7-(β-alanyl)paclitaxel | 153985-01-4

• 英文名称: 7-(β-alanyl)paclitaxel
• 英文别名: 7-O-β-alanylpaclitaxel；7-β-alanyltaxol；(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-4-((3-Aminopropanoyl)oxy)-9-(((2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate；[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-9-(3-aminopropanoyloxy)-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl]oxy-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 153985-01-4
• 化学式: C₅₀H₅₆N₂O₁₅
• 分子量: 924.999
• InChiKey: XNTALIXZDWZTNU-MJZMOBIKSA-N

物化性质

• 沸点：
  986.1±65.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  67
• 可旋转键数：
  18
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  253
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  (S)-11-formy-4-乙基-4-羟基-1,12-二氢-4H-2-噁-6,12a-二氮杂-二苯并b,h芴-3,13-二酮 、 7-(β-alanyl)paclitaxel 在 4 A molecular sieve 作用下， 以 苯 为溶剂， 以85.4%的产率得到[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl]oxy-9-[3-[[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-10-yl]methylideneamino]propanoyloxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
  参考文献：
  名称：

  Antitumor agents 216. Synthesis and evaluation of paclitaxel–camptothecin conjugates as novel cytotoxic agents1

  摘要：

  Five conjugates (16-20) composed of a paclitaxel and a camptothecin derivative joined by an imine linkage were synthesized and evaluated as cytotoxic agents and as inhibitors of DNA topoisomerase I. All of the conjugates were potent inhibitors of tumor cell replication with improved activity relative to camptothecin. Significantly, compounds 16-18 were more active than paclitaxel and camptothecin against HCT-8 (colon adenocarcinoma) cell replication, and the spectrum of activity was different from a simple mixture of paclitaxel and camptothecin. All of the conjugates were significantly less potent than camptothecin as inhibitors of human topoisomerase I in vitro with 16, 18, and 19 showing only marginal activity at 50 M Based on activity against drug-resistant cell line replication, one could conclude that the conjugates are simply acting as 'weak taxanes', but the spectrum of activity, particularly against MCF-7 and HCT-8, strongly suggests that a novel mechanism of action has been achieved through conjugation. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00040-3
• 作为产物：
  描述：

  2′-O-（苄氧羰基）紫杉醇 在 palladium on activated charcoal 4-二甲氨基吡啶 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 生成 7-(β-alanyl)paclitaxel
  参考文献：
  名称：

  Antitumor agents. 256. Conjugation of paclitaxel with other antitumor agents: Evaluation of novel conjugates as cytotoxic agents

  摘要：

  Sixteen different taxoid conjugates were prepared by linking various anticancer compounds, including camptothecin (CPT), epipodophyllotoxin (EP), colchicine (COL), and glycyrrhetinic acid (GA), at the 2'- or 7-position on paclitaxel (TXL, 1) through an ester, imine, amine, or amide bond. Newly synthesized conjugates were evaluated for cytotoxic activity against replication of several human tumor cell lines. Among them, TXL-CPT conjugates, 8-10, were more potent than TXL itself against the human prostate carcinoma cell line PC-3 (ED50 = 14.8, 3.1, 19.4 nM compared with 55.5 nM), and conjugate 10 was also 8-fold more active than TXL against the LN-CAP prostate cancer cell line. These compounds also possessed anti-angiogenesis ability as well as lower inhibitory effects against a normal cell line (MRC-5). Thus, conjugates 8-10 are possible antitumor drug candidates, particularly for prostate cancer. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.02.051

文献信息

• COMPOSITIONS AND METHODS FOR DELIVERING A SUBSTANCE TO A BIOLOGICAL TARGET
  申请人：The General Hospital Corporation

  公开号：EP3622968A1

  公开（公告）日：2020-03-18

  The present application provides compositions and methods using bioorthogonal inverse electron demand Diels-Alder cycloaddition reaction for rapid and specific covalent delivery of a "payload" to a ligand bound to a biological target.

  本申请提供了一种使用生物正交反向电子需求Diels-Alder环加成反应的组合物和方法，用于快速和特异性地将“有效载荷”共价地传递给结合在生物靶点上的配体。
• Mechanism‐Based Fluorogenic <i>trans</i> ‐Cyclooctene–Tetrazine Cycloaddition
  作者：Arcadio Vázquez、Rastislav Dzijak、Martin Dračínský、Robert Rampmaier、Sebastian J. Siegl、Milan Vrabel

  DOI：10.1002/anie.201610491

  日期：2017.1.24

  presented chemistry leads to the rapid formation of unprecedented fluorescent 1,4‐dihydropyridazines so that the fluorophore is built directly upon the chemical reaction. Attachment of an extra fluorophore moiety is therefore not needed. The photochemical properties of the resulting dyes can be easily tuned by changing the substitution pattern of the starting 1,2,4,5‐tetrazine. We support the claim with

  开发由两种非荧光起始材料形成荧光产物的荧光反应是非常理想的，但也具有挑战性。本文报道了 1,2,4,5-四嗪与特定反式环辛烯 (TCO) 异构体发生逆电子需求狄尔斯-阿尔德反应形成荧光产物的新概念。与已知的荧光试剂形成鲜明对比的是，所提出的化学反应导致前所未有的荧光 1,4-二氢哒嗪的快速形成，从而荧光团直接建立在化学反应的基础上。因此不需要附加额外的荧光团部分。通过改变起始 1,2,4,5-四嗪的取代模式可以轻松调节所得染料的光化学性质。我们通过核磁共振测量来支持这一说法，并通过计算研究使数据合理化。进行细胞标记实验以证明荧光反应用于生物成像的潜力。
• Synthesis and Biological Evaluation of a Biotinylated Paclitaxel with an Extra-Long Chain Spacer Arm
  作者：Lev. G. Lis、Mary A. Smart、Anna Luchniak、Mohan L. Gupta、Vadim J. Gurvich

  DOI：10.1021/ml300149z

  日期：2012.9.13

  A biotinylated paclitaxel derivative with an extra-long chain (LC-LC-biotin) spacer arm was synthesized using an improved synthetic reaction sequence. The biotinylated paclitaxel analogue retained excellent microtubule stabilizing activity in vitro. Furthermore, it was shown that this analogue can simultaneously engage streptavidin and the binding site on microtubules, making it suitable for localization

  使用改进的合成反应序列合成了具有超长链（LC-LC-生物素）间隔臂的生物素化紫杉醇衍生物。生物素化的紫杉醇类似物在体外保留了极好的微管稳定活性。此外，该类似物可以同时结合链霉亲和素和微管上的结合位点，使其适用于定位研究或通过链霉亲和素键将紫杉醇连接到固体基质上。
• Rapid, Photoactivatable Turn-On Fluorescent Probes Based on an Intramolecular Photoclick Reaction
  作者：Zhipeng Yu、Lok Yin Ho、Qing Lin

  DOI：10.1021/ja204758c

  日期：2011.8.10

  Photoactivatable fluorescent probes are invaluable tools for the study of biological processes with high resolution in space and time. Numerous strategies have been developed in generating photoactivatable fluorescent probes, most of which rely on the photo-"uncaging" and photoisomerization reactions. To broaden photoactivation modalities, here we report a new strategy in which the fluorophore is generated in

  光活化荧光探针是研究具有高时空分辨率的生物过程的宝贵工具。在产生可光活化的荧光探针方面已经开发了许多策略，其中大部分依赖于光“解笼锁”和光异构化反应。为了拓宽光活化方式，我们在这里报告了一种新策略，其中通过分子内四唑-烯烃环加成反应（“光点击化学”）原位生成荧光团。通过将特定的微管结合紫杉醇核心与四唑/烯烃前荧光团结合，在乙腈/PBS（1 :1)。当处理过的细胞暴露于通过 300/395 滤光片或 405 nm 激光束的金属卤化物灯时，在共聚焦荧光显微镜下也观察到哺乳动物细胞内紫杉醇四唑的高效光活化。此外，用长波长可光活化紫杉醇-四唑探针证明了活 CHO 细胞中微管的空间控制荧光标记。由于其模块化设计和光活化效率和光物理特性的可调性，这种基于分子内光点击反应的方法应该为设计用于各种生物过程的光活化荧光探针提供一个通用平台。
• Bioorthogonal Turn-On Probes for Imaging Small Molecules inside Living Cells
  作者：Neal K. Devaraj、Scott Hilderbrand、Rabi Upadhyay、Ralph Mazitschek、Ralph Weissleder

  DOI：10.1002/anie.200906120

  日期：2010.4.6

  tetrazine‐conjugated fluorescent probes was developed, which react rapidly in an inverse‐electron‐demand [4+2] cycloaddition with strained dienophiles such as trans‐cyclooctene, thereby strongly increasing the fluorescence intensity (see picture). The novel turn‐on probes were applied for intracellular live‐cell imaging of a microtubuli‐binding trans‐cyclooctene modified taxol.

  发光标签：开发了一系列可激活（“开启”）四嗪共轭荧光探针，它们在逆电子需求 [4+2] 环加成反应中与紧张的双烯体如反式环辛烯快速反应，从而大大增加荧光强度（见图）。新型开启探针用于微管结合反式环辛烯修饰紫杉醇的细胞内活细胞成像。