(S)-2-((2S,3S)-2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide | 1314556-93-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-((2S,3S)-2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
• 英文别名: ZYJ-34c；(3S)-2-[(2S,3S)-2-(3,3-dimethylbutanoylamino)-3-methylpentanoyl]-7-[2-(hydroxyamino)-2-oxoethoxy]-N-(4-methoxyphenyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide
• CAS: 1314556-93-8
• 化学式: C₃₁H₄₂N₄O₇
• 分子量: 582.697
• InChiKey: DMFYWVSGUMHBCM-TVIOGVOPSA-N

物化性质

• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  146
• 氢给体数：
  4
• 氢受体数：
  7

制备方法与用途

ZYJ-34c是一种有效的口服抗肿瘤活性组蛋白去乙酰化酶抑制剂（HDACi）。

反应信息

• 作为产物：
  描述：

  3,5-二碘-L-酪氨酸 在 盐酸 、 羟胺钾盐 、 palladium 10% on activated carbon 、 氢气 、 sodium carbonate 、 potassium carbonate 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.25h， 生成 (S)-2-((2S,3S)-2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
  参考文献：
  名称：

  Discovery of a Tetrahydroisoquinoline-Based Hydroxamic Acid Derivative (ZYJ-34c) as Histone Deacetylase Inhibitor with Potent Oral Antitumor Activities

  摘要：

  Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.

  DOI：

  10.1021/jm200577a

文献信息

• Discovery of a pair of diastereomers as potent HDACs inhibitors: determination of absolute configuration, biological activity comparison and computational study
  作者：Yingjie Zhang、Elizabeth S. Inks、Mengyuan Zhu、C. James Chou、Hao Fang、Minyong Li、Yuemao Shen、Fan Yi、Wenfang Xu

  DOI：10.1039/c3ra43249a

  日期：——

  Histone deacetylase inhibitors (HDACi) are still the focus of epigenetic modulator development due to their effective intervention in many pathological processes. In our previous research, a potent HDACi was designed, synthesized and validated as a promising antitumor candidate named ZYJ-34c. Enlarged scale synthesis of ZYJ-34c for further detailed research was hindered by the occurrence of a by-product, which was identified as an isomer of ZYJ-34c by HRMS and 1H NMR. Subsequent synthesis route modification and optimization revealed that these two isomers were a pair of epimers and their absolute configurations could be directly determined by our optimized synthesis routes, through which each optically pure epimer could be stereoselectively synthesized, respectively. Based on these results, we concluded that our previously reported absolute configuration of ZYJ-34c was incorrect. It is worth noting that the epimer of ZYJ-34c exhibited more potent HDACs inhibition and both in vitro and in vivo antitumor activities, and moreover, their different HDACs inhibitory activities could be rationalized by computational simulations of their binding modes in HDAC2.

  组蛋白去乙酰化酶抑制剂（HDACi）由于其在多种病理过程中的有效干预，仍然是表观遗传调节剂开发的重点。在我们之前的研究中，设计、合成并验证了一种名为ZYJ-34c的有前途的抗肿瘤候选药物，它是一种强效的HDACi。由于产生了一种副产物，阻碍了ZYJ-34c的扩大规模合成，以便进一步详细研究，该副产物通过HRMS和1H NMR被鉴定为ZYJ-34c的异构体。随后的合成路线修改和优化揭示，这两个异构体是一对差向异构体，它们的绝对构型可以通过我们优化的合成路线直接确定，通过这些路线，每个光学纯的差向异构体可以分别进行立体选择性合成。基于这些结果，我们得出结论，我们之前报道的ZYJ-34c的绝对构型是不正确的。值得注意的是，ZYJ-34c的差向异构体表现出更强的HDACs抑制活性以及体外和体内的抗肿瘤活性，而且，它们不同的HDACs抑制活性可以通过对其在HDAC2中结合模式的计算模拟得到合理化解释。