[(19S)-19-ethyl-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-19-yl] 2-[[2-(4-methoxyphenyl)-1-[(4-methylphenyl)sulfonylamino]ethylidene]amino]acetate

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: [(19S)-19-ethyl-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-19-yl] 2-[[2-(4-methoxyphenyl)-1-[(4-methylphenyl)sulfonylamino]ethylidene]amino]acetate
• 化学式: C₃₈H₃₄N₄O₈S
• 分子量: 706.776
• InChiKey: MQIGYWHKUYDGKM-LHEWISCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  51
• 可旋转键数：
  11
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  162
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  喜树碱 在 4-二甲氨基吡啶 、 三乙胺 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 17.17h， 生成 [(19S)-19-ethyl-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-19-yl] 2-[[2-(4-methoxyphenyl)-1-[(4-methylphenyl)sulfonylamino]ethylidene]amino]acetate
  参考文献：
  名称：

  [EN] NOVEL 20(S)-SULFONYLAMIDINE DERIVATIVES OF CAMPTOTHECIN AND THE USE THEREOF AS A POTENT ANTITUMOR AGENT
  [FR] NOUVEAUX DÉRIVÉS 20(S)-SULFONYLAMIDINE DE CAMPTOTHÉCINE ET LEUR UTILISATION EN TANT QUE PUISSANT AGENT ANTITUMORAL

  摘要：

  本发明涉及紫杉醇的新型20-磺酰胺基衍生物（1），其合成方法，以及将其用作抗肿瘤药物的用途，例如用作治疗鼻咽、肺、乳腺或前列腺癌的抗肿瘤药物。

  公开号：

  WO2015048365A1

文献信息

• Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20(<i>S</i>)-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents
  作者：Mei-Juan Wang、Ying-Qian Liu、Ling-Chu Chang、Chih-Ya Wang、Yong-Long Zhao、Xiao-Bo Zhao、Keduo Qian、Xiang Nan、Liu Yang、Xiao-Ming Yang、Hsin-Yi Hung、Jai-Sing Yang、Daih-Huang Kuo、Masuo Goto、Susan L. Morris-Natschke、Shiow-Lin Pan、Che-Ming Teng、Sheng-Chu Kuo、Tian-Shung Wu、Yang-Chang Wu、Kuo-Hsiung Lee

  DOI：10.1021/jm5003588

  日期：2014.7.24

  Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.