cyclized bicyclomycin | 71993-97-0

• 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: cyclized bicyclomycin
• 英文别名: (N(8)-C(3'))cyclized bicyclomycin；(1S,2S,3S,7R)-2,3,7-trihydroxy-3-methyl-8-methylidene-11-oxa-5,13-diazatricyclo[5.4.2.01,5]tridecane-6,12-dione
• CAS: 71993-97-0
• 化学式: C₁₂H₁₆N₂O₆
• 分子量: 284.269
• InChiKey: ATTHMHZCUTUTJJ-VKZDFBPFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.57
• 重原子数：
  20.0
• 可旋转键数：
  0.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  119.33
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  cyclized bicyclomycin 、 2,2-二甲氧基丙烷 在 对甲苯磺酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以31%的产率得到(1S,2S,6S,10R)-10-hydroxy-4,4,6-trimethyl-11-methylidene-3,5,14-trioxa-8,16-diazatetracyclo[8.4.2.01,8.02,6]hexadecane-9,15-dione
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jo00045a041
• 作为产物：
  描述：

  bicyclomycin 3'-O-methanesulfonate 在 硫酸 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.5h， 生成 cyclized bicyclomycin
  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

• Observations concerning the reactivity of bicyclomycin and bicyclomycin derivatives with organophosphorus reagents
  作者：Marco A. Vela、Harold Kohn

  DOI：10.1021/jo00050a055

  日期：1992.11