Construction of the Bicyclo[3.1.0]hexane Template of a Conformationally Locked Carbocyclic Adenosine via an Olefin Keto-Carbene Cycloaddition

Shin, Kye Jung; Moon, Hyung Ryong; George, and Clifford; Márquez, Víctor E.

doi:10.1021/jo9917691

Cited by 55 publications

(43 citation statements)

References 32 publications

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“…25,27 The more synthetically challenging (S)-isomer (5d) was available only as the racemate and therefore was tested as such. 23 At rat A 1 , rat A 2A , and human A 3 subtypes, the (N)-analogue proved to be of much higher affinity than the (S)-analogue. At the human A 2B receptor, binding was carried out using [ 3 H]ZM 241,385 (4-(2-[7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}-triazin-5-ylaminoethyl)phenol); 27 however, the affinity was too weak to establish selectivity for a specific isomer.…”

Section: Biological Activitymentioning

confidence: 87%

“…A sample of the antipodal (S)-methanocarba-adenosine, 5d, was synthesized in racemic form by Marquez and co-workers by an intramolecular carbene addition reaction. 23 …”

Section: Chemical Synthesismentioning

confidence: 99%

“…Optically active (1′R, 2′R,3′S,4′R,5′S)-4-(6-aminopurin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (5c) was synthesized as described. 18 4-(6-Aminopurin-9-yl)-1-(hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diol (11) and racemic rel-(1′R,2′S,3′R,4′R, 5′S)-1-(6-aminopurin-9-yl)-4-(hydroxymethyl)-bicyclo[3.1.0]hexane-2,3-diol (5d) were synthesized according to Marquez and colleagues (manuscript in preparation 23 ). Compounds 7a and 9a were synthesized as described.…”

Section: Chemical Synthesismentioning

confidence: 99%

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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: Biological Activitymentioning

confidence: 87%

“…A sample of the antipodal (S)-methanocarba-adenosine, 5d, was synthesized in racemic form by Marquez and co-workers by an intramolecular carbene addition reaction. 23 …”

Section: Chemical Synthesismentioning

confidence: 99%

Section: Chemical Synthesismentioning

confidence: 99%

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

et al. 2000

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“…Compound 3 was subjected to a diazo transfer reaction with tosyl azide in the presence of triethylamine to give the desired diazo compound 4 in an 89% yield. Unfortunately, the construction bicyclo[3.1.0]hexane system was performed using copper(II) acetylacetonate 10 to produce a 1 : 1 mixture of the desired less polar isomer 5 (43%) and an unwanted isomer and 5' (42%). Each isomer 5 and 5' was subjected to the carbonyl reduction procedure using NaBH 4 because it was too difficult to determine their stereochemistry at this stage.…”

Section: Resultsmentioning

confidence: 99%

The First Synthesis of Dually Modified Southern-Mimicking Nucleoside: 4'-Methyl Branched and Bicyclo [3.1.0] Hexane Locked Nucleoside

2004

Bulletin of the Korean Chemical Society

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“…A bicyclo[3.1.0]hexane scaffold in which a cyclopentane ring is fused with a cyclopropane ring is reported to adopt a rigid south or north conformation. 6 Therefore, rigid carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template [7][8][9][10][11] have received considerable attention as potential anticancer and antiviral agents.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Synthesis of Conformationally Fixed Bicyclo[3.1.0]hexyl Nucleosides with an Ethenyl Group at C3'-Position as Potential Antiviral Agents

Kim¹,

Woo²,

Park³

et al. 2014

Bulletin of the Korean Chemical Society

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Synthesis of north-5′-methylbicyclo[3.1.0]hexyl adenine and hypoxanthine nucleosides with an ethenyl group at C3′ position was successfully achieved by a highly facile method. Methylbicyclo[3.1.0]hexanone (±)-7 with three contiguous chiral centers and its epimer (±)-6 was remarkably simply constructed only by four steps involving a carbenoid insertion reaction in the presence of rhodium (II) acetate dimer as a metal catalyst, giving a correct relative stereochemistry of the generated three chiral centers. Due to steric hindrance from the concave face of the bicyclo[3.1.0]hexanone system, a Grignard reaction of (±)-7 with ethenylmagnesium bromide showed exclusive diastereoselectivity towards the b-face. The Grignard reaction chemoselectively proceeded without reacting with ester functionality. Coupling reaction of glycosyl donor (±)-11 with 6-chloropurine nucleobase afforded only the desired N 9 -alkylated nucleoside without the formation of N 7 -regioisomer. By the conventional method, 6-chloro group was converted into 6-amino and 6-hydroxy groups to give the desired adenine and hypoxanthine bicyclo[3.1.0]hexyl carbanucleosides with 3′-ethenyl group, respectively.

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Construction of the Bicyclo[3.1.0]hexane Template of a Conformationally Locked Carbocyclic Adenosine via an Olefin Keto-Carbene Cycloaddition

Cited by 55 publications

References 32 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

The First Synthesis of Dually Modified Southern-Mimicking Nucleoside: 4'-Methyl Branched and Bicyclo [3.1.0] Hexane Locked Nucleoside

Highly Efficient Synthesis of Conformationally Fixed Bicyclo[3.1.0]hexyl Nucleosides with an Ethenyl Group at C3'-Position as Potential Antiviral Agents

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