1-{(3'R,4'S)-5'-O-[(tert-butyl)diphenylsilyl]-2',3'-dideoxy-3'-C-(hydroxymethyl)-β-pentofuranosyl}thymine | 146557-80-4

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 1-{(3'R,4'S)-5'-O-[(tert-butyl)diphenylsilyl]-2',3'-dideoxy-3'-C-(hydroxymethyl)-β-pentofuranosyl}thymine
• 英文别名: 5'-O-(tert-butydiphenylsilyl)-3'-deoxy-3'-C-(hydroxymethyl)thymidine；5'-O-tert-butyldimethylsilyl-3'-deoxy-3'-(hydroxymethyl)thymidine；3'-Deoxy-3'-Hydroxymethyl-5'-O-(Tertbutyldiphenylsilyl)Thymidine；3'-Deoxy-3'-Hydroxymethyl-5'-O-(Tert-Butyldiphenylsilyl)Thymidine；1-[(2R,4R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 146557-80-4
• 化学式: C₂₇H₃₄N₂O₅Si
• 分子量: 494.663
• InChiKey: MAHADQMBYXSTDR-AGILITTLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.32
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  88.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-{(3'R,4'S)-5'-O-[(tert-butyl)diphenylsilyl]-2',3'-dideoxy-3'-C-(hydroxymethyl)-β-pentofuranosyl}thymine 在 2,6-二甲基吡啶 、 triethylamine trifluoride 、 甲基三苯氧基碘磷 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 生成 3'-deoxy-3'-C-(iodomethyl)-5'-O-(4-methoxytrityl)thymidine
  参考文献：
  名称：

  新型3'-C-亚甲基胸苷和5-甲基尿苷/胞苷H-膦酸酯和亚膦酸酯的合成，用于寡核苷酸的新骨架修饰。

  摘要：

  新型5'-O-DMT-和MMT保护的3'-C-亚甲基修饰的胸苷，5-甲基尿苷和5-甲基胞苷H-膦酸酯1-7与O-甲基，氟，氢和O-（2通过一种新的有效策略，由相应的关键中间体3'-C-碘甲基核苷和中间体BTSP（通过Arbuzov反应原位制备）合成了2'-位的-甲氧基乙基）取代基。Arbuzov反应的修饰反应条件防止了DMT和MMT保护基的丢失，并直接提供了所需的5'-O-DMT-和/或MMT保护的3'-C-亚甲基修饰的H-膦酸酯1 -6虽然在PC键形成后也通过操纵保护基制备了一些。3'-C-碘甲基-5-甲基胞嘧啶53的修饰Arbuzov反应 由其5-甲基尿苷衍生物42制备，并用BTSP提供5-甲基胞嘧啶H-膦酸酯54，将其进一步转移到相应的4-N-（N-甲基吡咯烷-2-亚基）-保护的H-膦酸酯单体7。5使用DCC作为偶联剂，将'-O-MMT保护的3'-C-亚甲基改性的H-膦酸酯5、3和7

  DOI：

  10.1021/jo001699u
• 作为产物：
  描述：

  5'-O-tert-butyldiphenylsilylthymidine 在 sodium tetrahydroborate 、 sodium periodate 、 四氧化锇 、 偶氮二异丁腈 、 甲基三苯氧基碘磷 、 N-甲基吗啉氧化物 作用下， 以 1,4-二氧六环 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 41.0h， 生成 1-{(3'R,4'S)-5'-O-[(tert-butyl)diphenylsilyl]-2',3'-dideoxy-3'-C-(hydroxymethyl)-β-pentofuranosyl}thymine
  参考文献：
  名称：

  Efficient and Stereoselective Synthesis of 3′-Deoxy 3′ -C-Branched-Chain Substituted Thymidine

  摘要：

  在本报告中，我们首次利用分子间自由基 C-C 键形成反应，简便、高效、立体选择性地合成了 1-[5-O-(叔丁基二苯基硅烷基)-2,3-二脱氧-3-C-甲酰基-δ²-D-赤式戊呋喃糖基]胸腺嘧啶（12）。讨论了这种化合物在反义应用中的效用，作为延伸，12 被转化为 1-[2,3-二脱氧-3-C-(羟甲基)-δ-D-赤式戊呋喃糖基]胸腺嘧啶（14），这是一种有效的抗病毒和抗肿瘤药物。

  DOI：

  10.1055/s-1994-25664

文献信息

• Dinucleoside Monophosphate Analogues Containing Disulfide Linkages
  作者：Emma M. Witch、Richard Cosstick

  DOI：10.1016/s0040-4039(97)01542-6

  日期：1997.9

  two dinucleoside monophosphate analogues is described in which the 3′-O-P-O-5′ phosphodiester linkage is replaced by either an isosteric 3′-C-S-S-5′ or a shorter 3′-S-S-5′ linkage. In both cases the -S-S- bond was formed through a disulfide exchange reaction using an activated S-nucleosidyl S-aryl disulfide and a suitably protected derivative of 5′-thiothymidine. © 1997 Elsevier Science Ltd.

  描述了两种二核苷单磷酸酯类似物的合成，其中3'-OPO-5'磷酸二酯键被等排3'-CSS-5'或更短的3'-SS-5'键取代。在这两种情况下，-SS-键都是通过二硫化物交换反应，使用活化的S-核苷基S-芳基二硫化物和适当保护的5'-硫代胸腺嘧啶核苷衍生物形成的。©1997爱思唯尔科学有限公司。
• Synthesis and Hybridisation Properties of Phosphonamidate Ester Modified Nucleic Acid
  作者：Robin A. Fairhurst、Stephen P. Collingwood、David Lambert、Roger J. Taylor

  DOI：10.1055/s-2001-12328

  日期：——

  The replacement of the two backbone oxygen atoms of the phosphodiester linkage of DNA with carbon and nitrogen in the form of a phosphonamidate ester linkage, in both possible regioisomeric forms, is described. An alkylation reaction with the 3′-C-P-N-5′ methyl phosphoamidate regioisomer yielded the corresponding N-methylated analogues. For each example separation into individual phosphonamidate ester diastereoisomers was performed prior to incorporation into oligonucleotides. The effect upon duplex stability for DNA oligonucleotides containing each of these modifications with complimentary RNA is reported.

  本文介绍了用碳和氮以膦酰胺酯连接的形式取代 DNA 磷酸二酯连接的两个骨架氧原子的两种可能的异构体形式。与 3′-C-P-N-5′甲基膦酰酰胺异构体的烷基化反应产生了相应的 N-甲基化类似物。在将每个实例掺入寡核苷酸之前，先将其分离成单个膦酰酰胺酯非对映异构体。报告了含有这些修饰的 DNA 寡核苷酸与互补 RNA 对双链稳定性的影响。
• Heteroatomic oligonucleoside linkages
  申请人：Isis Pharmaceuticals, Inc.

  公开号：US06087482A1

  公开（公告）日：2000-07-11

  Oligonucleotide-mimicking macromolecules that have improved nuclease resistance are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligonucleotides with four atom linking groups provide unique compounds that are useful in regulating RNA expression and in therapeutics. Methods of synthesis and use also are disclosed.

  提供了具有改善核酸酶抵抗力的寡核苷酸模拟大分子。用四原子连接基替换天然寡核苷酸中的正常磷酸二酯间糖连接，提供了独特的化合物，可用于调节RNA表达和治疗。还公开了合成和使用的方法。
• Rational Design of 5‘-Thiourea-Substituted α-Thymidine Analogues as Thymidine Monophosphate Kinase Inhibitors Capable of Inhibiting Mycobacterial Growth
  作者：Ineke Van Daele、Hélène Munier-Lehmann、Matheus Froeyen、Jan Balzarini、Serge Van Calenbergh

  DOI：10.1021/jm0706158

  日期：2007.11.1

  Recently, thymidine monophosphate kinase (TMPK) emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. The elucidation of the X-ray structure of TMPK of M. tuberculosis (TMPKmt), as well as the structure of an earlier serendipitously discovered dimeric thymidine inhibitor, laid the foundation for the design of potent and selective TMPKmt inhibitors reported here. Several hits identified within a series of 3'-C-branched thiourea-substituted P-thymidine derivatives inspired us to construct a set of 5'-thiourea-substituted a-thymidine derivatives characterized by a similar relative orientation of the thymine and arylthiourea moieties. (x-Thymidine derivative 15, featuring a (3-trifluoromethyl-4-chlorophenyl)thiourea moiety, has a K-i of 0.6 mu M and a selectivity index of 600 versus human TMPK. Moreover, it represents the first TMPK inhibitor showing good inhibitory activity on growing M. bovis (MIC99 = 20 mu g/mL) and M. tuberculosis (MIC50 = 6.25 mu g/mL) strains.
• ——
  作者：Daniel Hutter、Monika O. Blaettler、Steven A. Benner

  DOI：10.1002/1522-2675(200209)85:9<2777::aid-hlca2777>3.0.co;2-1

  日期：2002.9

  Chimeric DNA molecules containing four different linking groups, the natural phosphate, 5'-methylenephosphonate. bis(methylene)phosphinate, and bis(methylene) sulfone (see Fig.1), were directly compared for their ability to form duplexes with complementary DNA and DNA chimeras. From melting temperatures for analogous complementary sequences, general conclusions about the impact of geometric distortion of the internucleotide linkage around the two P-O-C bridges were drawn, as were conclusions about the impact on duplex stability that arises from the removal of the negative charge in the linking group. Each structural perturbation diminished the melting temperature, by ca. -2.5degrees per modification for the 5'-methylenephosphonate, -3.5degrees per modification for the bis(methylene)phosphinate, and -4.5degrees per modification for the bis(methylene) sulfone linker. These results have implications for DNA chemistry including the design of 'antisense' candidates and the proposal of alternative genetic materials in the search for non-terrean life.