tiazofurin 5'-monophosphate | 83161-83-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tiazofurin 5'-monophosphate
• 英文别名: 2-β-D-ribofuranosylthiazole-4-carboxamide 5'-phosphate；[(2R,3S,4R,5R)-5-(4-carbamoylthiazol-2-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl dihydrogen phosphate；[(2R,3S,4R,5R)-5-(4-carbamoyl-1,3-thiazol-2-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
• CAS: 83161-83-5
• 化学式: C₉H₁₃N₂O₈PS
• 分子量: 340.251
• InChiKey: XDDGVTBJYGSVPM-DBRKOABJSA-N

物化性质

• 沸点：
  766.9±70.0 °C(Predicted)
• 密度：
  1.830±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.4
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  201
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tiazofurin 5'-monophosphate 在 三正丁胺 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 75.5h， 生成 9-(5',6'-dideoxy-6'-phosphono-β-D-ribo-hexofuranosyl)adenine 6'<*>5' ester with 2-β-D-ribofuranosyl-4-thiazolecarboxamide
  参考文献：
  名称：

  Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogs stable to phosphodiesterase hydrolysis

  摘要：

  Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected adenosine 5'-(alpha, beta-methylene)diphosphate with isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against IMP dehydrogenase in vitro. beta-Methylene-TAD (3), the most stable of the TAD phosphonate analogues, produced a depletion of guanine nucleotide pools in an experimentally induced TR-resistant P388 tumor variant that was superior to that obtained with TR in the corresponding sensitive line.

  DOI：

  10.1021/jm00159a027
• 作为产物：
  描述：

  噻唑呋林 在 trichloropyrophosphopyridinium chloride 作用下， 以 乙腈 为溶剂， 反应 4.0h， 生成 tiazofurin 5'-monophosphate
  参考文献：
  名称：

  与抗肿瘤药2-β-D-呋喃核糖基噻唑-4-羧酰胺有关的核苷和核苷酸的合成及生物学活性。

  摘要：

  2-β-D-呋喃呋喃糖基噻唑-4-羧酰胺的磷酸化（1）提供了5'-磷酸2，将其转化为相应的5'-三磷酸4和环状3'，5'-磷酸5。处理2 -（2,3,5-三-O-乙酰基-β-D-呋喃呋喃糖基）噻唑-4-腈（6）与NH3-NH4Cl一起提供了2-β-D-呋喃核糖基噻唑-4-甲box盐酸盐（7），以及用H 2 S-吡啶处理得到相应的4-硫代羧酰胺9。将化合物9用溴代丙酮酸乙酯处理，然后用甲醇氨处理，得到2'-（2-β-D-呋喃呋喃糖基噻唑-4-基）噻唑-4'。 -羧酰胺（11）。5'-磷酸2对培养中的L1210细胞具有细胞毒性，并且对小鼠腹膜内植入的鼠白血病具有显着的有效作用。idine 7对培养中的L1210略有毒性，并抑制嘌呤核苷的磷解。环状3'，5'-磷酸酯5比相应的5'-磷酸酯2或母体核苷1作为抗肿瘤剂的效果差。

  DOI：

  10.1021/jm00369a006

文献信息

• Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2′ of the adenosine
  作者：Andrzej Zatorski、Pawell Lipla、Nevena Mollova、Karl H. Schram、Barry M. Goldstein、Kyoichi A. Watanabe、Krzysztof W. Pankiewicz

  DOI：10.1016/0008-6215(93)84063-c

  日期：1993.10

  Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the beta-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2'-deoxy-2'-fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5) have been synthesized. Adenosine 5'-difluoromethylenediphosphonate (8) was prepared

  已经合成了噻唑-4-羧酰胺腺嘌呤二核苷酸（TAD）的类似物3，其中焦磷酸桥的β-氧原子被二氟亚甲基取代。同样，已经合成了含有2'-脱氧-2'-氟腺苷的TAD类似物（4）及其二氟亚甲基二膦酸盐同类物（5）。腺苷5'-二氟亚甲基二膦酸酯（8）是由5'-O-甲苯磺酰基腺苷（6）和三（四正丁基铵）二氟亚甲基二膦酸酯（7）通过改进的Poulter方法制备的。通过用原甲酸三乙酯处理将化合物8转化为2'，3'-环状碳酸酯9。用2'，3'处理9 在DCC存在下，在吡啶中的-O-异亚丙基亚氮杂呋喃（10）得到二核苷酸11和异亚丙基保护的二腺苷四膦酸酯12的混合物。将11脱保护后，所需的β-二氟亚甲基TAD（3）通过HPLC分离为次要化合物。产品。获得了Ap4A的类似物二腺苷四膦酸腺苷12作为主要成分。或者，将2'，3'-O-异丙基亚氮杂呋喃酯（10）甲苯磺酸化，并通过与7偶合，将产物13进一步转化为相应的二
• A New Tiazofurin Pronucleotide: Synthesis and Biological Evaluation of<i>Cyclo</i>Saligenyl-Tiazofurin Monophosphate
  作者：L. Cappellacci、G. Barboni、P. Franchetti、C. Martini、H. N. Jayaram、M. Grifantini

  DOI：10.1081/ncn-120022674

  日期：2003.10

  Synthesis and biological activities of cyclosaligenyl-tiazofurin monophosphate (CycloSal-TRMP), a new tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.

  据报道，一种新的噻唑呋喃原核苷酸，即环saligenyl-tiazofurin单磷酸酯（CycloSal-TRMP）的合成和生物学活性。CycloSal-TRMP被证明在体外对人骨髓性白血病K562细胞具有活性，并作为A1腺苷受体激动剂。
• Use of 2-Beta-D-ribofuranosylthiazole-4-carboxamides for the manufacture of medicaments inhibiting malignant tumors
  申请人：VIRATEK, INC.

  公开号：EP0054432A1

  公开（公告）日：1982-06-23

  The compound 2-β-D-ribofuranosylthiazole-4-carboxamide has been found to be effective in the treatment of malignant tumors in warm blooded animals, as have esters of this compound, for instance 2-(2,3,5,-tri-O-acetyl-β-D-ribofuranosyl)-thiazole-4-carboxamide and 2-(5-0-phosphoryl-β-D-ribofuranosyl)-thiazole-4-carboxamide. Disclosed also are pharmaceutical compositions containing 2-p-D-ribofuranosylthiazole-4-carboxamide or a related compound as the active ingredient; as well as processes for producing the novel compounds and compositions.

  已发现化合物 2-β-D-呋喃核糖基噻唑-4-甲酰胺可有效治疗温血动物的恶性肿瘤，该化合物的酯类也是如此，例如 2-(2,3,5,-三-O-乙酰基-β-D-呋喃核糖基)-噻唑-4-甲酰胺和 2-(5-0-磷酸基-β-D-呋喃核糖基)-噻唑-4-甲酰胺。 还公开了含有 2-对-D-呋喃核糖基噻唑-4-甲酰胺或相关化合物作为活性成分的药物组合物；以及生产新型化合物和组合物的工艺。
• Novel azole dinucleotide compounds and methods for their production
  申请人：BRIGHAM YOUNG UNIVERSITY

  公开号：EP0090405A1

  公开（公告）日：1983-10-05

  A class of azole dinucleotide compounds of formula and the pharmaceutically acceptable salts of the compounds; wherein R is a heterocycle that is 3-carbamoyl-1,2,4-triazol-1-yl, 4-carbamoylthiazol-2-yl, or 4-carbamoylselenazol-2-yl and methods for their production are provided. Compounds of the class typically have pharmacological properties and are well tolerated, being useful, for example, in treating leukemias and solid tumors in warm blooded animals.

  一类式唑二核苷酸化合物及其药物可接受盐 其中 R 是 3-氨基甲酰基-1,2,4-三唑-1-基、4-氨基甲酰基噻唑-2-基或 4-氨基甲酰基硒唑-2-基的杂环。该类化合物通常具有药理特性，且耐受性良好，例如可用于治疗温血动物的白血病和实体瘤。
• Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase
  作者：Gulilat Gebeyehu、Victor E. Marquez、James A. Kelley、David A. Cooney、Hiremagalur N. Jayaram、David G. Johns

  DOI：10.1021/jm00360a025

  日期：1983.6

  The chemical synthesis of thiazole-4-carboxamide adenine dinucleotide (TAD), previously identified as the active anabolite of the oncolytic 2-beta-D-ribofuranosylthiazole-4-carboxamide (TR), has been achieved by three different approaches: (1) incubation of adenosine 5'-monophosphate (AMP) and 2-beta-D-ribofuranosylthiazole-4-carboxamide 5'-monophosphate (TRMP) with excess DCC in aqueous pyridine, (2) reaction of adenosine 5'-phosphoromorpholidate with TRMP in pyridine, and (3) reaction of adenosine-5'-phosphoric di-n-butylphosphinothioic anhydride with TRMP in the presence of AgNO3. While the first approach produced only traces of TAD, the last two afforded 31 and 16% yields, respectively, of isolated TAD. The synthetic material was indistinguishable from biosynthesized TAD as judged by its HPLC behavior, NMR, UV and mass spectra, enzymatic resistance to alkaline phosphatase and susceptibility to venom phosphodiesterase, IMP dehydrogenase inhibitory activity, and cytotoxicity. TAD and TR were equally effective against murine P388 leukemia when employed at equimolar doses.