adozelesin | 110314-48-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: adozelesin
• 英文别名: Adosar；N-[2-[(1R,12S)-3-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-10-carbonyl]-1H-indol-5-yl]-1-benzofuran-2-carboxamide
• CAS: 110314-48-2
• 化学式: C₃₀H₂₂N₄O₄
• 分子量: 502.529
• InChiKey: BYRVKDUQDLJUBX-JJCDCTGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  38
• 可旋转键数：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  4

制备方法与用途

这篇文章的PubMed链接是：https://pubmed.ncbi.nlm.nih.gov/1624543/

反应信息

• 作为反应物：
  描述：

  adozelesin 以70%的产率得到
  参考文献：
  名称：

  KELLY, ROBERT C.;GEBHARD, ILSE;WICNIENSKI, NANCY;ARISTOFF, PAUL A.;JOHNSO+, J. AMER. CHEM. SOC., 109,(1987) N 22, 6837-6838

  摘要：

  DOI：
• 作为产物：
  描述：

  Benzofuran-2-carboxylic acid [2-((S)-1-chloromethyl-5-hydroxy-8-methyl-1,6-dihydro-2H-pyrrolo[3,2-e]indole-3-carbonyl)-1H-indol-5-yl]-amide 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 反应 4.0h， 以49%的产率得到adozelesin
  参考文献：
  名称：

  Novel Syntheses of Optically Active CC-1065, U-73,975(Adozelesin), U-80,244(Carzelesin), U-77,779 (Bizelesin), KW-2189, and DU-86

  摘要：

  The title syntheses were achieved by the method featuring oxidative cyclization of the enamino esters [(S)-13 and (S)-24] derived from the 5-aminoindoline [(S)-12], acylation with various structural types of indole-2-carboxylic acids, and formation of cyclopropapyrroloindole moieties.

  DOI：

  10.3987/com-97-7920

文献信息

• BIS-ALKYLATING AGENTS AND THEIR USE IN CANCER THERAPY
  申请人：Szekely Zoltan

  公开号：US20090118349A1

  公开（公告）日：2009-05-07

  The present invention relates to (i) conjugates comprising two DNA alkylating subunits linked by a moiety fitting to the minor groove of the DNA, (ii) to their preparation and (iii) to their use in cancer therapy. The alkylating subunits are especially cytotoxic under hypoxic conditions found in cancer cells. The compounds of the present invention and compositions thereof are useful in the treatment of cancer in a mammal, both alone or in a combination with other anti-cancer agents (e.g. checkpoint abrogators) and/or radiation. They may also be used as cytotoxic units for gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme-prodrug therapy (ADEPT). The present invention provides the compounds of Formula (I), Formula (II) and Formula (III): for treating cancer in a mammal.

  本发明涉及（i）由适合于DNA小沟的基团连接的两个DNA烷基化亚基组成的共轭物，（ii）它们的制备和（iii）它们在癌症治疗中的应用。烷基化亚基在癌细胞中发现的低氧条件下特别具有细胞毒性。本发明的化合物及其组合物在哺乳动物中治疗癌症方面具有用途，可以单独使用或与其他抗癌药物（例如检查点阻断剂）和/或放射线结合使用。它们还可以用作基因定向酶-前药疗法（GDEPT）和抗体定向酶-前药疗法（ADEPT）的细胞毒性单位。本发明提供了式（I）、式（II）和式（III）的化合物，用于哺乳动物中治疗癌症。
• Coupling of cyclopropapyrroloindole (CPI) derivatives. The preparation of CC-1065, ent-CC-1065, and analogs
  作者：Robert C. Kelly、Ilse Gebhard、Nancy Wicnienski、Paul A. Aristoff、Paul D. Johnson、David G. Martin

  DOI：10.1021/ja00256a041

  日期：1987.10
• Acid-Dependent Electrophilicity of Cyclopropylpyrroloindoles. Nature's Masking Strategy for a Potent DNA Alkylator
  作者：M. A. Warpehoski、D. E. Harper

  DOI：10.1021/ja00096a014

  日期：1994.8

  Pseudo-first-order rate constants were determined for the solvolysis of adozelesin (2) and of several related cyclopropylpyrroloindoles (CPIs) as a function of pH and buffer concentration in mixed organic-aqueous solvents. Rate constants were proportional to the hydronium ion concentration at pH > 2, and the slope of the log k(obs) vs pH plot was -1. Both the pyrrolidinoindole (2a) and piperidinoindole (2b) alcohols (ca. 4:1) were produced upon acid-catalyzed solvolysis of 2. The products and kinetic behavior are consistent with rate-determining solvent attack on the protonated CPI and competing carbocation rearrangement. Reaction of 2 with HCl afforded predominantly the pyrrolidinoindole chloride 2e, with only a trace amount (<5%) of the piperidinoindole chloride 2f. Pseudo-first-order rate constants were proportional to both chloride and hydronium ion concentration. The products and kinetic behavior are consistent with attack of chloride ion on the protonated CPI. Comparison to the reported reactivity of spiro[2.5]octa-1 ,4-dien-3-one (6) and bis(trifluoromethyl) quinone methide 8 suggests that the conjugated cyclopropyl ring of the CPI imparts a strong acid dependence to its reactivity with nucleophiles. This property may be relevant to the exceptional reactivity of the parent CPI antibiotic, CC-1065, toward duplex DNA.
• Novel Syntheses of Optically Active CC-1065, U-73,975(Adozelesin), U-80,244(Carzelesin), U-77,779 (Bizelesin), KW-2189, and DU-86
  作者：Yasumichi Fukuda、Hirosuke Furuta、Futoshi Shiga、Yoshikazu Asahina、Shiro Terashima

  DOI：10.3987/com-97-7920

  日期：——

  The title syntheses were achieved by the method featuring oxidative cyclization of the enamino esters [(S)-13 and (S)-24] derived from the 5-aminoindoline [(S)-12], acylation with various structural types of indole-2-carboxylic acids, and formation of cyclopropapyrroloindole moieties.
• KELLY, ROBERT C.;GEBHARD, ILSE;WICNIENSKI, NANCY;ARISTOFF, PAUL A.;JOHNSO+, J. AMER. CHEM. SOC., 109,(1987) N 22, 6837-6838
  作者：KELLY, ROBERT C.、GEBHARD, ILSE、WICNIENSKI, NANCY、ARISTOFF, PAUL A.、JOHNSO+

  DOI：——

  日期：——