Synthesis and biological activity of a novel adenosine analogue, 3-beta-D-ribofuranosylthieno[2,3-d]pyrimidin-4-one.
Synthesis and biological activity of a novel adenosine analogue, 3-beta-D-ribofuranosylthieno[2,3-d]pyrimidin-4-one.
复制标题
新型腺苷类似物 3-β-D-呋喃核糖基噻吩并[2,3-d]嘧啶-4-酮的合成和生物活性。
DOI：
10.1021/jm00382a006
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发表时间：
1985
影响因子：
7.3
通讯作者：
Townsend,LB
中科院分区：
文献类型：
--
作者：
Patil,VD;Wise,DS;Wotring,LL;Bloomer,LC;Townsend,LB
通过甲硅烷基化的杂环噻吩并[2，3-d]嘧啶-4-酮（1）与1 -0-乙酰基-2，3，5-三-O-苯甲酰基-N-（2-（2-（三氟甲基）苯基）-2，3-d]嘧啶-4-酮（1）的缩合反应制备标题核苷5。|8-D-呋喃核糖（2a）在刘易斯酸存在下或与2，3，5-三-O-乙酰基-D-呋喃核糖基溴（2b）在氧化汞和溴化汞存在下反应。通过~ 1H NMR确定了该核苷的核糖基化位点和异头构型。3-/？-的合成D-呋喃核糖基吡咯并[2，3-d]嘧啶-4-酮（8），|还描述了SD-呋喃核糖基噻吩并[2，3-d]嘧啶-4-酮（10）和2-甲基-6-/3-D-呋喃核糖基三唑并[5，4-d]嘧啶-7-酮（11）。标题化合物在体外抑制小鼠L-1210白血病细胞的生长，IDS 0为3 × 10 - 6 M。尿苷、胞苷、胸苷、脱氧胞苷、胞嘧啶、次黄嘌呤或尿苷与次黄嘌呤联合应用均不能抑制细胞生长。另一方面，用10 ~（-7）M 5-iodotubercidin抑制腺苷激酶，可防止细胞毒作用.此外，对几种细胞毒性腺苷类似物耐药的L-1210细胞亚系也对这种核苷耐药。因此，化合物5可能作为腺苷类似物。我们一直对化学合成双环杂环核苷有浓厚的兴趣，这些核苷具有与各种五元杂环系统稠合的嘧啶环，其中糖苷键位于嘧啶环中的氮原子上。该方案的基本原理部分基于从接受别嘌呤醇治疗的患者中分离出7-dD-呋喃核糖基吡唑并[3，4-d]嘧啶-4，6-二酮的报道，以及该核苷从头抑制嘧啶生物合成的能力。[1] 3-dD-呋喃核糖腺嘌呤对各种肿瘤细胞系的体外和体内抑制作用的报道引起了对这一研究领域的额外兴趣。[2]在这一相当全面的研究过程中，我们合成了嘌呤核苷、3-5噻唑并[5，4-d]嘧啶核苷、6噻吩并[2，3-d]嘧啶核苷、7和恶唑并[5，4-d]嘧啶核苷，它们彼此相似，因为碳水化合物部分与嘧啶环结合，因此被视为嘧啶型核苷。这些化合物对L-1210白血病细胞的体外和体内评价表明，在嘌呤环系统中类似于N-3的位置，即噻唑并[5，4-d]嘧啶环系统中的N-6和噻吩并[2，3-d]嘧啶的N1的核糖基化的大多数核苷不抑制肿瘤
The title nucleoside 5 was prepared by a condensation of the silylated heterocycle thieno [2, 3-d] pyrimidin-4-one (1) with l-0-acetyl-2, 3, 5-tri-0-benzoyl-| 8-D-ribofuranose (2a) in the presence of a Lewis acid or with 2, 3, 5-tri-O-acetyl-D-ribofuranosyl bromide (2b) in the presence of mercuric oxide and mercuric bromide. The site of ribosylation and anomeric configuration of this nucleoside were established by 1H NMR. Thesynthesis of 3-/?-D-ribo-furanosylpyrrolo [2, 3-d] pyrimidin-4-one (8), l-phenyl-5-dD-ribofuranosylpyrazolo [3, 4-d] pyrimidin-4-one (9), 5-methyl-3-| SD-ribofuranosylthieno [2, 3-d] pyrimidin-4-one (10), and2-methyl-6-/3-D-ribofuranosyltriazolo [5, 4-d] py-rimidin-7-one (11) is also described. The title compound inhibited the growth of murine L-1210 leukemic cells in vitro with an IDS0 of 3 X 10" 6 M. The growth inhibition could not be prevented by uridine, cytidine, thymidine, deoxycytidine, cytosine, hypoxanthine, or uridine and hypoxanthine together. On the other hand, inhibition of adenosine kinaseby 10-7 M 5-iodotubercidinprevented the cytotoxic effect. Also a subline of L-1210 cells resistant to several cytotoxic adenosine analogues was also resistant to this nucleoside. Thus it appears that this compound 5 may act as an adenosine analogue.We have pursued a strong interest in the chemical synthesis of bicyclicheterocyclic nucleosides which possess a pyrimidine ring fused to various five-membered heter-ocyclic systems with the glycosidic linkage positioned on a nitrogen atom in the pyrimidine ring. The rationale behind this program was based in part on the reported isolation of 7-dD-ribofurariosylpyrazolo [3, 4-d] pyrimi-dine-4, 6-dione from patientsbeing treated with allopurinol and on the ability of this nucleoside to inhibit pyrimidine biosynthesis de novo. 1 Additional interest in this area of research was generated by the reported invitro and in vivo inhibition of various tumor cell lines by 3-dD-ribofuranosyladenine. 2 During the course of this rather comprehensive study we have synthesized purine, 3-5 thiazolo-[5, 4-d] pyrimidine, 6 thieno [2, 3-d] pyrimidine, 7 and oxazo-lo [5, 4-d] pyrimidine8 nucleosides which were similar to one another in that the carbohydrate moiety was bonded to the pyrimidine ring and as such were viewed as pyrimi-dine-type nucleosides. The evaluation of these compounds against L-1210 leukemic cells in vitro and in vivo showed that most of these nucleosides which were ribosylated at a position analogous tothe N-3 in the purine ring system, ie, N-6 in the thiazolo [5, 4-d] pyrimidine ring system and Nl of the thieno [2, 3-d] pyrimidine, did not inhibit tumor