Synthesis and biological evaluation of disubstituted N6-cyclopentyladenine analogues

Ligt, Rianne A.F. de; Klein, P. A. M. Van Der; Künzel, Jacobien K. Von Frijtag Drabbe; Lorenzen, Anna; Maate, Fatna Ait el; Fujikawa, Shelly; Westhoven, Rosemarijn van; Hoven, Thijs van den; Brussee, Johannes; IJzerman, Adriaan P.

doi:10.1016/j.bmc.2003.10.023

Cited by 25 publications

(21 citation statements)

References 19 publications

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“…Compound 30 (LUF 5608) with Nmethyl-isopropylamino constituent emerged as an inverse agonist with over 100-fold gain in adenosine A 1 affinity compared to N-0840 (K i (A 1 ) = 852 nM) [53,54]. N 6 -cyclopentyl-3'-substituted-xylofuranosyladenosine (e.g.…”

Section: Non-fused Ringsmentioning

confidence: 99%

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Yuzlenko

Kieć‐Kononowicz

2006

CMC

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This review summarizes the current tendencies observed in the past 5 years in the development of A(1) and A(2A) adenosine receptor antagonists performed in various academia and industry. A(1) and A(2A) AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A(1) AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)-substituent, while A(2A) AR antagonists with a high A(2A) AR affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A(1) and A(2A) ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A(1) receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A(2A) AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety.

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Section: Non-fused Ringsmentioning

confidence: 99%

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Yuzlenko

Kieć‐Kononowicz

2006

CMC

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“…Many publications have demonstrated that introduction of different substituents in the 2-, 8-, and 9-position of adenine result in high-affinity antagonists with distinct receptor selectivity profiles. [13][14][15][16][17] Hence, substituted adenine derivatives, prepared as hypoglycemic agents, were found to possess high potency for the AA 2B R subtype, [18] whereas novel N6-cyclopentyladenine derivatives were characterized as neutral antagonists endowed with high affinity for AA 1 R. [19] In contrast, 2-phenylaminoadenines bearing a variety of cycloalkyl rings at the N6 position were found to possess high affinity for AA 3 R. [20] Recent clinical evidence has demonstrated that AA 2A R antagonists effectively decrease motor impairment in Parkinsonian patients who have low risk of dyskinesia, potentially providing an alternative approach for the treatment of Parkinson's disease. [21][22][23] Accordingly, we reported that three 9-ethyladenine (1) derivatives, each bearing a bromine, ethoxy group, or furyl Clinical evidence has demonstrated that AA 2A R antagonists could be an alternative approach to the treatment of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Adenosine A_2A Receptor Antagonists: New 8‐Substituted 9‐Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease

et al. 2009

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A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat and human adenosine receptors. Binding data demonstrates that some compounds could represent new tools suitable for in vivo studies in rat models of Parkinson's disease and for the design of new molecules with improved affinity and selectivity at human AA(2A)R.Clinical evidence has demonstrated that AA(2A)R antagonists could be an alternative approach to the treatment of Parkinson's disease. Recently, three 9-ethyladenine derivatives bearing a bromine atom, an ethoxy group, and a furyl ring, respectively, in the 8-position have been reported to ameliorate motor deficits in rat Parkinson's disease models, suggesting a potential therapeutic role for these compounds. Starting from these observations, a new series of 9-ethyladenine derivatives, bearing different substituents such as halogens, alkoxy groups, aromatic and heteroaromatic rings in the 8-position, were synthesized. Radioligand binding assays demonstrated that some of the new compounds bind rat AA(2A)R with higher affinity than the previously reported congeners and that there is a good correlation between binding to rat and human receptors. Hence, the new molecules could represent new tools suitable for the in vivo studies in rat models of Parkinson's disease. Finally, a molecular docking analysis of the compounds was performed using a homology model of rat AA(2A)R, built using the human crystal structure as the template, and results are in agreement with the binding data.

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“…Compounds with N-9 substituents were synthesized next (Figure 7) using standard conditions 42, 43 to provide regioselective N-9 substitution. Analogous to the N-7 series, displacement of the chlorides in compounds 13 and 14 with hydroxylamines provided analogs 15-18 .…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Action of the Cytotoxic Asmarine Alkaloids

Lambrecht

Shenvi

2018

ACS Chem. Biol.

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The asmarines are a family of cytotoxic natural products whose mechanism of action is unknown. Here, we used chemical synthesis to reverse engineer the asmarines and understand the functions of their individual components. We found that the potent asmarine analog "delmarine" arrested the mammalian cell cycle in the G1 phase and that both cell cycle arrest and cytotoxicity were rescued by cotreatment with ferric and ferrous salts. Cellular iron deprivation was clearly indicated by changes in iron-responsive protein markers, and cytotoxicity occurred independently of radical oxygen species (ROS) production. Chemical synthesis allowed for annotation of the distinct structural motifs required for these effects, especially the unusual diazepine, which we found enforced an iron-binding tautomer without distortion of the NCNO dihedral angle out of plane. With this information and a correlation of cytotoxicity with logP, we could replace the diazepine by lipophilic group appendage to N9, which avoided steric clash with the N6-alkyl required to access the aminopyridine. This study transformed the asmarines, scarce marine metabolites, into easily synthesized, modular chemotypes that may complement or succeed iron-selective binders in clinical trials and use.

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Synthesis and biological evaluation of disubstituted N6-cyclopentyladenine analogues

Cited by 25 publications

References 19 publications

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Adenosine A_2A Receptor Antagonists: New 8‐Substituted 9‐Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease

Mechanism of Action of the Cytotoxic Asmarine Alkaloids

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Synthesis and biological evaluation of disubstituted N6-cyclopentyladenine analogues

Cited by 25 publications

References 19 publications

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Potent Adenosine A1 and A2A Receptors Antagonists: Recent Developments

Adenosine A2A Receptor Antagonists: New 8‐Substituted 9‐Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease

Mechanism of Action of the Cytotoxic Asmarine Alkaloids

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Adenosine A_2A Receptor Antagonists: New 8‐Substituted 9‐Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease