Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

Márquez, Víctor E.; Siddiqui, M. Arshad; Ezzitouni, Abdallah; Russ, Pamela; Wang, Jianying; Wagner, Richard W.; Matteucci, Mark D.

doi:10.1021/jm960306+

Cited by 252 publications

(238 citation statements)

References 31 publications

(88 reference statements)

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“…19,21 For example, HIV reverse transcriptase has shown almost exclusive preference for the (N)-isomer of AZT, and only the (N)-isomer of thymidine was demonstrated to have effective antiherpes activity. 19 In recent experiments kinases in general have shown preference for the opposite conformation (Victor E. Marquez, Staffan Eriksson, Riad Agbaria, and D. G. Johns, unpublished results). This could serve as the basis for distinguishing the activities of adenosine analogues at receptors and in metabolic processes.…”

Section: Discussionmentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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Section: Discussionmentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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“…Although the NoS energy difference is about 4 kcal/mol for classic nucleosides and nucleotides, [24] it can explain their differences in binding affinity. [29] We estimated the enthalpy (∆H°) and the entropy (∆S°) of the NoS twostate pseudorotational equilibrium for 7aϪb and 8aϪb from the slopes and intercepts of the van't Hoff plots [ln(X S / X N ) vs. 1/T] (see Table 4). The signs of the thermodynamic parameters (∆H°, ∆S°, and ∆G°) are arbitrary chosen so that positive values indicate the drive of NoS equilibrium to N, as is the case for 7aϪb and 8aϪb, whereas negative values would describe the drive towards S.…”

Section: Nos Energy Calculationsmentioning

confidence: 99%

Mycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors: Biological Evaluation and Conformational Analysis of 2′‐ and 3′‐Modified Thymidine Analogues

et al. 2003

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Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a−b, 6a−b, 7a−b, and 8a−b, modified in 2Ј-and 3Ј-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. K i between 118 and 1260 µM). This prompted us to investigate the conformational features of these nucleosides. We concluded

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“…In general, the ribose rings of nucleosides and nucleotides may adopt a range of conformations as described by a "pseudorotational cycle" (21). The Northern ((N), 2 ′ -exo, 3 ′ -endo) and Southern ((S), 2 ′ -endo, 3 ′ -exo) conformations are the most relevant to the biological activities observed for nucleosides and nucleotides in association with DNA, RNA, and various enzymes.…”

Section: Nucleosides and Nucleotides Having Methanocarba Rings As Ligmentioning

confidence: 99%

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

Ravi

Nandanan

Kim

et al. 2001

Nucleosides, Nucleotides and Nucleic Acids

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Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3 ′ ,5 ′ -bisphosphate derivatives act as selective P2Y 1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y 1 and A 1 and A 3 ARs.Modulation of adenosine receptors (P1) and nucleotide (P2) receptors by selective agonists and antagonists (1,2) has the potential for the treatment of wide range of diseases, including those of the cardiovascular, inflammatory, and central nervous systems. There are four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ), all of which are G protein-coupled receptors (GPCRs) generally coupled to adenylate cyclase. Extracellular nucleotides, principally ATP, ADP, UTP, and UDP, act through two families of membrane-bound P2 receptors: P2Y subtypes, GPCRs which are activated by both adenine and uracil nucleotides and generally coupled to phospholipase C; and P2X subtypes, ligand-gated ion channels which are activated principally by adenine nucleotides (2). As many as seven subtypes have been cloned within each family. Agonists of adenosine and P2 receptors are almost exclusively nucleosides and nucleotides, respectively, while antagonists of these receptors are structurally more diverse (1). In comparison to the adenosine receptors, much less is known about the specific effects of P2 receptors, largely due to the lack of selective ligands.We are currently designing and synthesizing novel ligands for both adenosine and P2 receptors. Recent methods utilized in these investigations include: conformationally constraining the ribose, or ribose-like, moiety of nucleosides and nucleotides to freeze a conformation that may provide favorable affinity and/or selectivity at P1 and P2 receptors (3,4); modifying known receptor antagonists (5-7); use of a template approach based on the

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Nucleosides with a Twist. Can Fixed Forms of Sugar Ring Pucker Influence Biological Activity in Nucleosides and Oligonucleotides?

Cited by 252 publications

References 31 publications

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Mycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors: Biological Evaluation and Conformational Analysis of 2′‐ and 3′‐Modified Thymidine Analogues

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

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