(1S,2S,3S,6S,7R)-7-(ethylsulfanylmethyl)-2,3,6-trihydroxy-3-methyl-5,10-dioxa-11-azatricyclo[5.3.3.01,6]tridecane-12,13-dione | 114944-07-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (1S,2S,3S,6S,7R)-7-(ethylsulfanylmethyl)-2,3,6-trihydroxy-3-methyl-5,10-dioxa-11-azatricyclo[5.3.3.01,6]tridecane-12,13-dione
• CAS: 114944-07-9
• 化学式: C₁₄H₂₁NO₇S
• 分子量: 347.389
• InChiKey: YDRFXUIIBZDZGS-HPCHECBXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  151
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  乙酰基-赖氨酰-甲胺 、 (1S,2S,3S,6S,7R)-7-(ethylsulfanylmethyl)-2,3,6-trihydroxy-3-methyl-5,10-dioxa-11-azatricyclo[5.3.3.01,6]tridecane-12,13-dione 以 甲醇 为溶剂， 反应 16.0h， 以51%的产率得到N-((S)-5-Acetylamino-5-methylcarbamoyl-pentyl)-N'-((2S,3S,3aS)-7-ethylsulfanylmethyl-3,7a-dihydroxy-2-hydroxymethyl-2-methyl-hexahydro-furo[3,2-b]pyran-3a-yl)-oxalamide
  参考文献：
  名称：

  Studies on the reactivity of bicyclomycin with nucleophilic amino acid derivatives

  摘要：

  DOI：

  10.1021/jo00277a052
• 作为产物：
  描述：

  二环霉素 、 乙硫醇 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 以46%的产率得到(1S,2S,3S,6S,7R)-7-(ethylsulfanylmethyl)-2,3,6-trihydroxy-3-methyl-5,10-dioxa-11-azatricyclo[5.3.3.01,6]tridecane-12,13-dione
  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

• Role of the C(6)-Hydroxy Group in Bicyclomycin:  Synthesis, Structure, and Chemical, Biochemical, and Biological Properties
  作者：Alejandro Santillán,、Xiangdong Zhang、Jon Hardesty、William R. Widger、Kohn

  DOI：10.1021/jm9708386

  日期：1998.3.1

  the C(6) hydroxy group in 1 was essential for activity. We found that replacing the C(6)-hydroxy group in 1 with weaker hydrogen bond donors led to low inhibitory activities in the rho-dependent ATPase and transcription termination assays. None of the bicyclomycin derivatives exhibited antibiotic activity against E. coli W3350 cells at a 32 mg/mL concentration. The apparent specificity for the C(6)-hydroxy

  双环霉素（1）是一种商业抗生素，其在大肠杆菌中的主要作用位点是转录终止因子rho。最近的结构活性关系研究为1，表明用烷氧基和硫代烷氧基取代基取代C（6）-羟基会导致rho生化分析中抑制活性的急剧下降。这种结构特异性的起源已通过C（6）-氨基-（13），C（6）-（羟基氨基）-（14）和C（6）的合成以及化学，生物化学和生物学评估进行了探索-巯基双环霉素（15）。这些化合物，像1一样，能够与​​rho进入氢键供体相互作用，并且能够进行C（6）开环以生成α，β-不饱和羰基，亚胺或硫酮系统。将13-15的化学反应性与1的化学反应性进行了比较。我们观察到1，在中性和碱性条件下用EtSH处理后，很容易进行C（6）的半胱氨酸键裂解，然后将共轭物添加到β-亚甲基-α-酮酰胺2中，从而得到迈克尔加成加合物，而13-15通过初始裂解C（1 ）-O（2）键。13-15和相关类似物的生化和生物学测定表明1中的C
• Studies on the reactivity of bicyclomycin with thiols
  作者：Syed Abuzar、Harold Kohn

  DOI：10.1021/ja00164a036

  日期：1990.4

  The chemical reactivity of the clinically important antibiotic bicyclomycin with thiols has been investigated. Emphasis has been placed on discerning the product profiles obtained with cycteine derivatives in light of earlier projections on the likely in vivo biological nucleophile in bicyclomycin-mediated transformations

  已经研究了临床上重要的抗生素双环霉素与硫醇的化学反应性。鉴于早期对双环霉素介导的转化中可能的体内生物亲核试剂的预测，重点放在辨别用半胱氨酸衍生物获得的产品概况
• 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
• Studies on the reactivity of bicyclomycin with nucleophilic amino acid derivatives
  作者：Syed Abuzar、Harold Kohn

  DOI：10.1021/jo00277a052

  日期：1989.8
• 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.