rapamycin 42-hemisuccinate | 155589-16-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: rapamycin 42-hemisuccinate
• 英文别名: 4-[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl]oxy-4-oxobutanoic acid
• CAS: 155589-16-5
• 化学式: C₅₅H₈₃NO₁₆
• 分子量: 1014.26
• InChiKey: JDBCXZQONKYZOY-VZNZNQFQSA-N

物化性质

• 沸点：
  1044.1±75.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  72
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  239
• 氢给体数：
  3
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 rapamycin 42-hemisuccinate 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 反应 2.0h， 生成 1-O-[(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl] 4-O-(2,5-dioxopyrrolidin-1-yl) butanedioate
  参考文献：
  名称：

  通过免疫调节生物共轭主动减少抗药物抗体。

  摘要：

  尽管聚乙二醇化在某种程度上降低了蛋白质药物的免疫原性，但已证明其对高免疫原性生物疗法的局限性。本文报道了一种通过免疫调节生物缀合来减轻针对蛋白药物的抗药物抗体（ADAs）开发的积极策略。雷帕霉素通过可裂解的二硫键与PEG化的蛋白质治疗剂结合。结合的雷帕霉素可从生物结合物中释放出来，并在抗原呈递细胞摄取生物结合物后阻止免疫反应。与聚乙二醇化的蛋白质相比，免疫调节生物结合物显着降低了ADAs的效价。免疫应答的抑制对结合抗原具有特异性，避免了全身性免疫抑制和增加了对感染的易感性的风险。

  DOI：

  10.1002/anie.201814275
• 作为产物：
  描述：

  雷帕霉素 在 吡啶 、 sodium phosphate buffer 、 水 、 lipase 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 22.0h， 生成 rapamycin 42-hemisuccinate
  参考文献：
  名称：

  脂肪酶介导的雷帕霉素42-半琥珀酸苄酯和甲酯的水解

  摘要：

  使用假单胞菌属的脂肪酶，在非常温和的条件下将雷帕霉素42-半琥珀酸酯的苄基和甲基酯水解为雷帕霉素半琥珀酸酯。两种酯均以≥100mg的规模进行选择性脱保护，从而从所需酸的甲酯中分离出50％的收率，从苄基酯中分离出29％的收率。

  DOI：

  10.1016/s0040-4039(00)79954-0

文献信息

• Lipase-Catalyzed Regioselective Esterification of Rapamycin:  Synthesis of Temsirolimus (CCI-779)
  作者：Jianxin Gu、Mark E. Ruppen、Ping Cai

  DOI：10.1021/ol0514395

  日期：2005.9.1

  A lipase-catalyzed acylation of the immunosuppressant rapamycin with complete regioselectivity is described. The method was successfully applied to the synthesis of 42-hemiesters and temsirolimus (CCI-779), an investigational oncology drug.[reaction: see text]

  描述了具有完全区域选择性的免疫抑制剂雷帕霉素的脂肪酶催化的酰化作用。该方法已成功应用于肿瘤研究药物42半胱氨酸和西罗莫司（CCI-779）的合成。
• WORTMANNIN-RAPAMYCIN CONJUGATE AND USES THEREOF
  申请人：GU JIANXIN

  公开号：US20080249123A1

  公开（公告）日：2008-10-09

  A rapamycin—wortmannin conjugate is described, in which the conjugate is formed by linking the rapamycin and wortmannin together in such a manner that the rapamycin and the wortmannin are separated following administration to a subject. Use of such a conjugate in an antineoplastic regimen is described.

  描述了一种雷帕霉素-沃特曼宾共轭物，其中共轭物通过将雷帕霉素和沃特曼宾连接在一起形成，以便在给予受试者后分离雷帕霉素和沃特曼宾。描述了在抗肿瘤方案中使用这种共轭物的方法。
• Dendrimer-Mediated Targeted Delivery of Rapamycin to Tumor-Associated Macrophages Improves Systemic Treatment of Glioblastoma
  作者：Anjali Sharma、Kevin Liaw、Rishi Sharma、Talis Spriggs、Santiago Appiani La Rosa、Sujatha Kannan、Rangaramanujam M. Kannan

  DOI：10.1021/acs.biomac.0c01270

  日期：2020.12.14

  Glioblastoma exhibits high mortality rates due to challenges with drug delivery to the brain and into solid tumors. This two-pronged barrier necessitates high doses of systemic therapies, resulting in significant off-target toxicities. Recently, dendrimer-nanomedicines (without ligands) have shown promise for targeting specific cells in brain tumors from systemic circulation, for improved efficacy and amelioration of systemic toxicities. A dendrimer–rapamycin conjugate (D-Rapa) is presented here that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration. D-Rapa improves suppression of pro-tumor expression in activated TAMs and antiproliferative properties of rapamycin in glioma cells in vitro. In vivo, D-Rapa localizes specifically within TAMs, acting as depots to release rapamycin into the tumor microenvironment. This targeted delivery strategy yields improved reduction in tumor burden and systemic toxicities in a challenging, clinically relevant orthotopic syngeneic model of glioblastoma, demonstrating the significant potential of dendrimers as targeted immunotherapies for improving glioblastoma treatment, still an unmet need.

  胶质母细胞瘤由于药物难以输送至大脑和实体瘤内部而具有高死亡率。这种双重屏障需要高剂量的全身治疗药物，导致显著的非靶点毒性。近期，树枝状纳米药物（无配体）展现出从全身循环中靶向特定脑瘤细胞的潜力，以提高疗效并减轻全身毒性。本文介绍了一种树枝状-雷帕霉素偶合物（D-Rapa），它能从全身给药途径特异性地靶向胶质母细胞瘤中的肿瘤相关巨噬细胞（TAMs）。D-Rapa 能增强激活的 TAMs 中的抗肿瘤表达抑制作用，并在体外增强雷帕霉素的抗增殖特性。在体内，D-Rapa 特异性地定位于 TAMs 内，作为储库向肿瘤微环境释放雷帕霉素。这种靶向输送策略在一种具有临床相关性的正位同基因胶质母细胞瘤模型中，显著降低了肿瘤负担和全身毒性，展示了树枝状分子作为靶向免疫疗法改善胶质母细胞瘤治疗的巨大潜力。胶质母细胞瘤的治疗仍是一个未被满足的需求。
• [EN] PROCESS FOR PREPARING RAPAMYCIN 42-ESTERS AND FK-506 32-ESTERS WITH DICARBOXYLIC ACID, PRECURSORS FOR RAPAMYCIN CONJUGATES AND ANTIBODIES<br/>[FR] PROCEDE D'ELABORATION DE 42-ESTERS DE RAPAMYCINE ET DE 32-ESTERS DE FK-506 AVEC DE L'ACIDE DICARBOXYLIQUE, PRECURSEURS POUR CONJUGUES DE RAPAMYCINE ET ANTICORPS VIS-A-VIS DE LA RAPAMYCINE
  申请人：WYETH CORP

  公开号：WO2005105812A1

  公开（公告）日：2005-11-10

  Methods for the synthesis of regiospecific rapamycin 42-hemiesters and regiospecific FK506 32-esters with dicarboxylic acids is described. The methods involve catalyzing the reaction between a rapamycin or a FK-506 and a dicarboxylic anhydride or a bifunctional activated ester of dicarboxylic acid with a lipase.

  本文描述了合成具有区域特异性的42-半酯化雷帕霉素和32-酯化FK506的方法，该方法涉及使用脂肪酶催化雷帕霉素或FK-506与二羧酸酐或双官能团活性二羧酸酯之间的反应。
• Enhanced Cytotoxicity to Cancer Cells by Codelivery and Controlled Release of Paclitaxel-loaded Sirolimus-conjugated Albumin Nanoparticles
  作者：Hossein Behrouz、Mehdi Esfandyari-Manesh、Mohammad Kazem Khoeeniha、Mohsen Amini、Behrang Shiri Varnamkhasti、Fatemeh Atyabi、Rassoul Dinarvand

  DOI：10.1111/cbdd.12750

  日期：2016.8

  Recently, it is suggested that mTOR signaling pathway is an important mediator in many cancers especially breast cancer. Therefore, effects of sirolimus as a mTOR inhibitor in breast cancer have been studied in combination with paclitaxel with or without controlled release effect. In this work, we prepared a water‐soluble formulation of sirolimus‐conjugated albumin nanoparticles loaded with paclitaxel, to study the effects of sirolimus concentration when it releases more later than paclitaxel in comparison with sirolimus–paclitaxel‐loaded albumin nanoparticles. Also effects of paclitaxel loading on cytotoxic properties of nanoparticles were studied. Sirolimus was succinylated at 42‐OH with enzymatic reaction of Candida antarctica lipase B, and then its carboxylic group was activated with EDC/NHS and conjugated to the lysine residues of albumin. Paclitaxel was loaded on albumin surface by nab technique in concentration range of 0–10 μg/mL. Sirolimus‐conjugated nanoparticles with 0.01 μg/mL paclitaxel showed lowest cell viability of 44% while it was 53% for non‐conjugated nanoparticles in MDA‐MB‐468 cell lines after 48 h (p‐value = 0.003). In MCF‐7 cell lines, sirolimus‐conjugated nanoparticles with 0.1 μg/mL paclitaxel showed lowest cell viability of 35.69% while it was 48% for non‐conjugated nanoparticles after 48 h (p‐value = 0.03). We guess that when cancer cell lines arrest in G2‐M by anticancer drugs like paclitaxel, Akt activates mTOR to make cells continue living, then inhibiting mTOR can enhance anticancer effects.