5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-3-C-(2-trimethylsilylethynyl)-α-D-ribofuranose | 155470-62-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-3-C-(2-trimethylsilylethynyl)-α-D-ribofuranose
• 英文别名: (3aR,5R,6R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-6-(2-trimethylsilylethynyl)-5,6a-dihydro-3aH-furo[2,3-d][1,3]dioxol-6-ol
• CAS: 155470-62-5
• 化学式: C₁₉H₃₆O₅Si₂
• 分子量: 400.663
• InChiKey: UPMQRQWMALRWFA-YYAJDYIMSA-N

物化性质

• 沸点：
  410.0±45.0 °C(predicted)
• 密度：
  1.04±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  57.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-3-C-(2-trimethylsilylethynyl)-α-D-ribofuranose 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 三氟甲磺酸三甲基硅酯 、 硫酸 、 四丁基氟化铵 作用下， 以 四氢呋喃 、 溶剂黄146 、 乙腈 为溶剂， 生成 1-(2,3,5-tri-O-benzoyl-3-C-ethynyl-β-D-ribofuranosyl)uracil
  参考文献：
  名称：

  Nucleosides and nucleotides. 152. 1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl)uracil as a broad spectrum antitumor nucleoside

  摘要：

  1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd) has been designed as a potential multifunctional antitumor nucleoside antimetabolite. EUrd was synthesized by condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-3-C-ethynyl-alpha,beta-D-ribo-pentofuranose (6) and bis(trimethylsilyl)uracil in the presence of trimethylsilyl triflate in CH3CN in good yield, followed by debenzoylation with NH3/MeOH. In vitro tumor cell growth inhibitory activity of EUrd against 14 human solid tumor cell lines was compared with 5-fluorouridine (FUrd), 2'-deoxy-5-fluorouridine (FdUrd), and 5-fluorouracil (5-FU) as positive controls. EUrd was a quite potent tumor cell growth inhibitor against almost ail the tumor cell lines examined in this study except for human pancreas PANC-1 cells, and the potency of EUrd is about 6 to 650 times stronger than that of 5-FU and comparable to that of FUrd and FdUrd. EUrd showed also potent antitumor activity against human tumors as xenografts in nude mice when given in a daily intravenous dose of 2 mg/kg on consecutive days. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00339-3
• 作为产物：
  描述：

  1,2-O-isopropylidene-5-O-(tert-butyl)dimethylsilyl-α-D-xylofuranoside 在 吡啶 、 chromium(VI) oxide 、 正丁基锂 、 乙酸酐 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-3-C-(2-trimethylsilylethynyl)-α-D-ribofuranose
  参考文献：
  名称：

  Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction

  摘要：

  A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-beta-C-ethynyl glycosyl donors in the key Vorbruggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(01)01249-2

文献信息

• Nucleosides and Nucleotides. 175. Structural Requirements of the Sugar Moiety for the Antitumor Activities of New Nucleoside Antimetabolites, 1-(3-<i>C</i>-Ethynyl-β-<scp>d</scp>-<i>r</i><i>ibo</i>-pentofuranosyl)cytosine and -uracil
  作者：Hideshi Hattori、Eisuke Nozawa、Tomoharu Iino、Yuichi Yoshimura、Satoshi Shuto、Yuji Shimamoto、Makoto Nomura、Masakazu Fukushima、Motohiro Tanaka、Takuma Sasaki、Akira Matsuda

  DOI：10.1021/jm9801814

  日期：1998.7.1

  1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)uracil (EUrd) and its cytosine congener (ECyd) as potential multifunctional antitumor nucleoside antimetabolites. They showed potent and broad-spectrum antitumor activity against various human and mouse tumor cells in vitro and in vivo. To clarify the structure-activity relationship of the sugar moiety, various 3'-C-carbon-substituted analogues, such as 1-propynyl

  我们以前设计1-（3-C-乙炔基-β-d-核糖基戊呋喃糖基）尿嘧啶（EUrd）及其胞嘧啶同源物（ECyd）作为潜在的多功能抗肿瘤核苷抗代谢物。他们在体外和体内显示出对各种人类和小鼠肿瘤细胞的有效和广谱抗肿瘤活性。为了阐明糖部分的结构-活性关系，合成了ECyd和EUrd的各种3'-C-碳取代的类似物，例如1-丙炔基，1-丁炔基，乙烯基，乙基和环丙基衍生物。我们还制备了具有不同构型的ECyd和EUrd的3'-脱氧类似物和3'-同源物，以确定3'-羟基的作用以及3'-碳原子与乙炔基之间的长度以及2'- ECyd的乙炔基衍生物可确定乙炔基的空间要求。这些核苷对小鼠白血病L1210和人KB细胞的体外肿瘤细胞生长抑制活性表明ECyd和EUrd是该系列中最有效的抑制剂，对于L1210细胞，IC50值为0.016和0.13 microM，对于L1210细胞，IC50值为0.028和0.029 microM
• 3'-substituted nucleoside derivatives
  申请人：Matsuda; Akira

  公开号：US05763418A1

  公开（公告）日：1998-06-09

  The invention relates to a 3'-substituted nucleoside derivative represented by the following general formula (1): ##STR1## wherein B means a nucleic acid base which may have a substituent, Z represents a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the formula: ##STR2## in which R.sup.a, R.sup.b and R.sup.c are individually a lower alkyl group or a phenyl group, or an oxiranyl group which may have at least one lower alkyl group, R.sup.1 and R.sup.2 individually represent H or an ester-forming residue capable of easily leaving in a living body, and R.sup.3 is H, a mono- or polyphosphoric acid residue, or an ester-forming residue capable of easily leaving in a living body, with the proviso that the sugar moiety is ribose, or a pharmaceutically acceptable salt thereof. The 3'-substituted nucleoside derivative according to the invention has an excellent antitumor activity and is hence useful for treatment for and prevention of cancers.

  该发明涉及一种由下述一般式(1)表示的3'-取代核苷衍生物：##STR1##其中B表示可能有取代基的核酸碱基，Z代表可能被下述式表示的基团取代的低炔基或低烯基基团：##STR2##其中R.sup.a、R.sup.b和R.sup.c分别为低烷基基团或苯基团，或者可能具有至少一个低烷基基团的环氧丙基基团，R.sup.1和R.sup.2分别表示H或者在活体中容易脱离的酯基残基，R.sup.3为H、单磷酸或多磷酸残基，或者在活体中容易脱离的酯基残基，但糖基是核糖，或其药用可接受盐。根据该发明的3'-取代核苷衍生物具有优异的抗肿瘤活性，因此对于癌症的治疗和预防非常有用。
• Nucleosides and Nucleotides. 158. 1-(3-<i>C</i>-Ethynyl<b>-</b>β-<scp>d</scp>-<i>ribo</i>-pentofuranosyl)- cytosine, 1-(3-<i>C</i>-Ethynyl-β-<scp>d</scp>-<i>ribo</i>-pentofuranosyl)uracil, and Their Nucleobase Analogues as New Potential Multifunctional Antitumor Nucleosides with a Broad Spectrum of Activity
  作者：Hideshi Hattori、Motohiro Tanaka、Masakazu Fukushima、Takuma Sasaki、Akira Matsuda

  DOI：10.1021/jm960537g

  日期：1996.1.1

  We previously designed 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd) as a potential multifunctional antitumor nucleoside antimetabolite. It showed a potent and broad spectrum of antitumor activity against various human tumor cells in vitro and in vivo. To determine the structure-activity relationship, various nucleobase analogues of EUrd, such as 5-fluorouracil, thymine, cytosine, 5-fluorocytosine, adenine, and guanine derivatives, were synthesized by condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-3-C-ethynyl-alpha,beta-D-ribo-pentofuranose (6) and the corresponding pertrimethylsilylated nucleobases in the presence of SnCl4 or TIMSOTf as a Lewis acid in CH3CN followed by debenzoylation. The in vitro tumor cell growth inhibitory activity of these 3'-C-ethynyl nucleosides against mouse leukemia L1210 and human nasopharyngeal KB cells showed that 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd) and EUrd were the most potent inhibitors in the series, with IC50 values for L1210 cells of 0.016 and 0.13 mu M and for KB cells of 0.028 and 0.029 mu M, respectively. 5-Fluorocytosine, 5-fluorouracil, and adenine nucleosides showed much lower activity, with IC50 values of 0.4-2.5 mu M, while thymine and guanine nucleosides did not exhibit any activity up to 300 mu M. We next evaluated the tumor cell growth inhibitory activity of ECyd and EUrd against 36 human tumor cell lines in vitro and found that they were highly effective against these cell lines with IC50 values in the nanomolar to micromolar range. These nucleosides have a similar inhibitory spectrum. The in vivo antitumor activities of ECyd and EUrd were compared to that of 5-fluorouracil against 11 human tumor xenografts including three stomach, three colon, two pancreas, one renal, one breast, and one bile duct cancers. ECyd and EUrd showed a potent tumor inhibition ratio (73-92% inhibition relative to the control) in 9 of 11 and 8 of 11 human tumors, respectively, when administered intravenously for 10 consecutive days at doses of 0.25 and 2.0 mg/kg, respectively, while 5-fluorouracil showed potent inhibitory activity against only one tumor. Such excellent antitumor activity suggests that ECyd and EUrd are worth evaluating further for use in the treatment of human cancers.
• Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction
  作者：Makoto Nomura、Tsutomu Sato、Masato Washinosu、Motoaki Tanaka、Tetsuji Asao、Satoshi Shuto、Akira Matsuda

  DOI：10.1016/s0040-4020(01)01249-2

  日期：2002.2

  A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-beta-C-ethynyl glycosyl donors in the key Vorbruggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Nucleosides and nucleotides. 152. 1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl)uracil as a broad spectrum antitumor nucleoside
  作者：Akira Matsuda、Hideshi Hattori、Motohiro Tanaka、Takuma Sasaki

  DOI：10.1016/0960-894x(96)00339-3

  日期：1996.8

  1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd) has been designed as a potential multifunctional antitumor nucleoside antimetabolite. EUrd was synthesized by condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-3-C-ethynyl-alpha,beta-D-ribo-pentofuranose (6) and bis(trimethylsilyl)uracil in the presence of trimethylsilyl triflate in CH3CN in good yield, followed by debenzoylation with NH3/MeOH. In vitro tumor cell growth inhibitory activity of EUrd against 14 human solid tumor cell lines was compared with 5-fluorouridine (FUrd), 2'-deoxy-5-fluorouridine (FdUrd), and 5-fluorouracil (5-FU) as positive controls. EUrd was a quite potent tumor cell growth inhibitor against almost ail the tumor cell lines examined in this study except for human pancreas PANC-1 cells, and the potency of EUrd is about 6 to 650 times stronger than that of 5-FU and comparable to that of FUrd and FdUrd. EUrd showed also potent antitumor activity against human tumors as xenografts in nude mice when given in a daily intravenous dose of 2 mg/kg on consecutive days. Copyright (C) 1996 Elsevier Science Ltd