HDAC6抑制剂(HPOB) | 1429651-50-2

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: HDAC6抑制剂(HPOB)
• 中文别名: HPOB抑制剂；化合物HPOB
• 英文名称: HPOB
• 英文别名: N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2-oxoethyl)benzamide；N-hydroxy-4-[2-[N-(2-hydroxyethyl)anilino]-2-oxoethyl]benzamide
• CAS: 1429651-50-2
• 化学式: C₁₇H₁₈N₂O₄
• 分子量: 314.341
• InChiKey: RFAZNTABYJYOAR-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：可溶1mg/mL，澄清（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  89.9
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

HPOB 是一种有效的、选择性 HDAC6 抑制剂，其 IC50 值为 56 nM，对其他 HDACs 的选择性高出约 30 多倍。

体外研究

在正常 (HFS) 和转化 (LNCaP、A549 和 U87) 细胞中，HPOB 诱导 α-微管蛋白乙酰化，但不作用于组蛋白，并抑制细胞生长，而不影响细胞活力。在 HFS 细胞中，HPOB 增强了依托泊苷、多柔比星或 SAHA 引起的转化细胞死亡。此外，在转化细胞中，HPOB 还通过凋亡途径增强了依托泊苷诱导的转化细胞死亡。

体内研究

在携带 CWR22 人前列腺癌异种移植物的小鼠中，当 HPOB (300 mg/kg/d 腹腔注射) 与 SAHA 结合使用时，可以抑制已建立肿瘤的增长，而单独使用则不会产生显著抑制效果。

反应信息

• 作为产物：
  描述：

  N-苯基乙醇胺 在 咪唑 、 potassium cyanide 、 羟胺 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 19.0h， 生成 HDAC6抑制剂(HPOB)
  参考文献：
  名称：

  [EN] NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE 1
  [FR] NOUVELLES MOLÉCULES QUI INHIBENT SÉLECTIVEMENT L'HISTONE-DÉACÉTYLASE 6 PAR RAPPORT À L'HISTONE-DÉACÉTYLASE 1

  摘要：

  本发明的化合物是HDAC6选择性抑制剂，其基于乙酰化微管蛋白的积累而被识别，而不是乙酰化组蛋白的积累。组蛋白去乙酰化酶或“HDAC”指的是能够从蛋白质（包括组蛋白和微管蛋白）中切除乙酰基（-C(=0)CH3）的酶。还公开了包含这些分子的组合物以及用于抑制组蛋白去乙酰化酶活性的方法，包括用于治疗的方法。

  公开号：

  WO2013052110A1

文献信息

• NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE 1
  申请人：The Trustees of Columbia University in the City of New York

  公开号：US20140288119A1

  公开（公告）日：2014-09-25

  This invention provides a compound having the structure: wherein R 1 is H, halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl; wherein X is Cl, Br, or F; R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is —Ar 1 —Z— or —Z—Ar 1 —Z—, wherein Ar 1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)— —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and R 4 is alkyl, —OR 11 or —NH—OR 11 , wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and when Q is —Ar 1 —Z—, Z is absent, Ar 1 is phenyl, R 2 and R 3 are H, n=1, and R 4 is —NHOH, then R 1 is other than carbazole, tetrahydro-β-carboline, tetrahydro-γ-carboline, —C(═O)—NR 5 R 6 and —NR 5 —C(═O)—R 6 , wherein one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H; or a pharmaceutically acceptable salt thereof.

  该发明提供了一种具有以下结构的化合物：其中，R1为H、卤素、—NR5R6、—NR5—C(═O)—R6、—NH—C(═O)—OR7、—OR7、—NO2、—CN、—SR7、—SO2R7、—CO2R7、CF3、—SOR7、—POR7、—C(═S)R7、—C(═O)—NR5R6、—CH2—C(═O)—NR5R6、—C(═NR5)R6、—P(═O)(OR5)(OR6)、—P(OR5)(OR6)、—C(═S)R7、C1-5烷基、C2-5烯基、C2-5炔基、芳基、杂芳基或杂环烷基，其中，R5、R6和R7各自独立地为H、C1-5烷基、C2-5烯基、C2-5炔基、杂基、环烷基、杂环烷基、芳基或杂芳基；m为0到2的整数；R2和R3各自独立地为H、卤素、—NH2、—CX3、—C(═O)OR8、C(═O)R8、—C(═O)NR9R10、C1-10烷基、C2-10烯基、C2-10炔基、杂基、芳基、杂芳基或杂环烷基，其中，X为Cl、Br或F；R8、R9和R10各自独立地为H、C1-5烷基、C2-5烯基、C2-5炔基、杂基、环烷基、杂环烷基、芳基或杂芳基；Q为—Ar1—Z—或—Z—Ar1—Z—，其中，Ar1为芳基或杂芳基；Z的每次出现都是独立存在或缺失的，当存在时为—O—、—S—、—CH2—、—C(O)——NH—、—NH—NH—、—NHC(═O)—、—C(═O)NH—、—NHC(═O)CH2NH—、—NHC(═O)CH2C(═O)—、—N(OH)—、—CH2CH2—或—NHC(═O)CH═CH—；R4为烷基、—OR11或—NH—OR11，其中，R11为H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、杂芳基或杂环烷基，当Q为—Ar1—Z—，Z不存在，Ar1为苯基，R2和R3为H，n=1，且R4为—NHOH时，R1不是咔唑、四氢-β-咔啉、四氢-γ-咔啉、—C(═O)—NR5R6和—NR5—C(═O)—R6，其中R5或R6之一为喹啉，另一个为H；或其药学上可接受的盐。
• P38 map kinase inhibitors
  申请人：City of Hope

  公开号：US11225665B2

  公开（公告）日：2022-01-18

  Provided herein, inter alia, are p38 mitogen-activated protein kinase inhibitors and methods of treating cancer using p38 mitogen-activated protein kinase inhibitors.

  本文特别提供了p38丝裂原活化蛋白激酶抑制剂和使用p38丝裂原活化蛋白激酶抑制剂治疗癌症的方法。
• NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE
  申请人：Breslow Ronald

  公开号：US20170066712A1

  公开（公告）日：2017-03-09

  This invention provides a compound having the structure: wherein R 1 is H, halogen, —NR 5 R 6 , —NR 5 —C(═0)-R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl; wherein X is Cl, Br, or F; R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is —Ar 1 —Z— or —Z—Ar 1 —Z—, wherein Ar 1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)—, —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and R 4 is alkyl, —OR 11 or —NH—OR 11 , wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and when Q is —Ar 1 —Z—, Z is absent, Ar 1 is phenyl, R 2 and R 3 are H, n=1, and R 4 is —NHOH, then R 1 is other than carbazole, tetrahydro-β-carboline, tetrahydro-γ-carboline, —C(═O)—NR 5 R 6 and —NR 5 —C(═0)-R 6 , wherein one of R 5 or R 6 is quinline and the other of R 5 or R 6 is H; or a pharmaceutically acceptable salt thereof.
• Compositions and Methods for the Treatment and Prevention of Cancer
  申请人：California State University Northridge

  公开号：US20190216751A1

  公开（公告）日：2019-07-18

  A method of treating a subject with cancer is provided. The method includes administering to a subject in need thereof an effective amount of a pharmaceutical composition that includes inhibitors of HDAC6 and/or sirtuins and an inhibitor of deoxyhypusine synthase (DHPS). Methods also include treating a subject with cancer by administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising at least one inhibitor of sirtuin and at least one inhibitor of histone deacetylase six (HDAC6); at least one inhibitor of sirtuin or at least one inhibitor of histone deacetylase six (HDAC6), or a combination thereof. Additional methods include treating a subject with cancer by administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising at least one inhibitor of sirtuin, an inhibitor of deoxyhypusine synthase (DHPS), and at least one inhibitor of histone deacetylase six (HDAC6); at least one inhibitor of sirtuin, an inhibitor of deoxyhypusine synthase (DHPS), or at least one inhibitor of histone deacetylase six (HDAC6), or a combination thereof.
• Methods of Treating Arid1A-Mutated Cancers With HDAC6 Inhibitors and EZH2 Inhibitors
  申请人：The Wistar Institute of Anatomy and Biology

  公开号：US20190192521A1

  公开（公告）日：2019-06-27

  In some embodiments, therapeutic treatments for a disease such as a cancer are disclosed, including pharmaceutical compositions and methods of using pharmaceutical compositions for treating the cancer, wherein the cancer is an ARID1A-mutated cancer. In some embodiments, the therapeutic treatments disclosed include methods of treating ARID1A-mutated cancer in a subject comprising the step of administering a therapeutically effective dose of a histone deacetylase 6 (HDAC6) inhibitor to the subject, including a human subject. In some embodiments, the HDAC6 inhibitors are administered in conjunction with a therapeutically effective dose of an enhancer of zeste homolog 2 (EZH2) inhibitor.