N-butyl-N-methyl-11-(3'-benzoyloxy-17'-oxo-1',3',5'(10')-oestratrien-7'α-yl)-undecanamide | 131811-95-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: N-butyl-N-methyl-11-(3'-benzoyloxy-17'-oxo-1',3',5'(10')-oestratrien-7'α-yl)-undecanamide
• 英文别名: N-n-butyl-N-methyl-11-(3'-(benzoyloxy)-17'-oxoestra-1',3',5'(10')-trien-7'α-yl)undecanamide；11-(3-hydroxy-17-keto-estra-1,3,5(10)-triene-7α-yl)-undecanoic acid n-butyl-methyl-amide 3-O-benzoate；[(7R,8R,9S,13S,14S)-7-[11-[butyl(methyl)amino]-11-oxoundecyl]-13-methyl-17-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-yl] benzoate
• CAS: 131811-95-5
• 化学式: C₄₁H₅₇NO₄
• 分子量: 627.908
• InChiKey: PVZSDSWIFXDTHO-TVIKXIEFSA-N

物化性质

• 沸点：
  729.8±60.0 °C(Predicted)
• 密度：
  1.063±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  10.4
• 重原子数：
  46
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  63.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-butyl-N-methyl-11-(3'-benzoyloxy-17'-oxo-1',3',5'(10')-oestratrien-7'α-yl)-undecanamide 在 sodium hydroxide 、 lithium aluminium tetrahydride 、 次氯酸叔丁酯 、 sodium acetate 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 溶剂黄146 、 丙酮 为溶剂， 反应 21.0h， 生成 N-丁基-11-[(7R,8R,9S,13S,14S,16R,17R)-16-氯-3,17-二羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢环戊烯并[a]菲-7-基]-N-甲基十一烷酰胺
  参考文献：
  名称：

  新型卤素甾体抗雌激素的合成和生物活性。

  摘要：

  抗雌激素疗法是最广泛使用的内分泌疗法，用于治疗乳腺癌，尤其是绝经后妇女。不幸的是，目前可获得的化合物具有混合的激动/拮抗活性，因此潜在地限制了它们的治疗功效。根据观察发现，在17β-雌二醇的7α位上的脂肪链不会阻止与雌激素受体的结合，而卤化雌二醇可以增加其结合（表示为RBA）对雌激素受体的亲和力，我们合成了一系列新的甾体类抗雌激素药（6-10），在16个α位上同时具有7个α-十一碳酰胺基和一个卤素原子（Cl，Br或I）。这些化合物的立体化学是通过高场（400-MHz）核磁共振确定的。获得的某些化合物具有有效的体内抗雌激素活性。在每天两次的低剂量3微克剂量下，16α-氯3,17β-二醇酰胺，16α-碘3,17β-二醇酰胺，16α-溴3,17β-二醇酰胺，16α-氯3,17α-二醇酰胺和16α-溴3,17α-二醇酰胺分别抑制74％，63％，52％，35％和60％的雌二醇诱导的去卵巢Balb /

  DOI：

  10.1021/jm00109a014
• 作为产物：
  描述：

  3-benzoyloxy 7α-(11'-hydroxy undecyl) estra-1,3,5(10)-trien-17β-ol 在 jones reagent 、 三正丁胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 5.83h， 生成 N-butyl-N-methyl-11-(3'-benzoyloxy-17'-oxo-1',3',5'(10')-oestratrien-7'α-yl)-undecanamide
  参考文献：
  名称：

  N-Butyl-N-methyl-11-(3'-hydroxy-21',17'-carbolactone-19'-nor-17'α-pregna-1',3',5'(10')-trien-7'α-yl)-undecanamide: an inhibitor of type 2 17β-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity

  摘要：

  It is well known that 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) play a key role in the formation and inactivation, from circulating precursors, of several active androgens and oestrogens. These enzymes can thus regulate tumoural cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in a novel inhibitor of type 2 17 beta-HSD, an enzyme that catalyses the interconversions between 4-androstene-3,17-dione and testosterone, and between oestrone and oestradiol. This finding motivated our introducing the spiro-gamma-lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'-hydroxy-21',17'-carbolactone-19'-nor-17'alpha-pregna-1',3',5'(10')-trien-7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological activity was assessed in vitro. Despite the presence of a bulky alkylamide side chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2 17 beta-HSD (IC50 = 0.35 and 0.25 mu M, with and without side chain, respectively). Furthermore, the selective inhibition by lactone 4 toward type 2 17 beta-HSD (microsomal fraction of human placenta) was demonstrated by the absence of inhibitory activity toward type 1 17 beta-HSD (cytosolic fraction of human placenta). Cell proliferation assays indicated that compound 4 had no oestrogenic activity but did show anti-oestrogenic activity on ER+ cell line ZR-75-1. No androgenic activity could be detected when assayed on the AR(+) cell Line Shionogi either. Based on these facts, we report the synthesis of a new steroidal derivative, one that inhibits type 2 17 beta-HSD while possessing anti-oestrogenic activity. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)00124-0

文献信息

• [EN] 17-METHYLENE-OR 17 - SPIRO - CYCLOPROPANE 7 - SUBSTITUTED ESTRA - 1, 3, 5 (10) - TRIENE DERIVATIVES WITH ANTI - ESTROGENIC ACTIVITY<br/>[FR] STEROIDES DESTINES AU TRAITEMENT DU CANCER
  申请人：INNOVENTUS PROJECT AB

  公开号：WO2005077968A3

  公开（公告）日：2006-08-31
• Estradiol and estrone C-16 derivatives as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Blocking of ER+ breast cancer cell proliferation induced by estrone
  作者：Yannick Laplante、Christine Cadot、Michelle-Audrey Fournier、Donald Poirier

  DOI：10.1016/j.bmc.2007.11.007

  日期：2008.2.15

  Estrogens play an important role in the development of breast cancer. Inhibiting 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1)-the enzyme responsible for the last step in the biosynthesis of the most potent estrogen, estradiol (E-2)-would thus allow hindering the growth of estrogen-sensitive tumors. Based on a previous study identifying 16 beta-benzyl-E-2 (1) as a lead compound for developing inhibitors of the transformation of estrone (E-1) into E-2, we modified the benzyl group of 1 to improve its inhibitory activity. Three strategies were also devised to produce compounds with less residual estrogenic activity: (1) replacing the hydroxy group by a hydrogen at position 3 (C3); (2) adding a methoxy at C2; and (3) adding an alkylamide chain known to be antiestrogenic at C7. In order to test the inhibitory potency of the new compounds, we used the human breast cancer cell line T-47D, which exerts a strong endogenous 17 beta-HSD1 activity. In this intact cell model, 16 beta-m-carbamoylbenzyl-E-2 (4m) emerged as a potent inhibitor of 17 beta-HSD1 with an IC50 value of 44 nM for the transformation of [C-14]-E-1 (60 nM) into [C-14]-E-2 (24-h incubation). In another assay aimed at assessing the unwanted estrogenic activity, a 10-day treatment with 4m at a concentration of 0.5 mu M induced some proliferation (38%) of T-47D estrogen-sensitive (ER+) breast cancer cells. Interestingly, when 4m (0.5 mu M) was given with E-1 (0.1 nM) in a 10-day treatment, it blocked 62% of the T-47D cell proliferation induced by E-1 after its reduction to E-2 by 17 beta-HSD1. Thus, in addition to generating useful structure-activity relationships for the development of 17 beta-HSD1 inhibitors, our study demonstrates that using such inhibitors is a valuable strategy for reducing the level of E-2 and consequently its proliferative effect in T-47D ER+ breast cancer cells. (C) 2007 Elsevier Ltd. All rights reserved.
• LEVESQUE, CHARLES;MERAND, YVES;DUFOUR, JEAN-MARC;LABRIE, CLAUDE;LABRIE, F+, J. MED. CHEM., 34,(1991) N, C. 1624-1630
  作者：LEVESQUE, CHARLES、MERAND, YVES、DUFOUR, JEAN-MARC、LABRIE, CLAUDE、LABRIE, F+

  DOI：——

  日期：——
• N-Butyl-N-methyl-11-(3'-hydroxy-21',17'-carbolactone-19'-nor-17'α-pregna-1',3',5'(10')-trien-7'α-yl)-undecanamide: an inhibitor of type 2 17β-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity
  作者：Kay-Mane Sam、Fernand Labrie、Donald Poirier

  DOI：10.1016/s0223-5234(00)00124-0

  日期：2000.2

  It is well known that 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) play a key role in the formation and inactivation, from circulating precursors, of several active androgens and oestrogens. These enzymes can thus regulate tumoural cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in a novel inhibitor of type 2 17 beta-HSD, an enzyme that catalyses the interconversions between 4-androstene-3,17-dione and testosterone, and between oestrone and oestradiol. This finding motivated our introducing the spiro-gamma-lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'-hydroxy-21',17'-carbolactone-19'-nor-17'alpha-pregna-1',3',5'(10')-trien-7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological activity was assessed in vitro. Despite the presence of a bulky alkylamide side chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2 17 beta-HSD (IC50 = 0.35 and 0.25 mu M, with and without side chain, respectively). Furthermore, the selective inhibition by lactone 4 toward type 2 17 beta-HSD (microsomal fraction of human placenta) was demonstrated by the absence of inhibitory activity toward type 1 17 beta-HSD (cytosolic fraction of human placenta). Cell proliferation assays indicated that compound 4 had no oestrogenic activity but did show anti-oestrogenic activity on ER+ cell line ZR-75-1. No androgenic activity could be detected when assayed on the AR(+) cell Line Shionogi either. Based on these facts, we report the synthesis of a new steroidal derivative, one that inhibits type 2 17 beta-HSD while possessing anti-oestrogenic activity. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
• Synthesis and biological activity of new halo-steroidal antiestrogens
  作者：Charles Levesque、Yves Merand、Jean Marc Dufour、Claude Labrie、Fernand Labrie

  DOI：10.1021/jm00109a014

  日期：1991.5

  postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7 alpha-position of 17 beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA)

  抗雌激素疗法是最广泛使用的内分泌疗法，用于治疗乳腺癌，尤其是绝经后妇女。不幸的是，目前可获得的化合物具有混合的激动/拮抗活性，因此潜在地限制了它们的治疗功效。根据观察发现，在17β-雌二醇的7α位上的脂肪链不会阻止与雌激素受体的结合，而卤化雌二醇可以增加其结合（表示为RBA）对雌激素受体的亲和力，我们合成了一系列新的甾体类抗雌激素药（6-10），在16个α位上同时具有7个α-十一碳酰胺基和一个卤素原子（Cl，Br或I）。这些化合物的立体化学是通过高场（400-MHz）核磁共振确定的。获得的某些化合物具有有效的体内抗雌激素活性。在每天两次的低剂量3微克剂量下，16α-氯3,17β-二醇酰胺，16α-碘3,17β-二醇酰胺，16α-溴3,17β-二醇酰胺，16α-氯3,17α-二醇酰胺和16α-溴3,17α-二醇酰胺分别抑制74％，63％，52％，35％和60％的雌二醇诱导的去卵巢Balb /