2-phenylethynyl-N⁶-isopropyladenosine

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 2-phenylethynyl-N⁶-isopropyladenosine
• 英文别名: (2R,3S,4R,5R)-2-(hydroxymethyl)-5-[2-(2-phenylethynyl)-6-(propan-2-ylamino)purin-9-yl]oxolane-3,4-diol
• 化学式: C₂₁H₂₃N₅O₄
• 分子量: 409.445
• InChiKey: BIXNOTYWAITWJJ-HAXDFEGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2',3',5'-三-O-乙酰-6-氯-2-碘嘌呤核苷 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.5h， 生成 2-phenylethynyl-N⁶-isopropyladenosine
  参考文献：
  名称：

  N⁶-Alkyl-2-alkynyl Derivatives of Adenosine as Potent and Selective Agonists at the Human Adenosine A₃ Receptor and a Starting Point for Searching A_2B Ligands

  摘要：

  A series of N-6-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A(1), A(2A), and A(3) receptors and for their potency at A(2B) adenosine receptor subtypes. The corresponding 2-(1-alkynyl) derivatives of 5'-N-ethylcarboxamidoadenosine (NECA) and Ado are used as reference compounds. Binding studies demonstrated that the activities of 2-alkynylAdos were slightly increased for the adenosine A, receptor and slightly decreased for both A(3) and A(2B) subtypes compared to those of their corresponding NECA derivatives, whereas the A(2A) receptor affinities of the two series of nucleosides were similar. The presence of a methyl group on N-6 of the 2-alkynyladenosines, inducing an increase in affinity at the human A(3) receptor and a decrease at the other subtypes, resulted in an increase in A(3) selectivity. In particular, 2-phenylethynyl-N-6-methylAdo (8b) showed an A(3) affinity in the low nanomolar range (K-i(A(3)) = 3.4 nM), with a A(1)/A(3) and A(2A)/A(3) selectivity of about 500 and 2500, respectively. These findings motivated us to search for the preparation of new selective radioligands for the A(3) subtype; hence, a procedure to introduce a tritiated alkylamino group in these molecules was carried out. As far as the potency at the A(2B) receptor, the type of 2-alkynyl chain and the presence of the ethylcarboxamido group on the sugar seem to be very important; in fact, the (S)-2-phenylhydroxypropynylNECA [(S)-PHPNECA, 1e, EC50(A(2B)) = 0.22 muM] proved to be one of the most potent A(2B) agonist reported so far. On the other hand, the (S)-2-phenylhydroxypropynyl-N-6-ethylAdo (9e, EC50(A(2B)) = 0.73 muM) showed a significantly increase of potency at the A(2B) subtype in comparison with the N-6-methyl, N-6-isopropyl, and the unsubstituted adenosine derivatives, although it resulted in being less potent than (S)PHPNECA (le, EC50(A(2B)) = 0.22 muM). These observations suggest that the introduction of an ethyl group in the N-6-position and an ethylcarboxamido substituent in the 4'-position of (S)2-phenylhydroxypropynyladenosine could lead to a compound endowed with high potency at the A(2B) receptor.

  DOI：

  10.1021/jm0109762

文献信息

• <i>N</i>⁶-Alkyl-2-alkynyl Derivatives of Adenosine as Potent and Selective Agonists at the Human Adenosine A₃ Receptor and a Starting Point for Searching A_2B Ligands
  作者：Rosaria Volpini、Stefano Costanzi、Catia Lambertucci、Sara Taffi、Sauro Vittori、Karl-Norbert Klotz、Gloria Cristalli

  DOI：10.1021/jm0109762

  日期：2002.7.1

  A series of N-6-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A(1), A(2A), and A(3) receptors and for their potency at A(2B) adenosine receptor subtypes. The corresponding 2-(1-alkynyl) derivatives of 5'-N-ethylcarboxamidoadenosine (NECA) and Ado are used as reference compounds. Binding studies demonstrated that the activities of 2-alkynylAdos were slightly increased for the adenosine A, receptor and slightly decreased for both A(3) and A(2B) subtypes compared to those of their corresponding NECA derivatives, whereas the A(2A) receptor affinities of the two series of nucleosides were similar. The presence of a methyl group on N-6 of the 2-alkynyladenosines, inducing an increase in affinity at the human A(3) receptor and a decrease at the other subtypes, resulted in an increase in A(3) selectivity. In particular, 2-phenylethynyl-N-6-methylAdo (8b) showed an A(3) affinity in the low nanomolar range (K-i(A(3)) = 3.4 nM), with a A(1)/A(3) and A(2A)/A(3) selectivity of about 500 and 2500, respectively. These findings motivated us to search for the preparation of new selective radioligands for the A(3) subtype; hence, a procedure to introduce a tritiated alkylamino group in these molecules was carried out. As far as the potency at the A(2B) receptor, the type of 2-alkynyl chain and the presence of the ethylcarboxamido group on the sugar seem to be very important; in fact, the (S)-2-phenylhydroxypropynylNECA [(S)-PHPNECA, 1e, EC50(A(2B)) = 0.22 muM] proved to be one of the most potent A(2B) agonist reported so far. On the other hand, the (S)-2-phenylhydroxypropynyl-N-6-ethylAdo (9e, EC50(A(2B)) = 0.73 muM) showed a significantly increase of potency at the A(2B) subtype in comparison with the N-6-methyl, N-6-isopropyl, and the unsubstituted adenosine derivatives, although it resulted in being less potent than (S)PHPNECA (le, EC50(A(2B)) = 0.22 muM). These observations suggest that the introduction of an ethyl group in the N-6-position and an ethylcarboxamido substituent in the 4'-position of (S)2-phenylhydroxypropynyladenosine could lead to a compound endowed with high potency at the A(2B) receptor.