[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-3-phenyl-2-[4-(pyridin-2-yldisulfanyl)butanoyloxy]propanoyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate | 1032313-96-4

• 英文名称: [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-3-phenyl-2-[4-(pyridin-2-yldisulfanyl)butanoyloxy]propanoyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
• CAS: 1032313-96-4
• 化学式: C₅₆H₆₀N₂O₁₅S₂
• 分子量: 1065.23
• InChiKey: LPWSIRYNJKSURG-PQXCICESSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  75
• 可旋转键数：
  22
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  291
• 氢给体数：
  3
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-3-phenyl-2-[4-(pyridin-2-yldisulfanyl)butanoyloxy]propanoyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate 、 C₉₃H₁₆₉N₁₉O₃₉S 以 二甲基亚砜 为溶剂， 反应 48.0h， 生成 spheropax
  参考文献：
  名称：

  Paclitaxel-Promoted Supramolecular Polymerization of Peptide Conjugates

  摘要：

  Spontaneous association above a threshold concentration is a hallmark of supramolecular polymerization, in which monomeric units self-assemble into polymeric aggregates through noncovalent interactions. This self-initiated supramolecular process differs from the conventional covalent chain-growth polymerization in that the latter often involves the use of a different chemical entity as an initiator to trigger/control the polymerization process. We report here the use of a small molecule hydrophobe, paclitaxel (PTX), as an effective promoter to induce the supramolecular polymerization of a peptide-paclitaxel conjugate, Spheropax (Spax). We found that Spax monomers alone in water self-assemble into spherical micelles of approximately 6.5 nm in diameter but, in the presence of free PTX, undergo a supramolecular polymerization process to form filamentous assemblies of several micrometers in length. Increasing the ratio of promoter to monomer (PTX/Spax) induces Spax's directional polymerization and expedites its kinetic process. We believe these findings provide important insight into the initiator-controlled supramolecular polymerization process.

  DOI：

  10.1021/jacs.9b04730
• 作为产物：
  描述：

  4-(吡啶-2-基二硫基)丁酸 、 紫杉醇 在 4-二甲氨基吡啶 、 N,N'-二异丙基碳二亚胺 作用下， 以 乙腈 为溶剂， 反应 48.0h， 以47%的产率得到[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-3-phenyl-2-[4-(pyridin-2-yldisulfanyl)butanoyloxy]propanoyl]oxy-1,9-dihydroxy-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：

  用于细胞敏感水凝胶降解和药物释放的不对称反向 Bolaamphiphiles 的超分子设计。

  摘要：

  基于肽的构建单元自组装成超分子纳米结构创造了一类重要的生物材料，具有强大的机械性能和更好的抗过早降解性。然而，在聚集时，由于大分子蛋白质与肽底物的接触有限，底物-酶相互作用通常会受到损害，从而导致对生物分子线索的反应性降低或丧失。这里报道的是不对称反向 bolaamphiphiles (RBA) 的超分子设计，能够在其丝状组件表面暴露基质金属蛋白酶 (MMP) 底物。添加 MMP-2 后，这些细丝在重新组装成球形胶束之前迅速分解成碎片。使用 3D 细胞培养，显示药物释放与细胞密度相称，当存在更多癌细胞时，揭示更有效的细胞杀伤。该设计平台可以作为局部化疗的细胞响应治疗库。

  DOI：

  10.1002/anie.201913087

文献信息

• NOVEL SELF-ASSEMBLING DRUG AMPHIPHILES AND METHODS FOR SYNTHESIS AND USE
  申请人：The Johns Hopkins University

  公开号：US20140113875A1

  公开（公告）日：2014-04-24

  The present invention provides herein the design of monodisperse, amphiphilic anticancer drugs—which are now termed “drug amphiphiles” (DAs)—that can spontaneously associate into discrete, stable supramolecular nanostructures with the potential for self-delivery (no additional carriers are needed). The quantitative drug loading in the resulting nanostructures is ensured by the very nature of the molecular design. The DA is a composition comprising: D-L-PEP; wherein D is 1 to 4 hydrophobic drug molecules which can be the same or different; L is 1 to 4 biodegradable linkers which can be the same or different; and PEP is a peptide that can spontaneously associate into discrete, stable supramolecular nanostructures. In an alternate embodiment, the DA composition also comprises a targeting ligand (T). Methods of making DA molecules, as well as their use in treatment of disease are also provided.

  本发明在此提供了单分散、两性抗癌药物的设计，现在被称为“药物两性分子”（DAs），它们可以自发地聚集成离散、稳定的超分子纳米结构，具有自我传递的潜力（无需额外的载体）。由于分子设计的本质，所得纳米结构中的药物负载是定量的。DA是一种包括：D-L-PEP的组合物；其中D是1到4个疏水性药物分子，可以相同也可以不同；L是1到4个可降解的连接剂，可以相同也可以不同；PEP是一种可以自发地聚集成离散、稳定的超分子纳米结构的肽。在另一实施例中，DA组合物还包括一个靶向配体（T）。还提供了制备DA分子的方法，以及它们在治疗疾病中的用途。
• COMPOSITIONS AND METHODS FOR TRANSPORT OF MOLECULES WITH ENHANCED RELEASE PROPERTIES ACROSS BIOLOGICAL BARRIERS
  申请人：Wender Paul A

  公开号：US20100255499A1

  公开（公告）日：2010-10-07

  Conjugates of a cargo molecule with a transporter molecule are disclosed, where the cargo molecule and the transporter molecule are linked covalently by a releasable linker. The cargo of the conjugate can be a biologically active agent or a reporter molecule. The transporter modulates the transport of the cargo across a biological barrier (e.g., a cell membrane) compared to the transport of the unconjugated cargo. Releasable linkers suitable for rapid and facile conjugation to various types of cargo and transporters are also disclosed, along with methods for using the linkers in the synthesis of conjugates.

  本发明公开了一种货物分子与运输蛋白分子的共轭体，其中货物分子和运输蛋白分子通过可释放的连接剂共价连接。共轭体的货物可以是生物活性剂或报告分子。与未共轭货物的运输相比，运输蛋白调节货物通过生物屏障（例如细胞膜）的运输。还公开了适用于快速和容易地与各种类型的货物和运输蛋白共轭的可释放连接剂，以及使用连接剂合成共轭体的方法。
• WO2008/69824
  申请人：——

  公开号：——

  公开（公告）日：——
• Conjungation of Small Molecules to Octaarginine Transporters for Overcoming Multi-Drug Resistance
  申请人：Wender Paul

  公开号：US20110160146A1

  公开（公告）日：2011-06-30

  Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp) mediated drug efflux. Here we provide compositions and methods that restore the efficacy of a therapeutic agent reduced by resistance by conjugation of the same agent to an oligoarginine transporter comprising from about 5 to about 25 guanidino or amidino moieties. We specifically show that the widely used chemotherapeutic agent taxol, ineffective against taxol-resistant human ovarian cancer cell lines, can be incorporated into an octaarginine conjugate that is effective against the same taxol-resistant cell lines. Significantly, the ability of the taxol conjugates to overcome taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with other Pgp substrate. This approach shows generality for overcoming the multidrug resistance elicited by small molecule cancer chemotherapeutics and could improve the prognosis for many cancer patients and fundamentally alter search strategies for novel therapeutic agents effective against resistant disease.
• [EN] CONJUGATION OF SMALL MOLECULES TO OCTAARGININE TRANSPORTERS FOR OVERCOMING MULTI-DRUG RESISTANCE<br/>[FR] CONJUGAISON DE PETITES MOLÉCULES À DES TRANSPORTEURS DE L'OCTA-ARGININE POUR SURMONTER LA RÉSISTANCE À DE MULTIPLES MÉDICAMENTS ET AMÉLIORER L'EFFICACITÉ ET LA SOLUBILITÉ
  申请人：UNIV LELAND STANFORD JUNIOR

  公开号：WO2009099636A1

  公开（公告）日：2009-08-13

  Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp) mediated drug efflux. Here we provide compositions and methods that restore the efficacy of a therapeutic agent reduced by resistance by conjugation of the same agent to an oligoarginine transporter comprising from about 5 to about 25 guanidino or amidino moieties. We specifically show that the widely used chemotherapeutic agent taxol, ineffective against taxol-resistant human ovarian cancer cell lines, can be incorporated into an octaarginine conjugate that is effective against the same taxol-resistant cell lines. Significantly, the ability of the taxol conjugates to overcome taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with other Pgp substrate. This approach shows generality for overcoming the multidrug resistance elicited by small molecule cancer chemotherapeutics and could improve the prognosis for many cancer patients and fundamentally alter search strategies for novel therapeutic agents effective against resistant disease.