阿霉酮 | 24385-10-2

• 物质功能分类: 有机原料 - 酮类化合物
• 分子结构分类: 有机化合物 - 苯类化合物 - 并四苯
• 中文名称: 阿霉酮
• 中文别名: 7,8,9,10-四氢-6,8,10,11-四羟基-8-(羟基乙酰)-1-甲氧基-(8S-CIS)-5,12-并四苯二酮
• 英文名称: adriamycinone
• 英文别名: doxorubicinone；Adriamycinon；doxorubicin aglycone；Adriamycin aglycone；Adriamycin-aglycon；(7S,9S)-6,7,9,11-tetrahydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 24385-10-2
• 化学式: C₂₁H₁₈O₉
• 分子量: 414.369
• InChiKey: IBZGBXXTIGCACK-CWKPULSASA-N

物化性质

• 熔点：
  223-225°C
• 沸点：
  741.2±60.0 °C(Predicted)
• 密度：
  1.671±0.06 g/cm3(Predicted)
• 溶解度：
  二恶烷（轻微）、DMSO（轻微）、甲醇（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  162
• 氢给体数：
  5
• 氢受体数：
  9

安全信息

• WGK Germany：
  3
• 储存条件：
  Amber Vial 存放于-20°C冷冻柜中。

制备方法与用途

用途：阿霉素的中间体。

反应信息

• 作为反应物：
  描述：

  阿霉酮 在 咪唑 、 三苯基膦氯金 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 双三氟甲烷磺酰亚胺银盐 作用下， 以 aq. phosphate buffer 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.75h， 生成 7-[2,3-dideoxy-4-ulo-α-L-fucopyranosyl-2-deoxy-3-p-methoxybenzyl-α-L-fucopyranosyl-(1→4)-3-amino-2,3-dideoxy-α-L-fucopyranoside]-14-O-tert-butyldimethylsilyl-doxorubicinone
  参考文献：
  名称：

  Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

  摘要：

  Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure-function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase II alpha in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing N,N-dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.

  DOI：

  10.1021/acs.jmedchem.0c01191
• 作为产物：
  描述：

  阿霉素 生成 阿霉酮
  参考文献：
  名称：

  Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

  摘要：

  抗肿瘤蒽环类阿霉素会引起剂量相关的心脏毒性，该毒性与其二级醇代谢物阿霉素的心肌水平相关。阿霉素与紫杉醇或多西紫杉醇等紫杉烷类药物联合使用可能会加重心脏毒性，可能是因为紫杉烷类药物会引起细胞质醛还原酶的变构样刺激，从而在心脏中将阿霉素转化为阿霉素。将紫杉烷类药物与表柔比星（阿霉素的一种密切相关的类似物）联合使用时，观察到心脏毒性的加重程度较轻。因此，我们表征了表阿霉素-紫杉烷疗法的心脏耐受性是否可能是由于紫杉烷刺激表阿霉素转化为其二级醇代谢物表阿霉素的缺陷所致。在分离的人心脏细胞质中对阿霉素和表阿霉素进行比较表明，表阿霉素与醛还原酶反应时表现出较低的 V max/K m 值，并且紫杉醇或多西他赛对表阿霉素形成的刺激有缺陷。在血浆中与蒽环类药物和紫杉醇或多西紫杉醇一起孵育的人心肌条的可溶部分也出现了类似的模式，这些心肌条是在其临床载体 Cremophor EL 或多西他赛 80 中配制的。多柔比星（但不是表柔比星）也能够在膜中产生活性氧。心肌条的分数；然而，紫杉醇并没有进一步提高阿霉素衍生的活性氧的水平。这些结果支持紫杉烷类可能通过特异性刺激阿霉素形成而加重阿霉素的心脏毒性的观点。因此，紫杉醇或多西紫杉醇不能刺激表柔比星醇形成，揭示了表柔比星-紫杉烷组合改善心脏耐受性的重要决定因素。

  DOI：

  10.1124/jpet.106.116160

文献信息

• Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug
  作者：Sebastian Imstepf、Vanessa Pierroz、Paula Raposinho、Matthias Bauwens、Michael Felber、Thomas Fox、Adam B. Shapiro、Robert Freudenberg、Célia Fernandes、Sofia Gama、Gilles Gasser、Felix Motthagy、Isabel R. Santos、Roger Alberto

  DOI：10.1021/acs.bioconjchem.5b00466

  日期：2015.12.16

  We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and 99mTc, an Auger and internal conversion electron emitter, into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to 99mTc afforded a construct which autonomously ferries a radioactive payload into the cell nucleus. At this site, damage is exerted by dose deposition from Auger radiation. The 99mTc-conjugate exhibited a dose-dependent inhibition of survival in a selected panel of cancer cells and an in vivo study in healthy mice evidenced a biodistribution which is comparable to that of the parent drug. The homologous Rhenium conjugate was found to effectively bind to DNA, inhibited human Topoisomerase II, and exhibited cytotoxicity in vitro. The collective in vitro and in vivo data demonstrate that the presented metallo-conjugates closely mimic native Doxorubicin.

  我们展示了临床上经过充分验证的化疗药物多柔比星（Doxorubicin）与99mTc（一种奥杰电子和内部转化电子发射体）的结合，形成一种双重作用的治疗剂。将多柔比星化学连接到99mTc上，构建了一个能够自主将放射性载荷运输到细胞核的结构。在此位置，通过奥杰辐射的剂量沉积造成了损伤。99mTc结合物在选定的癌细胞系中表现出剂量依赖性的存活抑制，而在健康小鼠中的体内研究则证明了其生物分布与母药相当。相应的铼结合物被发现能够有效结合DNA，抑制人类拓扑异构酶II，并在体外表现出细胞毒性。综合的体外和体内数据表明，所呈现的金属结合物与天然多柔比星的特性非常接近。
• Synthesis of adriamycin and 7,9-epiadriamycin
  申请人：Stanford Research Institute

  公开号：US04012448A1

  公开（公告）日：1977-03-15

  A process for the synthesis of adriamycin and 7,9-epiadriamycin, both active antineoplastic agents, in which 7-deoxydaunomycinone, in either the 9s or racemic (.+-.) form, is employed as the starting material, the process in one embodiment also being productive of the useful intermediate compound 4-methoxy-6,11-dihydroxy-7,8-dihydro-5,9(10H),12-naphthacenetrione. The process involves converting 7-deoxydaunomicinone successively to daunomycinone, adriamycinone, 14-0-p-anisyldiphenylmethyladriamycinone and finally to adriamycin or to both adriamycin and 7,9-epiadriamycin. When producing the latter mixture of diastereomers, the 7-deoxydaunomycinone starting material is first converted to racemate form by a process involving the successive production of 7-deoxydaunorubicinol, 4-methoxy-6,11-dihydroxy-7,8-dihydro-5,9(10H), 12-naphthacenetrione, (.+-.)-4-methoxy-9-cyano-6,9,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphth acenedione, (.+-.)-4-methoxy-9-cyano-9-(2'-tetrahydropyranyloxy)-6,11-dihydroxy-7,8,9, 10-tetrahydro-5,12-naphthacenedione and (.+-.)-7-deoxydaunomycinone.

  一种合成阿霉素和7,9-表阿霉素的过程，两者均为有效的抗肿瘤药剂，其中7-去氧葡萄霉素酮，以9s或racemic (.+-.)形式作为起始物质，该过程在一个实施例中还产生有用的中间化合物4-甲氧基-6,11-二羟基-7,8-二氢-5,9(10H),12-萘酞醌。该过程涉及将7-去氧葡萄霉素酮依次转化为葡萄霉素酮、阿霉素酮、14-0-p-苯甲氧基二苯甲基阿霉素酮，最终转化为阿霉素或阿霉素和7,9-表阿霉素。在生产后一混合二对映异构体时，首先将7-去氧葡萄霉素酮起始物质通过一个过程转化为外消旋体形式，其中包括依次生成7-去氧达诺鲁比信醇、4-甲氧基-6,11-二羟基-7,8-二氢-5,9(10H),12-萘酞醌、(.+-.)-4-甲氧基-9-氰基-6,9,11-三羟基-7,8,9,10-四氢-5,12-萘酞二酮、(.+-.)-4-甲氧基-9-氰基-9-(2'-四氢吡喃氧基)-6,11-二羟基-7,8,9, 10-四氢-5,12-萘酞二酮和(.+-.)-7-去氧葡萄霉素酮。
• PRODRUGS ACTIVATED BY CASPASE
  申请人：Kim Sang-Yoon

  公开号：US20160144050A1

  公开（公告）日：2016-05-26

  Described are prodrug conjugates that release a chemotherapeutic agent upon activation by caspase, and methods using such prodrug conjugates to induce apoptosis, amplify apoptosis, and treat cancer.

  介绍了一种通过caspase激活释放化疗药物的前药偶联物，以及使用这种前药偶联物诱导细胞凋亡、增强细胞凋亡和治疗癌症的方法。
• Stable lyophilized anthracycline glycosides
  申请人：Arosio Roberto

  公开号：US20070004653A1

  公开（公告）日：2007-01-04

  The present invention provides lyophilized and stable lyophilized anthracycline glycoside salts, in particular, the hydrochloride salt. Also, the present invention provides methods of stabilizing these anthracycline glycoside salts, and methods for producing stable lyophilized anthracycline glycoside salts, such as for example the antineoplastic compound idarubicin hydrochloride, or the compounds doxorubicin hydrochloride, and epirubicin hydrochloride.

  本发明提供了冻干和稳定的冻干蒽环类糖苷盐，特别是盐酸盐。此外，本发明提供了稳定这些蒽环类糖苷盐的方法，以及生产稳定的冻干蒽环类糖苷盐的方法，例如抗肿瘤化合物依达霉素盐酸盐，或化合物多柔比星盐酸盐和艾匹霉素盐酸盐。
• ALOE-EMODIN DERIVATIVES AND USE THEREOF FOR THE TREATMENT OF CANCER
  申请人：Fridman Micha

  公开号：US20130045933A1

  公开（公告）日：2013-02-21

  The present invention relates to anthracycline derivatives that are based on an Aloe-emodin (AE) backbone attached to a glycoside (an amino sugar or amino carba-sugar). These derivatives are useful as chemotherapeutic agents. Advantageously, these derivatives are potent cytotoxic agents against a variety of anthracycline-resistant tumors. In addition, they may have reduced cardiotoxicity. As such, the novel compounds of the invention offer an advantage over currently available drugs. The present invention further relates to methods for preparing the novel Aloe-Emodin Glycoside (AEG) based derivatives, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as chemotherapeutic agents for prevention and treatment of cancers.

  本发明涉及基于芦荟大黄素（AE）骨架与糖苷（氨基糖或氨基卡巴糖）相连的蒽环类衍生物，这些衍生物可用作化疗药物。这些衍生物对多种蒽环类耐药肿瘤具有强效的细胞毒性作用。此外，它们可能具有较低的心脏毒性。因此，本发明的新化合物比目前可用的药物具有优势。本发明还涉及制备新的芦荟大黄素糖苷（AEG）衍生物的方法，包括这些化合物的制药组合物，以及使用这些化合物和组合物的方法，特别是作为预防和治疗癌症的化疗药物。