5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate | 213982-96-8

• 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: 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate
• 英文别名: WHI-07；methyl (2S)-2-[[[(2S,3S,5R)-3-azido-5-(5-bromo-6-methoxy-5-methyl-2,4-dioxo-hexahydropyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-(4-bromophenoxy)phosphoryl]amino]propanoate；methyl (2S)-2-[[[(2S,3S,5R)-3-azido-5-(5-bromo-6-methoxy-5-methyl-2,4-dioxo-1,3-diazinan-1-yl)oxolan-2-yl]methoxy-(4-bromophenoxy)phosphoryl]amino]propanoate
• CAS: 213982-96-8
• 化学式: C₂₁H₂₇Br₂N₆O₉P
• 分子量: 698.262
• InChiKey: HDAYPZRVYJADHQ-ALFJRLJISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  156
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  4-bromophenyl methoxy-alanyl phosphorochloridate 在 氢溴酸 作用下， 以 四氢呋喃 为溶剂， 生成 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate
  参考文献：
  名称：

  Lack of adverse effects on fertility of female cd-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIV agent: aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07)

  摘要：

  5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07)是齐多夫定（ZDV）的一种新型溴代甲氧基取代芳基磷酸酯衍生物，是一种具有抗艾滋病毒活性的强效双功能避孕药。在将其用作阴道内杀微生物剂的条件下，使用 CD-1 小鼠进行了一系列实验，以评估其潜在的生殖毒性。雌性CD-1小鼠阴道内暴露于含0%、0.5%、1.0%或2.0% WHI-07的凝胶微乳剂配方中长达13周。按摩尔计算，这些浓度分别为体外杀精IC50的1400-5700倍和体外抗艾滋病毒IC50的1.4-5.7（×106）倍。我们研究了阴道内注射WHI-07对以下方面的影响：排卵效率；体内受精和早期胚胎、胎儿发育；以及生殖结果，包括新生儿存活率和幼崽发育。在超排卵期、器官形成期和交配前，分别连续5天、10天和13周阴道内注射化合物WHI-07。在注射人绒毛膜促性腺激素（hCG）14和40小时后，分别对小鼠的排卵效率、受精率和卵裂率进行评估。在妊娠期（GD）6-15天期间，给妊娠小鼠阴道内注射2% WHI-07，并在妊娠期（GD）17天对致畸性进行评估。在短期毒性研究中，小鼠阴道内注射含0%、0.5%、1.0%和2.0% WHI-07的凝胶微乳剂13周，然后与未注射的雄性小鼠交配，以评估潜在的生殖和发育影响。重复阴道内暴露于2% WHI-07对小鼠的排卵反应、平均卵子回收数量或受精卵或裂解卵子的百分比没有不良影响。在器官形成期间，重复阴道内施用2% WHI-07没有发现生殖毒性、胎儿毒性或致畸性的证据。此外，连续13周重复阴道内施用0.5-2.0% WHI-07对小鼠的生殖能力、围产期结果或后代的生长发育没有不良影响。化合物WHI-07作为一种安全的双功能阴道避孕药，在遏制粘膜和围产期艾滋病病毒传播方面显示出独特的临床潜力。Copyright © 2001 John Wiley & Sons, Ltd. 版权所有。

  DOI：

  10.1002/jat.762

文献信息

• Lack of adverse effects on fertility of female cd-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIV agent: aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07)
  作者：Osmond J. D'Cruz、Fatih M. Uckun

  DOI：10.1002/jat.762

  日期：2001.7

  5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel bromo-methoxy-substituted aryl phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent with anti-HIV activity. Its potential for reproductive toxicity was assessed in a series of experiments using CD-1 mice under the conditions of its intended use as an intravaginal microbicide. Female CD-1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0%, 0.5%, 1.0% or 2.0% WHI-07 for up to 13 weeks. On a molar basis, these concentrations represent 1400–5700 times its in vitro spermicidal IC50 and 1.4–5.7(×106) times its in vitro anti-HIV IC50. We examined the effects of intravaginally administered WHI-07 on: ovulation efficiency; in vivo fertilization and early embryonic, fetal development; and reproductive outcome, including neonatal survival and pup development. Compound WHI-07 was administered intravaginally during superovulation, organogenesis and prior to mating for 5 and 10 consecutive days and for 13 weeks, respectively. Mice were evaluated for ovulation efficiency and fertilization rate and cleavage 14 and 40 h after human chorionic gonadotropin (hCG) injection, respectively. Pregnant mice were administered 2% WHI-07 intravaginally during gestation days (GD) 6–15 and measures of teratogenicity were evaluated on GD 17. For short-term toxicity study, mice were given intravaginal treatment of gel–microemulsion containing 0%, 0.5%, 1.0% and 2.0% WHI-07 for 13 weeks and then mated with untreated males to evaluate potential reproductive and developmental effects. Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percentage of eggs fertilized or cleaved. No evidence of reproductive toxicity, fetal toxicity or teratogenicity was found following repetitive intravaginal application of 2% WHI-07 during the period of organogenesis. Furthermore, repeated intravaginal exposure of mice to 0.5–2.0% WHI-07 for 13 weeks had no adverse effect on the subsequent reproductive capability, perinatal outcome or growth and development of the offspring. Compound WHI-07 shows unique clinical potential as a safe, dual-function vaginal contraceptive for curbing mucosal and perinatal HIV transmission. Copyright © 2001 John Wiley & Sons, Ltd.

  5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07)是齐多夫定（ZDV）的一种新型溴代甲氧基取代芳基磷酸酯衍生物，是一种具有抗艾滋病毒活性的强效双功能避孕药。在将其用作阴道内杀微生物剂的条件下，使用 CD-1 小鼠进行了一系列实验，以评估其潜在的生殖毒性。雌性CD-1小鼠阴道内暴露于含0%、0.5%、1.0%或2.0% WHI-07的凝胶微乳剂配方中长达13周。按摩尔计算，这些浓度分别为体外杀精IC50的1400-5700倍和体外抗艾滋病毒IC50的1.4-5.7（×106）倍。我们研究了阴道内注射WHI-07对以下方面的影响：排卵效率；体内受精和早期胚胎、胎儿发育；以及生殖结果，包括新生儿存活率和幼崽发育。在超排卵期、器官形成期和交配前，分别连续5天、10天和13周阴道内注射化合物WHI-07。在注射人绒毛膜促性腺激素（hCG）14和40小时后，分别对小鼠的排卵效率、受精率和卵裂率进行评估。在妊娠期（GD）6-15天期间，给妊娠小鼠阴道内注射2% WHI-07，并在妊娠期（GD）17天对致畸性进行评估。在短期毒性研究中，小鼠阴道内注射含0%、0.5%、1.0%和2.0% WHI-07的凝胶微乳剂13周，然后与未注射的雄性小鼠交配，以评估潜在的生殖和发育影响。重复阴道内暴露于2% WHI-07对小鼠的排卵反应、平均卵子回收数量或受精卵或裂解卵子的百分比没有不良影响。在器官形成期间，重复阴道内施用2% WHI-07没有发现生殖毒性、胎儿毒性或致畸性的证据。此外，连续13周重复阴道内施用0.5-2.0% WHI-07对小鼠的生殖能力、围产期结果或后代的生长发育没有不良影响。化合物WHI-07作为一种安全的双功能阴道避孕药，在遏制粘膜和围产期艾滋病病毒传播方面显示出独特的临床潜力。Copyright © 2001 John Wiley & Sons, Ltd. 版权所有。
• Benyumov, Alexey O.; Venkatachalam, Taracad K.; Grigoriants, Olga O., Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 2, p. 114 - 122
  作者：Benyumov, Alexey O.、Venkatachalam, Taracad K.、Grigoriants, Olga O.、Vassilev, Alexei O.、Tibbles, Heather E.、Downs, Suzanne、Dumez, Darin、Uckun, Fatih M.

  DOI：——

  日期：——