bicyclomycin 3'-O-methanesulfonate | 71993-96-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: bicyclomycin 3'-O-methanesulfonate
• 英文别名: bicyclomycin-3'-O-methanesulfonate；[(2S,3S)-2,3-dihydroxy-3-[(1S,6R)-6-hydroxy-5-methylidene-8,10-dioxo-2-oxa-7,9-diazabicyclo[4.2.2]decan-1-yl]-2-methylpropyl] methanesulfonate
• CAS: 71993-96-9
• 化学式: C₁₃H₂₀N₂O₉S
• 分子量: 380.376
• InChiKey: LJWQJXMBDYRKEB-KNDHEWATSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  180
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  bicyclomycin 3'-O-methanesulfonate 在 水 作用下， 反应 24.0h， 以40%的产率得到(1R,2S,3S,9R)-1,2,3,9-tetrahydroxy-3-methyl-8-methylene-5-oxa-10,12-diazabicyclo<7.2.2>tridecane-11,13-dione
  参考文献：
  名称：

  Studies on the reactivity of bicyclomycin 3'-O-methanesulfonate. A novel ring-expansion transformation

  摘要：

  DOI：

  10.1021/jo00018a051
• 作为产物：
  描述：

  甲基磺酰氯 、 二环霉素 在 吡啶 作用下， 反应 2.0h， 以78%的产率得到bicyclomycin 3'-O-methanesulfonate
  参考文献：
  名称：

  Chemical, biochemical, and biological studies on select C1 triol modified bicyclomycins

  摘要：

  To determine the importance of the C(1) triol group to bicyclomycin (1)-mediated transformations we prepared the bicyclomycin diastereomers 6 (C(1')-R, C(2')-S) and 7 (C(1')-S, C(2')-R), in which the stereochemical configuration at C(1') and C(2') in the triol group in 1 (C(1')-S, C(2')-S) was reversed, and the C(1') ketone analogue 8 (C(2')-S), in which the stereogenic center at C(1') in 1 was removed. Synthesis of 6 and 8 proceeded from C(1') ketobicyclomycin C(2'), C(3') acetonide (10). Reduction (NaBH4, CeCl3) of 10 produced a diastereomeric mixture, that, after separation and removal of the acetonide protecting group, gave 6. Correspondingly, deprotection of 10 gave 8. Bicyclomycin analogue 7 was prepared by dissolving the known bicyclomycin C(2'), C(3') epoxide (13) in dilute methanolic sulfuric acid; this process produced the novel [O(9)-C(2')]cyclized bicyclomycin (14). Compound 14 formed with inversion of the C(2') center. Subsequent aqueous acid hydrolysis yielded 7. Data documenting the proposed reaction pathways and structures for compounds 6-8 are presented. The stability of bicyclomycin analogues 6-8 and 1 in deuterium oxide (pD 5.6-5.8, 7.4, 9.2-9.4) and in DMF-d(7) solutions were examined. Compounds 7 and 8 were stable under these conditions (room temperature, 14 days), whereas bicyclomycin underwent noticeable change only in basic deuterium oxide. Correspondingly, 6 was rapidly converted (t(1/2) < 30 h) to a new set of products in both acidic and basic deuterium oxide as well as in DMF-d(7). The facility of these conversions have been attributed in part to the role of the C(1) triol substituent in the ring opening of the C(6) hemiketal group in 6. All three bicyclomycin analogues reacted with ethanethiol at the C(5)-C(5a) exomethylene unit at rates comparable to 1 in buffered (''pH'' 8.0-8.5) THF-H2O (3:1) mixtures. The products generated from 6 and 7 were similar to those previously determined for 1, except for the configuration of the C(1') and C(2') substituents, whereas 8 yielded the novel piperidine adduct 33. The ethanethiol-8 reaction proceeded easily in spite of earlier projections that the C(1') hydroxyl group in bicyclomycin was required for exomethylene modification. Similarly the corresponding C(2'), C(3') acetonide of 8, 10, readily underwent reaction with ethanethiol. Significantly, compounds 6 and 7 only partially (25-35%) inhibited rho-dependent hydrolysis of ATP at the concentration levels observed to block ATPase activity by 1, and no inhibition of ATP hydrolysis was detected for 8. Our previous studies established that the primary site of bicyclomycin action in Escherichia coli is the cellular protein transcription termination factor rho. Similarly, none of the three compounds exhibited antibiotic activity at a concentration of 1200 mu g/mL, using a filter disc assay. These cumulative results suggested that key interactions existed between the C(1) triol group in bicyclomycin and the antibiotic binding site in rho, which are necessary for drug utilization and function.

  DOI：

  10.1021/ja00101a001

文献信息

• Synthesis and reactivity of bicyclomycin C(3') amines
  作者：Hyeung-Geun Park、Marco A. Vela、Harold Kohn

  DOI：10.1021/ja00081a006

  日期：1994.1

  The novel bicyclomycin C(3') tertiary amines 6-8 were prepared in which morpholine, N-acetylpiperazine, and N-carboethoxypiperazine were installed at the C(3') site in bicyclomycin (1), respectively. Previous attempts to synthesize bicyclomycin C(3') amines were unsuccessful. Compounds 68 were found to be more reactive than 1 in neutral and basic solutions. Under these conditions, a novel ring fragmentation

  制备了新型双环霉素 C(3') 叔胺 6-8，其中吗啉、N-乙酰哌嗪和 N-carboethoxypiperazine 分别安装在双环霉素 (1) 的 C(3') 站点上。以前合成双环霉素 C(3') 胺的尝试没有成功。发现化合物 68 在中性和碱性溶液中比 1 更具反应性。在这些条件下，发生了新的环断裂过程以产生单取代的乙内酰脲（即 15、18、19）和 α-亚甲基-γ-丁内酯（17）。提出了形成乙内酰脲 15、18 和 19 以及丁内酯 17 的途径，并提供了支持这些假设的证据。讨论了这种环断裂过程在未来药物设计中的潜在意义
• The role of the C-1 triol group in bicyclomycin
  作者：Zhuming Zhang、Harold Kohn

  DOI：10.1039/c39940001343

  日期：——

  Comparison of the chemical, biochemical, and biological activities of the antibiotic, bicyclomycin, with three C-1 triol modified derivatives demonstrated that all four compounds intercepted thiols but only bicyclomycin effectively inhibited the transcription termination factor rho and possessed significant antimicrobial activity, indicating that the stereochemical and chemical structure of the C-1 triol group played a key role in the drug recognition process.

  对抗生素双环霉素和三种 C-1 三醇修饰衍生物的化学、生化和生物活性进行比较后发现，这四种化合物都能拦截硫醇，但只有双环霉素能有效抑制转录终止因子 rho，并具有显著的抗菌活性，这表明 C-1 三醇基团的立体化学和化学结构在药物识别过程中起到了关键作用。
• The synthesis and reactivity of [N(8)-C(3')]-cyclized bicyclomycin. Evidence of the role of the C(1)-triol group in bicyclomycin-mediated processes
  作者：Marco A. Vela、Harold Kohn

  DOI：10.1021/jo00045a041

  日期：1992.9

  The C(1) triol group in the antibiotic, bicyclomycin (1) has been proposed to play an integral role in the bonding of key protein nucleophiles to the distal C(5)-C(5a) terminal double bond in the drug. Evidence in support of this concept has been provided by the comparison of the reactivities of bicyclomycin (1), the [N(8)-C(3')]-cyclized bicyclomycin adduct 3, 2',3'-bicyclomycin acetonide (17), and the acetonide derivative of 3, 18, with sodium ethanethiolate. Significantly, 3 displayed enhanced reactivity versus 1, 17, and 18 in this transformation. The controlling factors for the increased reactivity of 3 have been discerned and the importance of the C(1') hydroxyl group delineated. Key kinetic parameters are reported for the treatment of both 3 and 17 with 2-mercaptopyridine. Structural details are provided for both C(5a) thiolate and amine adducts of 3. The importance of these findings in relation to the mode of action of bicyclomycin are briefly discussed.
• Studies on the reactivity of bicyclomycin 3'-O-methanesulfonate. A novel ring-expansion transformation
  作者：Marco A. Vela、Harold Kohn

  DOI：10.1021/jo00018a051

  日期：1991.8
• Chemical, biochemical, and biological studies on select C1 triol modified bicyclomycins
  作者：Zhuming Zhang、Harold Kohn

  DOI：10.1021/ja00101a001

  日期：1994.11

  To determine the importance of the C(1) triol group to bicyclomycin (1)-mediated transformations we prepared the bicyclomycin diastereomers 6 (C(1')-R, C(2')-S) and 7 (C(1')-S, C(2')-R), in which the stereochemical configuration at C(1') and C(2') in the triol group in 1 (C(1')-S, C(2')-S) was reversed, and the C(1') ketone analogue 8 (C(2')-S), in which the stereogenic center at C(1') in 1 was removed. Synthesis of 6 and 8 proceeded from C(1') ketobicyclomycin C(2'), C(3') acetonide (10). Reduction (NaBH4, CeCl3) of 10 produced a diastereomeric mixture, that, after separation and removal of the acetonide protecting group, gave 6. Correspondingly, deprotection of 10 gave 8. Bicyclomycin analogue 7 was prepared by dissolving the known bicyclomycin C(2'), C(3') epoxide (13) in dilute methanolic sulfuric acid; this process produced the novel [O(9)-C(2')]cyclized bicyclomycin (14). Compound 14 formed with inversion of the C(2') center. Subsequent aqueous acid hydrolysis yielded 7. Data documenting the proposed reaction pathways and structures for compounds 6-8 are presented. The stability of bicyclomycin analogues 6-8 and 1 in deuterium oxide (pD 5.6-5.8, 7.4, 9.2-9.4) and in DMF-d(7) solutions were examined. Compounds 7 and 8 were stable under these conditions (room temperature, 14 days), whereas bicyclomycin underwent noticeable change only in basic deuterium oxide. Correspondingly, 6 was rapidly converted (t(1/2) < 30 h) to a new set of products in both acidic and basic deuterium oxide as well as in DMF-d(7). The facility of these conversions have been attributed in part to the role of the C(1) triol substituent in the ring opening of the C(6) hemiketal group in 6. All three bicyclomycin analogues reacted with ethanethiol at the C(5)-C(5a) exomethylene unit at rates comparable to 1 in buffered (''pH'' 8.0-8.5) THF-H2O (3:1) mixtures. The products generated from 6 and 7 were similar to those previously determined for 1, except for the configuration of the C(1') and C(2') substituents, whereas 8 yielded the novel piperidine adduct 33. The ethanethiol-8 reaction proceeded easily in spite of earlier projections that the C(1') hydroxyl group in bicyclomycin was required for exomethylene modification. Similarly the corresponding C(2'), C(3') acetonide of 8, 10, readily underwent reaction with ethanethiol. Significantly, compounds 6 and 7 only partially (25-35%) inhibited rho-dependent hydrolysis of ATP at the concentration levels observed to block ATPase activity by 1, and no inhibition of ATP hydrolysis was detected for 8. Our previous studies established that the primary site of bicyclomycin action in Escherichia coli is the cellular protein transcription termination factor rho. Similarly, none of the three compounds exhibited antibiotic activity at a concentration of 1200 mu g/mL, using a filter disc assay. These cumulative results suggested that key interactions existed between the C(1) triol group in bicyclomycin and the antibiotic binding site in rho, which are necessary for drug utilization and function.