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Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C(2)-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC(50) = 82 nM, hA(3) K (i) > 5 muM) and its 2-chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC(50) = 210 nM, hA(3) K (i) > 5 muM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA(1), hA(2A), hA(3) EC(50) > 10 muM; hA(2B) EC(50) = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.

RESUMEN

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C(2)-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC(50) = 82 nM, hA(3) K (i) > 5 muM) and its 2-chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC(50) = 210 nM, hA(3) K (i) > 5 muM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA(1), hA(2A), hA(3) EC(50) > 10 muM; hA(2B) EC(50) = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.

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Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. Bioisosteres are substituents or groups that have chemical or physical similarities and that produce broadly similar biological effects. The sulfone moiety is recognized as a nonclassical bioisostere for replacement of the carbonyl group. When sulfonyl derivatives 5a-e were compared with carbonyl compounds 4a-e, the sulfone substitution dramatically decreased the antiproliferative activity of the series.

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Allosteric enhancers at the adenosine A(1) receptor have received attention as anti-arrhythmic cardiac agents, and, more recently, as anti-lipolytic agents. In addition, allosteric modulators at the adenosine A(1) receptor have therapeutic potential as analgesics and neuroprotective agents. In particular, the compounds with improved potency as enhancers and reduced antagonist properties are mentioned.

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Two new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene molecular skeleton and its 3-amino positional isomer were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. Although many more 3-amino derivatives have been synthesized so far, the most promising compound in this series was 2-amino-6-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene, which inhibits cancer cell growth at subnanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site.

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The synthesis and biological activity of a series of hybrids 1-5 prepared combining a benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole and different benzoheterocyclic alpha-bromoacryloyl amides have been described and their structure-activity relationships discussed. All these hetero-bifunctional compounds were highly cytotoxic against the human myeloid leukaemia cell lines HL-60 and U937 (IC(50) 0.24-1.72microM), significantly superior to that of both alkylating units alone. In human myeloid leukaemia HL-60 cells we observed that these compounds suppress survival and proliferation by triggering morphological changes and internucleosomal DNA fragmentation characteristic of apoptotic cell death. The apoptosis induced by these compounds is mediated by caspase-3 activation and is also associated to an early release of cytochrome c from the mitochondria.

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A new series of N(6)-[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5'-N-ethylcarboxamido-adenosines (24-43) has been synthesised and tested in binding assays at hA(1), hA(2A) and hA(3) adenosine receptors, and in a functional assay at the hA(2B) subtype. The examined compounds displayed high potency in activating A(2B) receptors with good selectivity versus A(2A) subtypes. The introduction of an unsubstituted 4-[(phenylcarbamoyl)-methoxy]-phenyl chain at the N(6) position of 5'-N-ethylcarboxamido-adenosine led us to the recognition of compound 24 as a full agonist displaying the highest efficacy of the series (EC(50) hA(2B)=7.3 nM). These compounds represent the first report about adenosine-related structures capable of activating hA(2B) subtype in the low nanomolar range.

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The lack of molecules endowed with selective and potent agonistic activity toward the hA2B adenosine receptors has limited the studies on this pharmacological target and consequently the evaluation of its therapeutic potential. We report the design and the synthesis of the first potent (EC50 in the nanomolar range) and selective hA2B adenosine receptor agonists consisting of 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamide derivatives. The concurrent effect of 6-substitution of the purine nucleus with a ((hetero)arylcarbonyl)hydrazino function and a 2-chloro substitution has been investigated in such NECA derivatives.

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The DNA minor groove is an attractive target for the design and development of molecules able to specifically recognize predetermined DNA sequences. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets. Selectivity for specific sequences may be of particular importance in affecting the activity of regulatory genes (oncogenes and tumor suppressor genes). Recent work on a number of hybrid compounds, in which known antitumor compounds or simple active moieties of known antitumor agents have been tethered to distamycin frame or hairpin polyamides derived from distamycin, is reviewed. The DNA alkylating and growth inhibition activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrolic rings and the type of the alkylating unit tethered to the oligopyrrolic frame.

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Naturally occurring methyl xanthines, especially caffeine and theophylline, have been widely investigated for their pharmacological properties as cognition enhancers, bronchodilator agents and mild diuretics. The xanthine core (3,7-dihydro-1H-purine-2,6-dione) has been largely manipulated in the search for selective ligands for different pharmacological targets, proving to be a versatile scaffold for the development of lead compounds in multiple therapeutic areas. The introduction of a heterocycle at the 8-position of some xanthine derivatives demonstrated to be a successful strategy for the identification of potent and selective A1 or A2B adenosine receptors antagonists as potential agents for the treatment of Alzheimer's disease and asthma, respectively. Interesting examples of 8-heterocyclyl-xanthines as dipeptidyl peptidase IV inhibitors and liver X receptor agonists have been claimed for their possible therapeutic use in the treatment of Type 2 diabetes and atherosclerosis.

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Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A(1), A(2A), A(2B), and A(3). The A(2B) subtype is a low affinity receptor, which couples to stimulation of adenylyl cyclase and also leads to a rise in intracellular calcium modulating important physiological processes. Adenosine exhibiting activity at this subtype is at concentrations greater than 10 microM. The A(2B) receptors show a ubiquitous distributions, the highest levels are present in cecum, colon and bladder, followed by blood vessels, mast cells and lung. Through A(2B) receptors, adenosine also regulates the growth of smooth muscle cell populations in blood vessels, cell growth, intestinal function, inhibition of Tumor Necrosis Factor (TNF-alpha), vascular tone, and inflammatory processes such as diarrhea and asthma. Potent and selective adenosine agonists are the result of modifications of the parent ligand adenosine by substitution, namely at N(6) or C(2) position of the purine heterocycle or at the 5' position of the ribose moiety. 5'-N-ethylcarboxamidoadenosina (NECA) is one of the most potent A(2B) adenosine receptor agonist. Classical antagonists for A(2B) adenosine receptors are xanthine analogues obtained from multiple substitutions of the parent heterocycle by C(8) substitution combined with N(1) and N(3) (and sometimes N(7)) substitutions.

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2-(3',4',5'-Trimethoxybenzoyl)-3-amino-5-aryl/heteroaryl thiophene derivatives were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. SARs were elucidated with various substitutions on the aryl moiety 5-position of the thienyl ring. Substituents at the para-position of the 5-phenyl group showed antiproliferative activity in the order of F=CH(3) > OCH(3)=Br=NO(2) > CF(3)=I > OEt. Several of these compounds led to arrest of HL-60 cells in the G2/M phase of the cell cycle and induction of apoptosis.

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The microwave-assisted aromatization method has been used for the synthesis of a series of novel thieno[2,3-c]pyridines. This rapid method produces compounds in good yield within minutes in comparison with conventional heating method. The synthesized molecules have been evaluated as a potential new series of allosteric enhancers acting at the adenosine A(1) receptor. In a functional assay, one compound (3h) showed activity comparable with that of reference compound PD 81,723.

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To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecular model of the receptor built by homology modeling. The alignment of the ligands proposed by Catalyst was then used to manually dock a set of known A(3) antagonists into the binding site, and as a result, the model was able to explain the different binding mode of very active compounds with respect to less active ones and to reproduce, with good accuracy, free energies of binding. The docking highlighted that the nonconserved residue Tyr254 could play an important role for A(3) selectivity, suggesting that a mutagenesis study on this residue could be of interest in this respect. The reliability of the whole approach was successfully tested by rational design and synthesis of new compounds.

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A new series of compounds in which the 2-amino-5-chlorophenyl ring of phenstatin analogue 7 was replaced with a 2-amino-5-aryl thiophene was synthesized and evaluated for antiproliferative activity and for inhibition of tubulin polymerization and colchicine binding to tubulin. 2-Amino-3-(3',4',5'-trimethoxybenzoyl)-5-phenyl thiophene (9f) as well as the p-fluoro-, p-methyl-, and p-methoxyphenyl substituted analogues (9i, j, and l, respectively) displayed high antiproliferative activities with IC50 values from 2.5 to 6.5 nM against the L1210 and K562 cell lines. Compounds 9i and j were more active than combretastatin A-4 as inhibitors of tubulin polymerization. Molecular docking simulations to the colchicine site of tubulin were performed to determine the possible binding mode of 9i. The results obtained demonstrated that antiproliferative activity correlated well with the inhibition of tubulin polymerization and the lengthening of the G2/M phase of the cell cycle. Moreover, a good correlation was found between these inhibitory effects and the induction of apoptosis in cells treated with the compounds.

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Compounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity toward the four adenosine receptors subtypes A(1), A(2A), A(2B), and A(3). This paper reports synthesis and biological evaluation of new 1-benzyl-3-propyl-1H,6H-pyrrolo[2,1-f]purine-2,4-diones and 1-benzyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-diones, among which we identified potent and selective A(3) adenosine receptors antagonists. In particular, 1-benzyl-7-methyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-dione (11e) shows a K(i) (hA(3)) value from binding assay of 0.8 nM.

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In this paper we report the synthesis and biological evaluation of a new class of 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-ones as A(3) adenosine receptor antagonists. We designed a new route based on the Kira-Vilsmeier reaction for the synthesis of this class of compounds. Some of the synthesized compounds showed A(3) adenosine receptor affinity in the nanomolar range and good selectivity as evaluated in radioligand binding assays at human (h) A(1), A(2A), A(2B), and A(3) adenosine receptor subtypes. We introduced several substituents on the 2-phenyl ring. In particular substitution at the 4-position by methyl, methoxy, and chlorine gave optimal activity and selectivity 6c (K(i)hA(1), A(2A)>1000 nM, EC(50)hA(2B)>1000 nM, K(i)hA(3) = 9 nM), 6d (K(i)hA(1), A(2A)>1000 nM, EC(50)hA(2B)>1000 nM, K(i)hA(3) = 16 nM), 6b (K(i)hA(1), A(2A) >1000 nM, EC(50)hA(2B)>1000 nM, K(i)hA(3) = 19 nM). In conclusion, the 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one derivatives described herein represent a new family of in vitro selective antagonists for the adenosine A(3) receptor.

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Increased concentrations of extracellular adenosine are reached in ischemic or inflamed tissues but have also been detected inside tumoral masses. If this finding may account for an important role of adenosine in the pathogenesis of tumors remains to be determined in view of its contradictory effects on cell survival and proliferation. In particular, adenosine was found to exert its effects on proliferation and on cell death mainly through the A(3) adenosine receptor. Therefore, a complete pharmacological characterization of the subtype and number of the expressed A(3) adenosine receptors is necessary for the elucidation of the role of adenosine via A(3) receptors in a specific cell subtype. The lack of potent and selective radiolabelled A(3) receptor antagonists has been, in the past, the major obstacle in the characterization of structure, function and regulation of this adenosine receptor subtype. Recently, our group has identified a series of substituted pyrazolotriazo-lopyrimidine derivatives as potent and selective antagonists to human A(3) adenosine receptors. The most recent results obtained in this field will be summarized in the present review. Furthermore, the review will report the results of the biochemical and pharmacological characterization of A(3) receptors in different human tumor cell lines and the multiple A(3) receptor-sustained ways that could prime tumor development.

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Extracellular adenosine and adenine nucleotides induce various cellular responses through activation of P1 and P2 receptors. P1 receptors preferentially recognize adenosine and four different G protein-coupled receptors (A(1), A(2A), A(2B), and A(3) subtypes) have been identified. On the other hand, P2 receptors are activated by adenine and/or uridine nucleotides and classified into two families: ionotropic P2X and G protein-coupled P2Y receptors. In this article, we summarize our studies which led to development of new potent and selective heterocyclic ligands for the adenosine receptors P1 and for the ATP receptors P2X(7).

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A new series of 1-deoxy-1-[(6-(4-(substituted-aminosulfonyl)phenyl)amino)carbonylamino-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamides (83-102) have been synthesized and tested at the human A3 adenosine receptor subtype. All the derivatives described in this work displayed affinity versus this receptor in the nanomolar range and good selectivity versus A1 adenosine receptor subtype, confirming that the p-sulfonamido moiety positively affected the activity of the molecules. The best substituents at the sulfonamido nucleus were found to be small alkyl groups, like methyl, isopropyl, ethyl, or allyl moieties (compounds 96-100), whereas monosubstitution at the amino group led to a decrease in A3 affinity values. The selectivity versus A1 adenosine receptor subtype is increased when the amino group in the sulfonamido core is represented by a hydrogenated heterocyclic ring like piperidine, morpholine, or pyrroline. Bulky groups, like adamantane and alkyl chains with more than four carbon atoms, are detrimental for the affinity and the selectivity of the A3 adenosine receptor agonists described here.

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