3β-cyclobutylcarbonyloxy-5-androsten-17-one | 1345406-89-4

• 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: 3β-cyclobutylcarbonyloxy-5-androsten-17-one
• 英文别名: 17-oxaandrost-5-ene-3β-yl cyclobutanoate
• CAS: 1345406-89-4
• 化学式: C₂₄H₃₄O₃
• 分子量: 370.532
• InChiKey: HEKGRVRTJDLRJK-IGJOJHROSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.23
• 重原子数：
  27.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  43.37
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  3β-cyclobutylcarbonyloxy-5-androsten-17-one 在 caesium carbonate 、 三氯氧磷 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.5h， 生成 16-formyl-17-(1H-pyrazole-1-yl)androsta-5,16-dien-3β-yl cyclobutanoate
  参考文献：
  名称：

  Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase

  摘要：

  The enzyme type 5 17 beta-hydroxysteroid dehydrogenase 5 (17 beta-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17 beta-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Delta(4)-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17 beta-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17 beta-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.

  DOI：

  10.3109/14756366.2014.1003926
• 作为产物：
  描述：

  醋酸去氢表雄酮 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 生成 3β-cyclobutylcarbonyloxy-5-androsten-17-one
  参考文献：
  名称：

  新型脱氢表雄酮苯并咪唑基衍生物作为5α-还原酶同工酶抑制剂。

  摘要：

  5α-R同工酶（1型和2型）在前列腺发育中起重要作用，因为当生理性血清睾丸激素（T）浓度低时，它们负责前列腺内二氢睾丸激素（DHT）的水平。在这项研究中，我们合成了7个在C-17上具有苯并咪唑部分的新型脱氢表雄酮衍生物，并确定了它们对1α和2型5α-还原酶活性的影响。抑制5α-R1活性，而那些在C-3上带有脂环族酯（环丙基，环丁基或环戊基环）或醇基的化合物抑制两种同工酶的活性。在C-3处具有环己基或环庚基酯的衍生物没有抑制活性。在药理实验中 具有C 3-3的具有醇或脂族基团的酯或三个较小的脂环族环之一的酯的衍生物降低了雄性仓鼠胁腹器官的直径，其中环丁酯和环戊基酯显示出更高的作用。除环丁酯和环戊酯外，这些化合物可减轻前列腺和精囊的重量。

  DOI：

  10.3109/14756366.2015.1070843

文献信息

• Crystal Structure and Synthesis of Three New Steroidal Derivatives as Antiandrogens
  作者：Manuel Soriano-García、Tania Segura、Norma Valencia、Eugene Bratoeff、Marisa Cabeza

  DOI：10.1007/s10870-010-9806-7

  日期：2010.12

  The structures of 3β-cyclobutyl carbonyloxy-5-androsten-17-one (C24H34O3), compound 1; 3β-cyclopentyl carbonyloxy-5-androsten-17-one (C25H36O3), compound 2; and 3β-cyclohexyl carbonyloxy-5-androsten-17-one (C26H38O3) compound 3 were established by spectral and X-ray diffraction studies. Steroidal derivatives 1–3 exhibited a high antiandrogenic effect and could be considered as potential drugs for the treatment of prostate cancer. Compound 1 crystallizes in the orthorhombic space group P212121 with unit cell parameters a = 6.618(2), β = 14.167(3), c = 22.329(5) Å, Z = 4. Compound 2 crystallizes in the orthorhombic space group P212121 with unit cell parameters a = 6.631(2), b = 13.865(4), c = 23.952(7) Å, Z = 4. Compound 3 crystallizes in the orthorhombic space group P212121 with unit cell parameters a = 6.6100(9), b = 13.896(2), c = 24.491(3) Å, Z = 4. All three structures (1–3) were solved by direct methods and refined to R = 0.0708, 0.0750 and 0.0496, respectively. For compound 2, there is positional disorder of the side chain at C3. All the rings of both steroid skeletons are trans connected. For structures 1–3, the six-membered rings A, B and C have a deformed chair, half chair and deformed chair conformations. The five-membered rings D adopt an intermediate envelope and half-chair conformations. For structure 2, the five-membered rings E and EA have a deformed envelope and an intermediate envelope and half-chair conformations, respectively. For structure 3, the six-membered ring E adopts a deformed chair conformation. Cohesion of the crystals can be attributed to van der Waals and weak C–H⋯O interactions. The crystal structures of three new steroidal derivatives as antiandrogens and their conformation were obtained by X-ray diffraction techniques from suitable single crystals. Steroidal derivatives 1–3 exhibited a high antiandrogenic effect and could be considered as potential drugs for the treatment of prostate cancer.

  通过光谱和 X 射线衍射研究，确定了化合物 1-3β-环丁基碳酰氧基-5-雄烯-17-酮（C24H34O3）、化合物 2-3β-环戊基碳酰氧基-5-雄烯-17-酮（C25H36O3）和化合物 3-3β-环己基碳酰氧基-5-雄烯-17-酮（C26H38O3）的结构。类固醇衍生物 1-3 具有很强的抗雄激素作用，可作为治疗前列腺癌的潜在药物。化合物 1 结晶于正交空间群 P212121，单胞参数 a = 6.618(2), β = 14.167(3), c = 22.化合物 2 在正交空间群 P212121 中结晶，其单胞参数为 a = 6.631(2)，b = 13.865(4)，c = 23.化合物 3 在正交空间群 P212121 中结晶，单胞参数 a = 6.6100(9), b = 13.这三种结构（1-3）均采用直接法求解，并分别精制为 R = 0.0708、0.0750 和 0.0496。化合物 2 的 C3 侧链存在位置紊乱。两个类固醇骨架的所有环均为反式连接。对于结构 1-3，六元环 A、B 和 C 具有变形椅状、半椅状和变形椅状构象。五元环 D 采用中间包络和半椅构象。在结构 2 中，五元环 E 和 EA 分别具有变形包络、中间包络和半椅构象。对于结构 3，六元环 E 采用变形椅构象。晶体的内聚力可归因于范德华和微弱的 C-H⋯O 相互作用。通过 X 射线衍射技术从合适的单晶体中获得了作为抗雄激素的三种新甾体衍生物的晶体结构及其构象。甾体衍生物 1-3 具有很强的抗雄激素作用，可作为治疗前列腺癌的潜在药物。
• Cytotoxic effect of novel dehydroepiandrosterone derivatives on different cancer cell lines
  作者：Mariana Garrido、Marisa Cabeza、Francisco Cortés、José Gutiérrez、Eugene Bratoeff

  DOI：10.1016/j.ejmech.2013.02.031

  日期：2013.10

  The aim of this study was to determine the cytotoxic effect of human cancer cells on three series of novel dehydroepiandrosterone derivatives containing triazole or pyrazole rings at C-17 and an ester moiety at C-3 of the androstane skeleton. The panel cancer cells used in this study were the following: PC-3, MCF-7 and SKLU-1.The results from this study indicated that the steroidal derivatives 4a-4e and 4f-4k showed the highest cytotoxic potency. This difference in this activity could be attributed to the ability of the triazole (three nitrogen atoms) to form stronger hydrogen bonds with the active site of the cell as compared to the pyrazole group having two nitrogen atoms.Compounds 4f-4k having an aromatic ester at C-3 showed an enhanced cytotoxic activity as compared to their aliphatic counterparts 4a-4e. Apparently the electronegative phenyl ring increased the polarity of the molecule, thus increasing the dipole dipole association of the steroidal molecule with the reactive site of the cell. (C) 2013 Elsevier Masson SAS. All rights reserved.
• Effect of dehydroepiandrosterone derivatives on the activity of 5α-reductase isoenzymes and on cancer cell line PC-3
  作者：Eugene Bratoeff、Mariana Garrido、Teresa Ramírez-Apan、Yvonne Heuze、Araceli Sánchez、Juan Soriano、Marisa Cabeza

  DOI：10.1016/j.bmc.2014.08.019

  日期：2014.11

  It is well known that testosterone (T) under the influence of 5 alpha-reductase enzyme is converted to dihydrotestosterone (DHT), which causes androgen-dependent diseases. The aim of this study was to synthesize new dehydroepiandrosterone derivatives (3a-e, 4a-i, 6 and 7) having potential inhibitory activity against the 5 alpha-reductase enzyme. This paper also reports the in vivo pharmacological effect of these steroidal molecules. The results from this study showed that all compounds exhibited low inhibitory activity for 5 alpha-reductase type 1 and 2 enzymes and they failed to bind to the androgen receptor. Furthermore, in the in vivo experiment, steroids 3b, 4f, and 4g showed comparable antiandrogenic activity to that of finasteride; only derivatives 4d and 7 produced a considerable decrease in the weight of the prostate gland of gonadectomized hamsters treated with (T). On the other hand, compounds 4a, f and h showed 100% inhibition of the growth of prostate cancer cell line PC-3, with compound 4g having a 98.2% antiproliferative effect at 50 mu M. The overall data indicated that these steroidal molecules, having an aromatic ester moiety at C-3 (4f-h), could have anticancer properties. (C) 2014 Elsevier Ltd. All rights reserved.