(1S,2R,4S,5R)-4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexan-2-ol | 259659-49-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1S,2R,4S,5R)-4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexan-2-ol
• 英文别名: (1S,2R,4S,5R)-4-benzyloxy-5-benzyloxymethyl-bicyclo[3.1.0]hexan-2-ol；5-(benzyloxymethyl)-4-(benzyloxy)bicyclo[3.1.0]hexan-2-ol；(1S,2R,4S,5R)-4-phenylmethoxy-5-(phenylmethoxymethyl)bicyclo[3.1.0]hexan-2-ol
• CAS: 259659-49-9
• 化学式: C₂₁H₂₄O₃
• 分子量: 324.42
• InChiKey: FOELPHBFNKROTN-CGXNFDGLSA-N

物化性质

• 沸点：
  451.7±30.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1S,2R,4S,5R)-4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexan-2-ol 在 四氢呋喃 、 二氯甲烷 、 三氯化硼 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 生成 (1R,2S,4S,5S)-4-(2,6-二氯-9H-嘌呤-9-基)-1-(羟甲基)双环[3.1.0]己烷-2-醇
  参考文献：
  名称：

  使用高亲和力放射性标记拮抗剂对 P2Y(1) 受体进行定量。

  摘要：

  2-氯-N(6)-甲基-(N )-methanocarba-2'-脱氧腺苷-3',5'-二磷酸 (MRS2279) 之前被开发为选择性高亲和力非核苷酸 P2Y(1) 受体(P2Y1-R)拮抗剂(J Med Chem 43：829-842，2002；Br J Pharmacol 135：2004-2010，2002)。我们利用腺嘌呤碱基中的 N(6)-甲基取代，将 [(3)H]甲胺掺入 [(3)H]MRS2279 的合成中，以获得高 (89 Ci/mmol) 比放射性，并使用该分子作为 P2Y1-R 的放射性配体。 [(3)H]MRS2279 与来自表达重组人 P2Y1-R 的 Sf9 昆虫细胞的膜结合，但不与来自野生型 Sf9 细胞或表达高水平重组 P2Y(2) 或 P2Y(12) 受体的 Sf9 细胞的膜结合。 [(3)H]MRS2279 与 Sf9 膜中表达的 P2Y1-R 的平衡结合具有高亲和力

  DOI：

  10.1124/mol.62.5.1249
• 作为产物：
  描述：

  (1S,2S,3R,4S)-4-(phenylmethoxy)-3-[(phenylmethoxy)methyl]-2-(phenylseleno)cyclopentan-1-ol 在 sodium periodate 、 diethylzinc 、 potassium carbonate 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 甲醇 、 正己烷 、 二氯甲烷 、 水 、 苯 为溶剂， 反应 10.5h， 生成 (1S,2R,4S,5R)-4-(phenylmethoxy)-5-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexan-2-ol
  参考文献：
  名称：

  Synthesis of Conformationally Restricted Carbocyclic Nucleosides: The Role of the O(4′)-Atom in the Key Hydration Step of Adenosine Deaminase

  摘要：

  DOI：

  10.1002/(sici)1522-2675(19991215)82:12<2119::aid-hlca2119>3.0.co;2-y

文献信息

• Synthesis, Biological Activity, and Molecular Modeling of Ribose-Modified Deoxyadenosine Bisphosphate Analogues as P2Y₁ Receptor Ligands
  作者：Erathodiyil Nandanan、Soo-Yeon Jang、Stefano Moro、Hea Ok Kim、Maqbool A. Siddiqui、Pamela Russ、Victor E. Marquez、Roger Busson、Piet Herdewijn、T. Kendall Harden、José L. Boyer、Kenneth A. Jacobson

  DOI：10.1021/jm990249v

  日期：2000.3.1

  than the corresponding (S)-isomer. The 2-chloro-N(6)-methyl-(N)-methanocarba analogue was an antagonist of IC(50) 51.6 nM. Thus, the ribose ring (N)-conformation appeared to be favored in recognition at P2Y(1) receptors. A cyclobutyl analogue was an antagonist with IC(50) of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives

  已经探索了腺苷 3', 5'-二磷酸作为 P2Y(1) 受体拮抗剂的构效关系，揭示了 N(6)-甲基基团的效力增强作用和取代核糖部分的能力。 Nandanan et al. J. Med. Chem. 1999, 42, 1625-1638)。我们引入了受约束的碳环（以探索糖褶皱的作用）、与腺嘌呤部分的非糖基键以及磷酸基团移位。每种类似物对 P2Y(1) 受体的生物学活性的特点是测量其刺激火鸡红细胞膜中的磷脂酶 C（激动剂作用）和抑制其由 30 nM 2-甲基硫腺苷-5'-二磷酸（拮抗剂作用）引起的刺激的能力）。N(6)-甲基在几个案例中的加入将纯激动剂转化为拮抗剂。碳环 N(6)-methyl-2'-deoxyadenosine bisphosphate 类似物是纯 P2Y(1) 受体拮抗剂，与核糖类似物 (MRS 2179) 等效。在一系列环约束的甲卡巴衍生物中，稠合环丙烷部分将核苷的假糖环约束为北
• A greener enantioselective synthesis of the antiviral agent North-methanocarbathymidine (N-MCT) from 2-deoxy-d-ribose
  作者：Olaf R. Ludek、Victor E. Marquez

  DOI：10.1016/j.tet.2009.08.035

  日期：2009.10

  An enantioselective synthesis of suitably protected (1R,2S,4S,5S)-4-amino-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol, a key starting material for the synthesis of conformationally locked carbocyclic nucleosides, including the antiviral active North-methanocarbathymidine, is reported. Starting from 2-deoxyribose the target Boc-protected amine was prepared in 33% overall yield under conditions that are

  适当保护的 (1 R ,2 S ,4 S ,5 S )-4-氨基-1-(羟甲基)双环[3.1.0]己-2-醇的对映选择性合成，这是构象合成的关键原料据报道，锁定碳环核苷，包括具有抗病毒活性的 North-methanocarbathymidine。从 2-脱氧核糖开始，在比以前的方法更生态友好的条件下，以 33% 的总收率制备了目标 Boc 保护的胺。
• Is the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration
  作者：Susana Hernandez、Harry Ford、Victor E Marquez

  DOI：10.1016/s0968-0896(02)00099-8

  日期：2002.8

  [(N)-MCdA, (5)], a relatively weak substrate for adenosine deaminase (ADA)-relative rate of deamination ca. 100 times lower than adenosine-was modified with substitutions at positions 6 (6-fluoro, compound 6) and 8 (8-aza, compound 7) with the intent to improve the level of hydration and hence hydrolysis by ADA. In these substrates the fused cyclopropane moiety constrains the cyclopentane ring to mimic the

  （North）-methanocarbadeoxyadenosine [（N）-MCdA，（5）]的糖苷配基，相对较弱的腺苷脱氨酶（ADA）相对脱氨速率。比腺苷低100倍-在6位（6-氟，化合物6）和8位（8-氮杂，化合物7）处被取代，目的是提高水合度，从而提高ADA的水解度。在这些底物中，稠合的环丙烷部分约束环戊烷环以模拟假旋转周期北半球中呋喃糖的构象，这与腺苷与ADA复合形成的核糖环的构象相匹配。对ADA水解的敏感性顺序为腺苷>>（N）-MCdA（5）大约等于（N）-6F-MCdP（6）>（N）-8-氮杂-MCdA（7）。尽管已知8-氮杂腺苷的水解速度是腺苷的两倍，
• A Conformationally Locked Analogue of the Anti-HIV Agent Stavudine. An Important Correlation between Pseudorotation and Maximum Amplitude
  作者：Yongseok Choi、Clifford George、Maria J. Comin、Joseph J. Barchi,、Hak Sung Kim、Kenneth A. Jacobson、Jan Balzarini、Hiroaki Mitsuya、Paul L. Boyer、Stephen H. Hughes、Victor E. Marquez

  DOI：10.1021/jm030116g

  日期：2003.7.1

  The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N-3-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
• 2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation:  Enhanced Potency as P2Y₁ Receptor Antagonists
  作者：Hak Sung Kim、Michihiro Ohno、Bin Xu、Hea Ok Kim、Yongseok Choi、Xiao D. Ji、Savitri Maddileti、Victor E. Marquez、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm030127+

  日期：2003.11.1

  Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1), receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1), receptor and by using the radiolabeled antagonist [H-3](2)-chloro-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N-6-methyl-2-iodo analogue 12, which displayed a K-i value in competition for binding of [H-3]5 of 0.79 nM and a K-B value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1), receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(l-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1), receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.