| 1245657-05-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• CAS: 1245657-05-9
• 化学式: C₇₃H₁₂₄N₁₂O₁₄
• 分子量: 1393.86
• InChiKey: LWINRYPKSYVPOF-VCIIBOSASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.43
• 重原子数：
  99.0
• 可旋转键数：
  18.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  317.13
• 氢给体数：
  6.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Facile Synthesis of a Fluorescent Cyclosporin A Analogue To Study Cyclophilin 40 and Cyclophilin 18 Ligands

  摘要：

  There are strong indications for the involvement of cyclophilin 40 in diseases caused by misregulation of steroid hormone receptors, like prostate or breast cancer To identify novel inhibitors for this immunophilin, we developed a simplified fluorescence polarization assay based on the synthesis Of a fluorescein labeled tracer. This tracer was produced by a facile four-step synthesis involving Grubbs metathesis and standard amide bond coupling, to label cyclosporin A with fluorescein. We show the binding of this tracer to Cyp40 and Cyp18 with K-D values of 106 +/- 13 or 12 +/- 1 nM, respectively, by analyzing the anisotropy change and demonstrate its competition with cyclosporin A. Binding data obtained by fluorescence polarization were corroborated by an enzymatic activity assay. The described tracer allows for a robust assay in a high-throughput format to support the development of novel Cyp40 ligands.

  DOI：

  10.1021/ml1001272
• 作为产物：
  描述：

  p-vinyl-N-t-butoxycarbonylbenzylamine 、 cyclosporin A 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Facile Synthesis of a Fluorescent Cyclosporin A Analogue To Study Cyclophilin 40 and Cyclophilin 18 Ligands

  摘要：

  There are strong indications for the involvement of cyclophilin 40 in diseases caused by misregulation of steroid hormone receptors, like prostate or breast cancer To identify novel inhibitors for this immunophilin, we developed a simplified fluorescence polarization assay based on the synthesis Of a fluorescein labeled tracer. This tracer was produced by a facile four-step synthesis involving Grubbs metathesis and standard amide bond coupling, to label cyclosporin A with fluorescein. We show the binding of this tracer to Cyp40 and Cyp18 with K-D values of 106 +/- 13 or 12 +/- 1 nM, respectively, by analyzing the anisotropy change and demonstrate its competition with cyclosporin A. Binding data obtained by fluorescence polarization were corroborated by an enzymatic activity assay. The described tracer allows for a robust assay in a high-throughput format to support the development of novel Cyp40 ligands.

  DOI：

  10.1021/ml1001272

文献信息

• Targeted cutaneous delivery of ciclosporin A using micellar nanocarriers and the possible role of inter-cluster regions as molecular transport pathways
  作者：Maria Lapteva、Verena Santer、Karine Mondon、Ilias Patmanidis、Gianpaolo Chiriano、Leonardo Scapozza、Robert Gurny、Michael Möller、Yogeshvar N. Kalia

  DOI：10.1016/j.jconrel.2014.09.021

  日期：2014.12

  Oral administration of ciclosporin A (CsA) is indicated in the treatment of severe recalcitrant plaque psoriasis. However, CsA is both nephro- and hepatotoxic and its systemic administration also exposes the patient to other severe side effects. Although topical delivery of CsA, targeted directly to psoriatic skin, would offer significant advantages, there are no topical formulations approved for dermatological use. The aim of this work was to formulate CsA loaded polymeric micelles using the biodegradable and biocompatible MPEG-dihexPLA diblock copolymer and to evaluate their potential for delivering the drug selectively into the skin without concomitant transdermal permeation. Micelle formulations were characterised with respect to drug content, size and morphology. Micelle and drug penetration pathways were subsequently visualised with confocal laser scanning microscopy (CLSM) using fluorescein labelled CsA (Fluo-CsA) and Nile-Red (NR) labelled copolymer. Visualisation studies typically use fluorescent dyes as "model drugs"; however, these may have different physicochemical properties to the drug molecule under investigation. Therefore, in this study it was decided to chemically modify CsA and to use this structurally similar fluorescent analogue to visualise molecular distribution and transport pathways. Molecular modelling techniques and experimental determination of log D served as molecular scale and macroscopic methods to compare the lipophilicity of CsA and Fluo-CsA. The spherical, homogeneous and nanometre-scale micelles (with Zav from 25 to 52 nm) increased the aqueous solubility of CsA by 518-fold. Supra-therapeutic amounts of CsA were delivered to human skin (1.4 +/- 0.6 mu g/cm(2), cf. a statistically equivalent 1.1 +/- 0.5 mu g/cm(2) for porcine skin) after application of the formulation with the lowest CsA and copolymer content (1.67 +/- 0.03 mg/ml of CsA and 5 mg/ml of copolymer) for only 1 h without concomitant transdermal permeation. Fluo-CsA was successfully synthesised, characterised and incorporated into fluorescent NR-MPEG-dihexPLA micelles; its conformation was not modified by the addition of fluorescein and its log D, measured from pH 4 to 8, was equivalent to that of CsA. Fluo-CsA and NR-MPEG-dihexPLA copolymer were subsequently visualised in skin by CLSM. The images indicated that micelles were preferentially deposited between corneocytes and in the inter-cluster regions (i.e. between the clusters of corneocytes). Fluo-CsA skin penetration was deeper in these structures, suggesting that inter-cluster penetration is probably the preferred transport pathway responsible for the increased cutaneous delivery of CsA. (C) 2014 Elsevier B.V. All rights reserved.