Trans-(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-dioxolane | 1224885-01-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Trans-(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-dioxolane
• 英文别名: (cis-2-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate；[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate
• CAS: 1224885-01-1
• 化学式: C₂₀H₁₉Cl₂N₃O₅S
• 分子量: 484.36
• InChiKey: USLNGHIZGCHFQQ-JXFKEZNVSA-N

物化性质

• 沸点：
  657.7±65.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-(sec-butyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 、 Trans-(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-dioxolane 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 以62%的产率得到(2R,4R,2'S)-Itraconazole
  参考文献：
  名称：

  Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

  摘要：

  Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (la h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and If, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole.

  DOI：

  10.1021/ml1000068
• 作为产物：
  描述：

  对甲苯磺酸(S)-(-)-2,2-二甲基-1,3-二氧戊环基-4-基甲基酯 在 盐酸 、 三氟甲磺酸 、 水 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 66.0h， 生成 Trans-(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-dioxolane 、 ((2S,4S)-2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methyl 4-methyl-benzenesulfonate
  参考文献：
  名称：

  设计和合成含四唑和吡啶的伊曲康唑类似物作为强效血管生成抑制剂。

  摘要：

  伊曲康唑是一种广泛使用的抗真菌药物，被发现具有抗血管生成活性，目前正接受多种临床试验来治疗不同类型的癌症。但是，它具有极低的溶解度和通过抑制CYP3A4与许多药物的强烈相互作用，限制了其作为新的抗血管生成和抗癌药物的潜力。为了解决这些问题，合成了一系列类似物，其中苯基被吡啶或氟取代的苯取代。其中，与伊曲康唑相比，含吡啶和四唑的化合物24的溶解度显着提高，并且对CYP3A4的抑制作用降低。与伊曲康唑相似，化合物24抑制AMPK / mTOR信号轴和VEGFR2的糖基化。在模拟研究中，它还诱导胆固醇在溶酶体中积累，并证明与NPC1的固醇感应域结合。这些结果表明，化合物24可以作为开发新一代抗血管生成药物的有吸引力的候选物。

  DOI：

  10.1021/acsmedchemlett.9b00438

文献信息

• Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesis inhibitor
  作者：Keimei Oh、Kazuhiro Yamada、Yuko Yoshizawa

  DOI：10.1016/j.bmcl.2013.09.056

  日期：2013.12

  by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and

  2 RS，4 RS -1-[[2-（2,4-二氯苯基）-4-（2-（2-丙烯氧基）苯氧基甲基）-1,3-二氧戊环-2-基]甲基]-的四个立体异构体制备了新型油菜素类固醇生物合成抑制剂1 H -1,2,4-三唑（YCZ - 2013）。通过使用相应的旋光纯R和S甲苯-4-磺酸2,3-二羟丙酯（R - 4，S - 4）制备2 RS，4 R - 5和2 RS，4 S - 5的非对映异构体）。通过对甲苯磺酸盐的非对映选择性结晶，然后用母液再平衡和色谱法，获得对映体和非对映体纯的丙酮化物（5）。通过手性高效液相色谱（HPLC）和NMR证实了四种目标化合物（YCZ - 2013）的光学纯度。这些立体异构体对拟南芥茎伸长的影响表明2 S，4 R - YCZ - 2013和2 R，4 S - YCZ - 2013的顺式异构体表现出强大的抑制活性，IC 50值分别约为24±3和24±2 nM。2 S，4 S
• CHIRALLY PURE ISOMERS OF ITRACONAZOLE FOR USE AS ANGIOGENESIS INHIBITORS
  申请人：Liu Jun O.

  公开号：US20130102614A1

  公开（公告）日：2013-04-25

  Described herein are methods of inhibiting angiogenesis, and treating and preventing disorders associated with angiogenesis by administering anti-angiogenesis compounds to a subject.

  本文描述了通过向受试者施用抗血管生成化合物来抑制血管生成并治疗和预防与血管生成相关的疾病的方法。
• US9095589B2
  申请人：——

  公开号：US9095589B2

  公开（公告）日：2015-08-04
• Design and Synthesis of Tetrazole- and Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors
  作者：Yingjun Li、Kalyan Kumar Pasunooti、Hanjing Peng、Ruo-Jing Li、Wei Q. Shi、Wukun Liu、Zhiqiang Cheng、Sarah A. Head、Jun O. Liu

  DOI：10.1021/acsmedchemlett.9b00438

  日期：2020.6.11

  group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound 24 has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound 24 inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome

  伊曲康唑是一种广泛使用的抗真菌药物，被发现具有抗血管生成活性，目前正接受多种临床试验来治疗不同类型的癌症。但是，它具有极低的溶解度和通过抑制CYP3A4与许多药物的强烈相互作用，限制了其作为新的抗血管生成和抗癌药物的潜力。为了解决这些问题，合成了一系列类似物，其中苯基被吡啶或氟取代的苯取代。其中，与伊曲康唑相比，含吡啶和四唑的化合物24的溶解度显着提高，并且对CYP3A4的抑制作用降低。与伊曲康唑相似，化合物24抑制AMPK / mTOR信号轴和VEGFR2的糖基化。在模拟研究中，它还诱导胆固醇在溶酶体中积累，并证明与NPC1的固醇感应域结合。这些结果表明，化合物24可以作为开发新一代抗血管生成药物的有吸引力的候选物。
• Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole
  作者：Wei Shi、Benjamin A. Nacev、Shridhar Bhat、Jun O. Liu

  DOI：10.1021/ml1000068

  日期：2010.7.8

  Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (la h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and If, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole.