Structure-activity relationships of adenosines with heterocyclic N6-substituents

Trent Damon Ashton, Kylee M Aumann, Stephen P Baker, Carl Herbert Schiesser, Peter John Scammells

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Abstract

Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 51 nM, IC50 = 35 nM) while further substitution on the 7 -nitrogen with tert-butoxycarbonyl (31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)6779 - 6784
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number24
Publication statusPublished - 2007

Cite this

Ashton, Trent Damon ; Aumann, Kylee M ; Baker, Stephen P ; Schiesser, Carl Herbert ; Scammells, Peter John. / Structure-activity relationships of adenosines with heterocyclic N6-substituents. In: Bioorganic and Medicinal Chemistry Letters. 2007 ; Vol. 17, No. 24. pp. 6779 - 6784.
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title = "Structure-activity relationships of adenosines with heterocyclic N6-substituents",
abstract = "Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 51 nM, IC50 = 35 nM) while further substitution on the 7 -nitrogen with tert-butoxycarbonyl (31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.",
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Ashton, TD, Aumann, KM, Baker, SP, Schiesser, CH & Scammells, PJ 2007, 'Structure-activity relationships of adenosines with heterocyclic N6-substituents', Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 24, pp. 6779 - 6784.

Structure-activity relationships of adenosines with heterocyclic N6-substituents. / Ashton, Trent Damon; Aumann, Kylee M; Baker, Stephen P; Schiesser, Carl Herbert; Scammells, Peter John.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 24, 2007, p. 6779 - 6784.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure-activity relationships of adenosines with heterocyclic N6-substituents

AU - Ashton, Trent Damon

AU - Aumann, Kylee M

AU - Baker, Stephen P

AU - Schiesser, Carl Herbert

AU - Scammells, Peter John

PY - 2007

Y1 - 2007

N2 - Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 51 nM, IC50 = 35 nM) while further substitution on the 7 -nitrogen with tert-butoxycarbonyl (31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.

AB - Two series of N-6-substituted adenosines with monocyclic and bicyclic N-6 substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([H-3]CPX), potency, and intrinsic activity (cAMP accumulation) at the A, adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N-6-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N-6-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the AIAR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N-6-position was explored. N6- (7-Azabicyclo[2.2.1] heptan-2-yl)adeno sine (38) proved to be a reasonably potent A, agonist (K-i = 51 nM, IC50 = 35 nM) while further substitution on the 7 -nitrogen with tert-butoxycarbonyl (31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A(1)AR agonists. (c) 2007 Elsevier Ltd. All rights reserved.

M3 - Article

VL - 17

SP - 6779

EP - 6784

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 24

ER -