M-', respectively) indicated that the tryptophan residues are relatively buried in the native molecule. Tryptophan residues also showed a high heterogeneity, with a fractional accessible fluorescence value for iodide of 0.65. The enzyme fluorescence was very sensitive to substrate binding, which induced a marked fluorescence quenching, a lower tryptophan accessibility to acrylamide and iodide, and an increase in the tryptophan heterogeneity. ADP or ATP showed a monophasic saturation curve consistent with the existence of one binding site. In contrast, adenosine and AMP gave biphasic saturation curves, suggesting the existence of at least two binding sites, with a high and a low affinity. The presence of MgCl, increased the affinity of ATP or ADP, whereas the binding of adenosine or AMP was not affected.

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Section: Discussionmentioning

confidence: 99%

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Elalaoui

Divita

Maury

et al. 1994

European Journal of Biochemistry

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“…We describe here the alternative and direct route to 9,9′‐disubstituted O 6 ‐guanine‐alkylene‐ O 6 ‐guanine dimers, that is compounds, the biological properties of which also might turn out to be interesting. Such an expectation could be derived from the reported inhibition of adenosine kinase by α,ω‐di(adenosine‐ N 6 ‐yl)alkanes …”

Section: Resultsmentioning

confidence: 99%

“…Such an expectation could be derived from the reported inhibition of adenosine kinase by α,ω-di(adenosine-N 6 -yl)alkanes. [25] It has been found that when the exocyclic amine of the guanosine derivative is protected as a N,N-dialkylformamidine, the alkylation reaction becomes regioselective favoring compounds alkylated at N1. [26] We followed this strategy to obtain dimeric products bearing the N1-guanine-butylene-N1-guanine spacer.…”

Section: Resultsmentioning

confidence: 99%

Alkylation of 9‐substituted guanine derivatives with α,ω‐dihaloalkanes

Framski

Gośliński

Januszczyk

et al. 2017

Heteroatom Chemistry

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Reactions of 9‐substituted guanine derivatives with NaH/1,2‐dibromoethane, 1,3‐dibromopropane, or 1,4‐dibromobutane at room temperature resulted in the isolation of tricyclic 1,N2‐(1,2‐ethano)guanine, 1,N2‐(1,3‐propano)guanine, or 1,N2‐(1,4‐butano)guanine products, respectively. O6‐Haloalkyl and N1‐haloalkyl products were obtained following the use of NaH/1,4‐dibromobutane, higher α,ω‐dibromoalkanes, or α‐bromo‐ω‐fluoroalkanes. Raising the reaction temperature opened the synthetic way toward O6‐guanine‐alkylene‐O6‐guanine and N1‐guanine‐alkylene‐O6‐guanine symmetric and unsymmetric dimers. Protection of the substrate amine group to form N,N‐dialkylformamidine provided the access to N1‐guanine‐alkylene‐N1‐guanine dimers.

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“…As an interesting aside, synthesis of compounds 16a-20a and 16b-20b via Scheme 1 invariably led to N 6 ,N 6 ′alkanediylbisadenosines (16a′-20a′ and 16b′-20b′) for which 16a′, 17a′, 19a′, and 20a′ are known inhibitors of adenosine kinase. 33 We isolated/synthesized the bisadenosines and screened them against parasite PGK to find that most of the C2 amino-bearing compounds had some marginal activity and N 6 ,N 6 ′-1,3-propanediylbis-2-aminoadenosine (17b′) had an IC 50 of 50 µM (Table 4). Compound 17b′ was competitive with ATP, noncompetitive with 3-PGA (data not shown), and not selective for T. brucei PGK over rabbit muscle PGK.…”

Section: Resultsmentioning

confidence: 99%

Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase: Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine

et al. 2000

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As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N(6)-, 2-amino-N(6)-, and N(2)-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N(6)-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N(6)- [2''(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC(50) of 130 microM. 2-[[2''-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC(50) of 500 microM. To explore the potential of an additive effect that having the N(6) and N(2) substitutions in one molecule might provide, the best ligands from the two series were incorporated into N(6),N(2)-disubstituted adenosine analogues to yield N(6)-(2''-phenylethyl)-2-[(2'' -phenylethyl)amino]adenosine (69) as a 30 microM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this "flipped and rotated" binding mode.

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The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin -N⁶- YL) Alkanes¹

Cited by 7 publications

References 13 publications

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Alkylation of 9‐substituted guanine derivatives with α,ω‐dihaloalkanes

Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase: Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine

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The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin -N6- YL) Alkanes1

Cited by 7 publications

References 13 publications

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Intrinsic tryptophan fluorescence of bovine liver adenosine kinase, characterization of ligand binding sites and conformational changes

Alkylation of 9‐substituted guanine derivatives with α,ω‐dihaloalkanes

Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase: Elucidation of a Novel Binding Mode for a 2-Amino-N6-Substituted Adenosine

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The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin -N⁶- YL) Alkanes¹

Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase: Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine