[(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

• [EN] NOVEL 20(S)-SULFONYLAMIDINE DERIVATIVES OF CAMPTOTHECIN AND THE USE THEREOF AS A POTENT ANTITUMOR AGENT<br/>[FR] NOUVEAUX DÉRIVÉS 20(S)-SULFONYLAMIDINE DE CAMPTOTHÉCINE ET LEUR UTILISATION EN TANT QUE PUISSANT AGENT ANTITUMORAL
  申请人：LEE KUO-HSIUNG

  公开号：WO2015048365A1

  公开（公告）日：2015-04-02

  The present invention is related to novel 20-sulfonylamidine derivatives of camptothecin (1), method of synthesizing the same, and use thereof as an antitumor agent, for examples an antitumor agent for treating nasopharyngeal, lung, breast or prostate cancer.

  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。
• 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.