卡利奇霉素 | 108212-75-5

• 物质功能分类: 原料药 - 抗生素类药物 - 氨基糖苷类药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 卡利奇霉素
• 中文别名: 卡奇霉素gamma1
• 英文名称: calicheamicin γ₁^I
• 英文别名: S-[(2R,3S,4S,6S)-6-({[(2R,3S,4S,5R,6R)-5-{[(2S,4S,5S)-5-(ethylamino)-4-methoxytetrahydro-2H-pyran-2-yl]oxy}-4-hydroxy-6-{[(2S_,5Z_,9R_,13E)-9-hydroxy-12-[(methoxycartonyl)amino]-13-[2-(methyltrisulfanyl)ethylidene]-11-oxobicyclo[7.3.1]trideca-1(12),5-diene-37-diyn-2-yl]oxy}-2-methyltetrahydropyran-3-yl]amino}oxy)-4-hydroxy-2-methyltetrahydro-2H-pyran-3-yl] 4-{[(2S,3R,4R,5S,6S)-3,5-dihydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3-iodo-5,6-dimethoxy-2-methylbenzenecarbothioate；calicheamicin gamma(1)I；S-[(2R,3S,4S,6S)-6-[[(2R,3S,4S,5R,6R)-5-[(2S,4S,5S)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2S,5Z,9R,13E)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-methyloxan-3-yl]amino]oxy-4-hydroxy-2-methyloxan-3-yl] 4-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-4-methoxy-6-methyloxan-2-yl]oxy-5-iodo-2,3-dimethoxy-6-methylbenzenecarbothioate
• CAS: 108212-75-5
• 化学式: C₅₅H₇₄IN₃O₂₁S₄
• 分子量: 1368.37
• InChiKey: HXCHCVDVKSCDHU-PJKCJEBCSA-N

物化性质

• 比旋光度：
  D26 -124° (c = 0.98%, EtOH)
• 密度：
  1.57±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：≥ 100 mg/mL (73.08 mM)；水：< 0.1 mg/mL（不溶）

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  84
• 可旋转键数：
  24
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  410
• 氢给体数：
  8
• 氢受体数：
  27

制备方法与用途

简介

卡奇霉素（calicheamicins，CLM）是从稀有放线菌小单孢菌发酵液中分离得到的烯二炔类抗肿瘤抗生素。

作用机制

卡奇霉素的生物活性浓度低于1Pg·mL-1，对白血病如淋巴细胞白血病P388和L1210细胞以及实体瘤如结肠癌26和黑色素瘤B-16细胞有极强的杀伤作用。其生物活性主要通过与细胞DNA特异序列的小沟结合，直接断裂细胞DNA，进一步诱导肿瘤细胞凋亡；同时，卡奇霉素对细胞RNA也有非特异性的损伤作用。卡奇霉素与抗CD33单抗偶联物Mylotarg是第一个被FDA批准用于肿瘤治疗的单抗导向药物，并已在临床应用。

用途

卡奇霉素是一种有效的细胞毒性试剂，可引起DNA双链断裂。

毒性

卡奇霉素具有剧毒，是土壤细菌产生的数百种代谢物之一。

生物活性

Calicheamicin 是一种肿瘤抗生素，也是有效的细胞毒性试剂，可引起DNA双链断裂。它还能抑制 DNA 合成。

靶点

Calicheamicins

体外研究

PF-06647263（anti-EFNA4-ADC）是通过将人E22赖氨酸残基与AcButDMH-N-Ac-calicheamicin-γ1链接物-有效载荷偶联而成，平均药物到抗体比值(DAR)为4.6。PF-06647263表现出抗原和浓度依赖性的细胞毒性，在96小时暴露后导致细胞死亡（EC50 ≈ 1 ng/mL）。CMC-544由人源化CD22单克隆抗体与卡奇霉素连接而成，有效用于儿科前体B淋巴母细胞性白血病(BCP-ALL)的体外研究。CMC-544在剂量和时间依赖性的各种ALL细胞系中诱导细胞死亡，IC50值范围从0.15到4.9 ng/mL。CMC-544 (10 ng/mL) 对原发性BCP-ALL细胞有效且具有特异性。在CMC-544处理的细胞中，CD22的水平相对于G5/44处理细胞有所下降，并持续减少。

体内研究

一种由人源化抗EFNA4单克隆抗体与DNA损伤剂卡奇霉素偶联而成的ADC，在TNBC和卵巢癌PDX的小鼠模型中实现持续的肿瘤消退。PF-06647263 (0.27, 0.36 mg/kg) 在TNBC异种移植瘤中产生显著的肿瘤消退效果。

反应信息

• 作为反应物：
  描述：

  卡利奇霉素 在 甲醇 、 sodium tetrahydroborate 、 Dowex 50W-X₈ 、 碘甲烷 作用下， 以 乙醇 为溶剂， 反应 18.33h， 生成 dihydrocalicheamicin pseudoaglycon
  参考文献：
  名称：

  Calicheamicins, a novel family of antitumor antibiotics. 4. Structure elucidation of calicheamicins .beta.1Br, .gamma.1Br, .alpha.2I, .alpha.3I, .beta.1I, .gamma.1I, and .delta.1I

  摘要：

  The details of the structural assignment of the potent antitumor antibiotic, calicheamicin gamma-1I (6, C55H74IN3O21S4), is reported. Methanolysis studies on 6 and N-acetylcalicheamicin gamma-1I (8, C57H76IN3022S4) permitted the structural assignment of the glycosidic chain. Details of the spectral analysis supporting the assignments of the 3-O-methyl-alpha-L-rhamnopyranoside (D-ring) and the methyl 2,4-dideoxy-3-O-methyl-4-(N-acetyl-N-ethylamino)-a-L-xylopyranoside (E-ring) is reported. The structure of calicheamicinone (32, C18H17NO5S3), containing a bicyclo[7.3.1 ] tridec-9-ene-2,6-diyne system and a methyl trisulfide, was elucidated by a series of chemical degradation studies, which included an unexpected free radical cycloaromatization reaction. The presence of 4,6-dideoxy-4-(hydroxyamino)-beta-D-glucopyranoside (A-ring) and its N-O glycosidic linkage to the thio sugar (B-ring) was ascertained by X-ray crystallography of 24 (C36H40INO13S2), a degradation product of 6. The chemical structures of calicheamicins beta-1Br (1), gamma-1Br (2), alpha-2I (3), alpha-3I (4), beta-1I (5), and delta-1I (7) were assigned by correlating their H-1 and C-13 NMR data with that of calicheamicin gamma-1I. By tracking the biological activities of the degradation products, the enediyne system of calicheamicinone was shown to be essential for the DNA-damaging abilities of the calicheamicins. A mechanism whereby the enediyne could be triggered to cyclize via a 1,4-diyl, the putative DNA cleaving species, is proposed.

  DOI：

  10.1021/ja00029a030
• 作为产物：
  描述：

  在 camphor-10-sulfonic acid 、 四丁基氟化铵 作用下， 生成 卡利奇霉素
  参考文献：
  名称：

  Hitchcock, Stephen A.; Chu-Moyer, Margaret Y.; Boyer, Serge H., Journal of the American Chemical Society, 1995, vol. 117, # 21, p. 5750 - 5756

  摘要：

  DOI：

文献信息

• CYCLIC ETHER PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20140088117A1

  公开（公告）日：2014-03-27

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I的环醚吡唑-4-基-杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2为环醚，X为噻唑基、吡啶基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物进行体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• Heterobicyclic pyrazole compounds and methods of use
  申请人：Blake F. James

  公开号：US20070238726A1

  公开（公告）日：2007-10-11

  Compounds of Formulas Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

  化合物Ia和Ib的结构，以及其立体异构体、几何异构体、互变异构体、溶剂合物、代谢物和药学上可接受的盐，可用于抑制受体酪氨酸激酶并治疗由此介导的疾病。公开了使用化合物Ia和Ib的结构，以及其立体异构体、几何异构体、互变异构体、溶剂合物和药学上可接受的盐的方法，用于体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病，或相关的病理条件。
• [EN] PYRAZOLOPYRIDINE DERIVATIVES FOR THE TREATMENT OF CANCER<br/>[FR] DÉRIVÉS DE PYRAZOLOPYRIDINE POUR LE TRAITEMENT DU CANCER
  申请人：GENENTECH INC

  公开号：WO2017205538A1

  公开（公告）日：2017-11-30

  The present invention relates to a compound formula (I): and to salts thereof, wherein R1, R2X, and Y have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders such as cancer, inflammatory disorders and autoimmune diseases.

  本发明涉及一种化合物公式（I）及其盐，其中R1、R2X和Y具有本文中定义的任何值，以及其组合物和用途。这些化合物可用作CBP和/或EP300的抑制剂。还包括包含公式（I）化合物或其药学上可接受的盐的药物组合物，以及在治疗各种CBP和/或EP300介导的疾病，如癌症、炎症性疾病和自身免疫疾病中使用这些化合物和盐的方法。
• [EN] CALICHEAMICIN DERIVATIVES AND ANTIBODY DRUG CONJUGATES THEREOF<br/>[FR] DÉRIVÉS DE CALICHÉAMICINE ET CONJUGUÉS ANTICORPS-MÉDICAMENTS DE CEUX-CI
  申请人：PFIZER

  公开号：WO2018138591A1

  公开（公告）日：2018-08-02

  The present invention is directed to novel calicheamicin derivatives useful as payloads in antibody-drug-conjugates (ADC's), and to payload-linker compounds and ADC compounds comprising the same; to pharmaceutical compositions comprising the same and to methods for using the same to treat pathological conditions such as cancer.

  本发明涉及新型calicheamicin衍生物，用作抗体-药物偶联物（ADC）的有效载荷，以及包含相同有效载荷-连接剂化合物和ADC化合物；涉及包含它们的药物组合物以及使用它们治疗诸如癌症等病理状态的方法。
• [EN] PROTAC ANTIBODY CONJUGATES AND METHODS OF USE<br/>[FR] CONJUGUÉS ANTICORPS-PROTAC ET PROCÉDÉS D'UTILISATION
  申请人：GENENTECH INC

  公开号：WO2017201449A1

  公开（公告）日：2017-11-23

  The subject matter described herein is directed to antibody-PROTAC conjugates (PACs), to pharmaceutical compositions containing them, and to their use in treating diseases and conditions where targeted protein degradation is beneficial.

  本主题描述的是抗体-PROTAC偶联物（PACs），包含它们的药物组合物，以及它们在治疗那些有靶向蛋白质降解有益的疾病和状况中的用途。