Synthesis of novel 1-alkyl-8-substituted-3-(3-methoxypropyl) xanthines as putative A2B receptor antagonists

Nieto, Marı́a Luisa; Balo, María Carmen; Brea, José; Caamaño, Olga; Cadavid, Marı́a Isabel; Fernández, Fernando Nieto; Mera, Xerardo García; López, Carmen; Rodríguez‐Borges, José E.

doi:10.1016/j.bmc.2009.03.029

Cited by 13 publications

(4 citation statements)

References 26 publications

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“…Direct alkylation of commercially available uracil derivatives 17 with either ethyl iodide or n -propyl iodide in the presence of 10–15% aqueous NaOH afforded the corresponding 1,3-disubstituted-6-aminouracils 18c – 18e in 40–53% yield (Scheme 1). 17 To construct the pyridine ring of pyrido[2,3- d ]pyrimidine 6 , uracil 18c was treated with the Vilsmeier reagent 19 , which was generated in situ from phosphoryl chloride in dimethyl formamide, followed by solvent evaporation and treatment of the residue with triethylamine and cyanoacetamide in ethanol. 18 However, addition of traces of water present in the reaction mixture to the hydrochloride salt 20c resulted in hydrolyzed product 21 in 66% yield, but not the required pyrido[2,3- d ]pyrimidine 6 (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors

Edupuganti

Wang

Tavares

et al. 2014

Bioorganic & Medicinal Chemistry

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A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6-16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R(1), R(2), and R(3)). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC50=420nM) and 9 (IC50=930nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-d-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors

Edupuganti

Wang

Tavares

et al. 2014

Bioorganic & Medicinal Chemistry

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“…One of the last and original variations regarded the insertion of a 3-methoxy propyl substituent [45] or a furfuryl [46] at 3-position of the xanthine core, correlated to various modifications at the 1-and 8-positions. Some of the 1-ethyl-3-(3-methoxy propyl)-8-aryl xanthines showed moderate-tohigh affinity at human A 2B AR, in particular compound 28 showed A 2B selectivity over the other adenosine subtypes of 34-fold or over.…”

Section: Xantinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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“…Nevertheless, [ 3 H]MRS1754 has found application as a useful radioligand of the A 2B AR (Ji et al 2001). Structurally related 8-phenylxanthine derivatives include CVT-5440 ( 40 ), in which additional aromatic rings were attached by an ether linkage, and 42 with a modified 3-substituent (3-methoxypropyl), have been developed as potent and selective A 2B antagonists (Kim et al 2000; Nieto et al 2009). Newer derivatives in this series, which have two pyridine rings linked by an amide group, include the highly selective A 2B AR antagonists ATL-802 ( 57 ) and ATL-852 ( 58 ).…”

Section: Adenosine A2b Receptor Antagonistsmentioning

confidence: 99%

Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.

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Synthesis of novel 1-alkyl-8-substituted-3-(3-methoxypropyl) xanthines as putative A2B receptor antagonists

Cited by 13 publications

References 26 publications

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors

A2B Receptor Ligands: Past, Present and Future Trends

Xanthines as Adenosine Receptor Antagonists

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