7-Ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone | 128517-07-7

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: 7-Ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
• CAS: 128517-07-7
• 化学式: C₂₄H₃₆N₄O₆S₂
• 分子量: 540.7
• InChiKey: OHRURASPPZQGQM-UHFFFAOYSA-N

物化性质

• 熔点：
  219-224°C
• 沸点：
  942.8±65.0 °C(Predicted)
• 密度：
  1.174
• 溶解度：
  溶于DMSO（高达10mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  36
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

毒理性

• 肝毒性

在 romidepsin 治疗皮肤 T 细胞淋巴瘤 (CTLC) 和外周 T 细胞淋巴瘤 (PTLC) 的临床试验中，治疗期间血清酶水平升高的发生率在 7% 到 20% 之间，但这些异常通常是短暂的、轻微的，并不需要调整剂量。血清丙氨酸转氨酶（ALT）升高超过 5 倍正常上限（ULN）的患者占 6%。在 romidepsin 的上市前临床试验中，没有报告肝炎、黄疸或临床上明显的肝脏损伤的案例。Romidepsin 在临床上使用有限，但没有证据表明它与显著的肝脏损伤有关。 Romidepsin 还具有免疫调节活性，据报道可以引起潜伏 DNA 病毒的再激活，包括Epstein-Barr病毒、水痘带状疱疹病毒和乙型肝炎病毒。在一例最初 HBsAg 阴性但抗 HBc 和抗 HBs 阳性的患者中发生了乙型肝炎的再激活。尽管如此，乙型肝炎再激活的临床特征是轻微的，并对口服抗病毒治疗有反应。在 EBV 相关淋巴瘤患者中，romidepsin 与 EBV 感染的严重再激活和急性肝炎有关，这些肝炎可能非常严重，甚至致命。 可能性评分：C（可能是临床上明显肝脏损伤的原因，可能是由乙型肝炎或 EBV 感染再激活引起的）。

In clinical trials of romidepsin in patients with CTLC and PTLC, the rates of serum enzyme elevations during therapy ranged from 7% to 20%, but the abnormalities were usually transient and mild and did not require dose modifications. Serum ALT elevations above 5 times ULN occurred in 6% of patients. In the preregistration clinical trials of romidepsin, there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Romidepsin has had limited clinical use, but there is no evidence that it is associated with significant liver injury. Romidepsin also has immunomodulatory activities and has been reported to cause reactivation of latent DNA viruses including Epstein-Barr, varicella zoster and hepatitis B virus. Reactivation of hepatitis B occurred in a patient who was initially negative for HBsAg, but reactive for anti-HBc and anti-HBs. Nevertheless, the clinical features of hepatitis B reactivation were mild and responded to oral antiviral therapy. In patients with EBV associated lymphoma, romidepsin has been associated with severe reactivation of EBV infection and acute hepatitis that can be severe and even fatal. Likelihood score: C (probable cause of clinically apparent liver injury, which can be due to reactivation of hepatitis B or EBV infection).

来源:LiverTox

安全信息

• 海关编码：
  29349990
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  Amber vial, stored at -20°C in a freezer under an inert atmosphere.

制备方法与用途

罗米地辛简介

罗米地辛是从革兰氏阴性细菌中分离出的一种组蛋白去乙酰化酶抑制剂（HDACi），也被称为968号青紫色杆菌。目前，罗米地辛在临床领域主要用于治疗外周T细胞淋巴瘤，并且是应用最成功和使用最广泛的药物之一。然而，在包括肝细胞癌（HCC）在内的实体肿瘤中的应用仍在研究阶段。

生物活性

罗米地辛 (FK228, Depsipeptide, FR 901228, NSC 630176) 是一种有效的HDAC1和HDAC2抑制剂，其无细胞试验中IC50分别为36 nM和47 nM。在神经母细胞瘤肿瘤细胞中，罗米地辛可以控制生长并诱导凋亡。

靶点

• HDAC1 (Cell-free assay): 36 nM
• HDAC2 (Cell-free assay): 47 nM

体外研究

罗米地辛能够抑制非小细胞肺癌（NSCLC）细胞系的生长，IC50范围从1.3 ng/mL到4.9 ng/mL。此外，罗米地辛还能降低厄洛替尼对NSCLC细胞系的抑制浓度，从而增加其对厄洛替尼的敏感性。处理72小时后，罗米地辛可以显著抑制6/6 人神经母细胞瘤（NB）肿瘤细胞系的生长，而 NIH3T3细胞系则未受影响。

罗米地辛表现出选择性的细胞毒性作用，不仅针对单拷贝或N-myc多拷贝的NB细胞系，还对含有正常或突变p53以及携带ALK突变体的细胞系具有剂量依赖性的影响。

体内研究

与PBS对照组相比，单独使用厄洛替尼和罗米地辛分别可以抑制NCI-H1299细胞系异种移植生长72%和43%，但无显著统计学意义。只有当两种药物联用时，才能对肿瘤生长产生明显抑制作用，此时生长被抑制到约28%。在免疫功能低下的小鼠中，罗米地辛能够剂量依赖性地抑制皮下NB异种移植的生长。此外，在NB病人的肿瘤组织中，罗米地辛可诱导某些基因的表达，如p21、p75和NTRK (TrkA)。

反应信息

• 作为产物：
  描述：

  以81的产率得到7-Ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
  参考文献：
  名称：

  Org. Lett. 2008, 10, 613-616

  摘要：

  DOI：

文献信息

• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION DE (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ÉTHYLIDÈNE-4,21-BIS(1-MÉTHYLÉTHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TÉTRAAZABICYCLO[8.7.6]TRICOS-16-ÈNE-3, 6, 9, 19, 22-PENTONE
  申请人：MSN LABORATORIES PRIVATE LTD

  公开号：WO2017068596A1

  公开（公告）日：2017-04-27

  The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.

  本发明涉及一种改进的制备过程，用于制备式I的(1S,4S,7Z,10S,16E,21R)-7-乙烯基-4,21-双(1-甲基乙基)-2-氧-12,13-二硫-5,8,20,23-四氮杂环[8.7.6]三十一烯-16-烯-3,6,9,19,22-五酮。
• FR901228 substance and preparation thereof
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US04977138A1

  公开（公告）日：1990-12-11

  The invention relates to a compound having antimicrobial and antitumor activity, the compound being designated FR901228 substance of the following formula: ##STR1##

  该发明涉及一种具有抗微生物和抗肿瘤活性的化合物，该化合物被指定为FR901228物质，其化学式如下：##STR1##
• J. Am. Chem. Soc. 1996, 118, 7237-7238
  作者：

  DOI：——

  日期：——
• Methods of Managing Vascular Conditions and Diabetic Peripheral Neuropathies
  申请人：Emory University

  公开号：US20220168300A1

  公开（公告）日：2022-06-02

  This disclosure relates to managing diabetic neuropathy using compounds disclosed herein. In certain embodiments, this disclosure relates to methods of treating or preventing vascular conditions such as diabetic neuropathy comprising administering a compound capable of epigenetic modification, such as histone deacetylase inhibitors, to a subject in need thereof. In certain embodiments, this disclosure relates to the use of HDAC inhibitors to treat directly diabetic neuropathies and pain without the use of progenitor cells or stem cells. In certain embodiments, the subject is at risk of, exhibiting symptoms of, or diagnoses with diabetes, diabetic neuropathy, peripheral neuropathy, autonomic neuropathy, radiculoplexus neuropathy, mononeuropathy, diabetic retinopathy, or complications related thereto. In certain embodiments, the compound is selected from belinostat, quisinostat, and vorinostat.
• [EN] METHODS OF MANAGING VASCULAR CONDITIONS AND DIABETIC PERIPHERAL NEUROPATHIES<br/>[FR] MÉTHODES DE PRISE EN CHARGE D'AFFECTIONS VASCULAIRES ET DE NEUROPATHIES PÉRIPHÉRIQUES DIABÉTIQUES
  申请人：UNIV EMORY

  公开号：WO2020167886A1

  公开（公告）日：2020-08-20

  This disclosure relates to managing diabetic neuropathy using compounds disclosed herein. In certain embodiments, this disclosure relates to methods of treating or preventing vascular conditions such as diabetic neuropathy comprising administering a compound capable of epigenetic modification, such as histone deacetylase inhibitors, to a subject in need thereof. In certain embodiments, this disclosure relates to the use of HDAC inhibitors to treat directly diabetic neuropathies and pain without the use of progenitor cells or stem cells. In certain embodiments, the subject is at risk of, exhibiting symptoms of, or diagnoses with diabetes, diabetic neuropathy, peripheral neuropathy, autonomic neuropathy, radiculoplexus neuropathy, mononeuropathy, diabetic retinopathy, or complications related thereto. In certain embodiments, the compound is selected from belinostat, quisinostat, and vorinostat.