7α-allyl-3-oxoandrost-4-en-17β-yl acetate | 137107-61-0

• 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: 7α-allyl-3-oxoandrost-4-en-17β-yl acetate
• 英文别名: 7α-allyl-4-androstene-17β-ol-3-one acetate；7α-allyl-4-androsten-17β-ol-3-one acetate；17beta-Acetoxy-7alpha-allyl-4-androsten-3-one；[(7R,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-7-prop-2-enyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
• CAS: 137107-61-0
• 化学式: C₂₄H₃₄O₃
• 分子量: 370.532
• InChiKey: LGGKYTTVCYZYNC-LDBDOVKYSA-N

物化性质

• 熔点：
  148-150 °C
• 沸点：
  471.8±45.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7α-allyl-3-oxoandrost-4-en-17β-yl acetate 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 以95%的产率得到17β-hydroxy-7α-allyl-4-androsten-3-one
  参考文献：
  名称：

  Synthesis and preliminary in vitro biological evaluation of 7α-testosterone–chlorambucil hybrid designed for the treatment of prostate cancer

  摘要：

  The synthesis of 7 alpha-testosterone-chlorambucil hybrid is reported. This compound is made from testosterone in a 6 step reaction sequence and with 23% overall yield. An alternative convergent reaction sequence yielded the same hybrid through a Grubbs metathesis reaction between chlorambucil allyl ester and 7 alpha-allyltestosterone with 35% overall yield. KIT assays showed that the hybrid is selective towards hormone-dependent prostate cancer cell line (LNCaP (AR+)) and shows similar activity than the parent drug, chlorambucil. Thus, the new hybrid shows promising potential for drug targeting of hormone-dependent prostate cancer through its capacity of delivering chlorambucil directly to the site of treatment. This could extend the use of chlorambucil to prostate cancer in the future. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.027
• 作为产物：
  描述：

  醋酸睾酮 、 烯丙基三甲基硅烷 在 N-溴代丁二酰亚胺(NBS) 、 lithium carbonate 、 lithium bromide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 7α-allyl-3-oxoandrost-4-en-17β-yl acetate
  参考文献：
  名称：

  Synthesis and preliminary in vitro biological evaluation of 7α-testosterone–chlorambucil hybrid designed for the treatment of prostate cancer

  摘要：

  The synthesis of 7 alpha-testosterone-chlorambucil hybrid is reported. This compound is made from testosterone in a 6 step reaction sequence and with 23% overall yield. An alternative convergent reaction sequence yielded the same hybrid through a Grubbs metathesis reaction between chlorambucil allyl ester and 7 alpha-allyltestosterone with 35% overall yield. KIT assays showed that the hybrid is selective towards hormone-dependent prostate cancer cell line (LNCaP (AR+)) and shows similar activity than the parent drug, chlorambucil. Thus, the new hybrid shows promising potential for drug targeting of hormone-dependent prostate cancer through its capacity of delivering chlorambucil directly to the site of treatment. This could extend the use of chlorambucil to prostate cancer in the future. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.04.027

文献信息

• New Testosterone Derivatives as Semi-Synthetic Anticancer Agents Against Prostate Cancer: Synthesis and Preliminary Biological Evaluation
  作者：Nathalie Morin、Julie Bruneau、Sebastien Fortin、Kevin Brasseur、Valerie Leblanc、Eric Asselin、Gervais Berube

  DOI：10.2174/1573406411666150212120628

  日期：2015.7.24

  Prostate cancer (PC) is a major health issue in the world. Treatments of localized PC are quite efficient and usually involve surgery, radiotherapy and/or hormonal therapy. Metastatic PC is however rarely curable to this day. Treatments of metastatic PC involve radiotherapy, chemotherapy and hormonal treatment such as orchiectomy, antiandrogens and luteinizing hormone-releasing hormone agonists. The suppression of tumor growth by hormonal treatment is efficient but overtime resistance still occurs and the disease progresses. Thus, more urgently than ever there is a need for discovery of new treatment options for castration-resistant PC (CRPC). Hence, we designed and tested a series of amide derivatives located at position 7α of testosterone as prospective “natural” or “semisynthetic” anticancer agents against CRPC with the goal of discovering therapeutic alternatives for the disease. This manuscript describes an efficient path towards the target molecules that are made in only 6 or 7 chemical steps from testosterone in good overall yields. This strategy can be used to make several compounds of interest that present higher biological activity than the classic antiandrogen; cyproterone acetate (3). The best testosterone-7α-amide was the N-2-pyridylethylamide (25) which was as active as the antiandrogen cyproterone acetate (3) on androgen-dependent LNCaP cells and 2.7 times more active on androgen-independent PC3 prostate cancer cells. The results obtained show the synthetic feasibility and the potential for future development of this unique class of semi-synthetic anticancer agents that offer the premise of new treatment modalities for patients afflicted with CRPC.

  前列腺癌（PC）是全球主要的健康问题。局部前列腺癌的治疗相当有效，通常包括手术、放射治疗和/或激素治疗。然而，转移性前列腺癌至今仍很少能治愈。转移性 PC 的治疗包括放疗、化疗和激素治疗，如睾丸切除术、抗雄激素和促黄体生成素释放激素激动剂。激素治疗能有效抑制肿瘤生长，但随着时间的推移，仍会出现耐药性，导致病情恶化。因此，现在比以往任何时候都更迫切需要发现治疗阉割耐药 PC（CRPC）的新方案。因此，我们设计并测试了一系列位于睾酮 7α 位的酰胺衍生物，将其作为治疗 CRPC 的 "天然 "或 "半合成 "抗癌药物，目的是发现该疾病的替代治疗方法。本手稿介绍了一种高效的目标分子制备途径，只需 6 或 7 个化学步骤，就能从睾酮中制备出总体产量良好的目标分子。这种策略可用于制造几种感兴趣的化合物，其生物活性高于传统的抗雄激素醋酸环丙孕酮（3）。最好的睾酮-7α-酰胺是 N-2-吡啶乙酰胺（25），它对依赖雄激素的 LNCaP 细胞的活性与抗雄激素醋酸环丙孕酮（3）相当，而对不依赖雄激素的 PC3 前列腺癌细胞的活性是后者的 2.7 倍。研究结果表明，这类独特的半合成抗癌剂具有合成可行性和未来发展潜力，为 CRPC 患者提供了新的治疗方式。
• Aromatase inhibitors
  申请人：Endorecherche, Inc.

  公开号：US05227375A1

  公开（公告）日：1993-07-13

  Novel aromatase inhibitors are disclosed for use in therapeutic preparations for treatment of estrogen-dependent diseases. The compounds are specified 7.alpha.-substituted androstanedione and androstenedione derivatives which show a strong inhibitory activity towards aromatase. The invention includes synthesis and pharmaceutical compositions of said compounds.

  本发明涉及一种新型芳香化酶抑制剂，用于治疗雌激素依赖性疾病的治疗制剂。该化合物为7α-取代的雄甾烷二酮和雄烯二酮衍生物，具有强烈的抑制芳香化酶的活性。本发明还包括合成和药物组成物的制备。
• Synthesis of novel C2-symmetric testosterone dimers and evaluation of antiproliferative activity on androgen-dependent and -independent prostate cancer cell lines
  作者：Anne-Rose Vesper、Jacques Lacroix、René C.-Gaudreault、Heidar-Ali Tajmir-Rihai、Gervais Bérubé

  DOI：10.1016/j.steroids.2016.08.012

  日期：2016.11

  A series of 7 alpha-linked testosterone dimers were made and tested for biological activity on both androgen dependent (LNCaP) and androgen-independent (DU-145 and PC3) prostate cancer cell lines. The synthesis proceeds through the formation of a trans-4-(17 beta-acetoxy-4-androsten-3-one-7 alpha-yl)-but-2-enoic acid 4-hydroxy-alkyl ester intermediate of various length (7a-d) followed by the final dimerization step. The dimers showed interesting biological activity in comparison to the omega-hydroxyalkyl ester intermediates 7a-d. The most active dimer 8a (n = 1) showed IC50 of 3.8, 1.4 and 1.8 mu M, respectively on LNCaP, DU-145 and PC3 cancer cell lines. On these cell lines, this dimer is about 12, 70 and 47 times more powerful than cyproterone acetate (CPA) the reference antiandrogen. Furthermore, dimers 8b-d (n = 2, 3, 4) were less active than 8a but showed selective activity on androgen-dependent LNCaP prostate cancer cells. This indicates possible application for the treatment of androgen-dependent prostate cancer. (C) 2016 Elsevier Inc. All rights reserved.
• Second-generation testosterone-platinum(II) hybrids for site-specific treatment of androgen receptor positive prostate cancer: Design, synthesis and antiproliferative activity
  作者：Vincent Ouellette、Marie-France Côté、René C. Gaudreault、Heidar-Ali Tajmir-Riahi、Gervais Bérubé

  DOI：10.1016/j.ejmech.2019.06.090

  日期：2019.10

  Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 mu M on LNCaP (AR+) in comparison to 13.3 mu M on PC3 (AR-) and 8.8 mu M on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 mu M, 0.5 mu M and 1.0 mu M, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 mu M. This is not the case for CDDP showing IC50 of 1.3 mu M and 5.1 mu M on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Design, synthesis and biochemical studies of new 7α-allylandrostanes as aromatase inhibitors
  作者：Carla L. Varela、Cristina Amaral、Georgina Correia-da-Silva、Rui A. Carvalho、Natércia A. Teixeira、Saul C. Costa、Fernanda M.F. Roleira、Elisiário J. Tavares-da-Silva

  DOI：10.1016/j.steroids.2013.02.016

  日期：2013.7

  Two series of derivatives of 7 alpha-allylandrostenedione, namely its 3-deoxo and 1-ene analogs, were designed and synthesised and their biochemical activity towards aromatase evaluated. In each of these series, the C-17 carbonyl group was further replaced by the hydroxyl and acetoxyl groups. The attained data pointed out that the absence of the C-3 carbonyl group led to a slightly decrease in the inhibitory activity and the introduction of an additional double bond in C-1 revealed to be a very beneficial structural change in the studied compounds (compound 12, IC50 = 0.47 mu M, K-i = 45.00 nM). Furthermore, the relevance of the C-17 carbonyl group in the D-ring as a structural feature required to achieve maximum aromatase inhibitory activity is also observed for this set of derivatives. (C) 2013 Elsevier Inc. All rights reserved.