2. Academic Validation
  3. Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity

Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity

  • Eur J Med Chem. 2023 Nov 15;260:115776. doi: 10.1016/j.ejmech.2023.115776.
Xin Chen 1,  Jiayun Wang 2,  Peng Zhao 2,  Baiyun Dang 2,  Ting Liang 2,  Raphael R Steimbach 3,  Aubry K Miller 4,  Jia Liu 5,  Xin Wang 6,  Tongtong Zhang 2,  Xiaofa Luan 2,  Jiadong Hu 7,  Jinming Gao 8
Affiliations

Affiliations

  • 1 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: chenxin1888@nwsuaf.edu.cn.
  • 2 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
  • 3 Cancer Drug Development Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; Biosciences Faculty, University of Heidelberg, 69120, Heidelberg, Germany.
  • 4 Cancer Drug Development Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
  • 5 Pharmaceutical Animal Experimental Center, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 6 Department of Clinical Research Center, Chia Tai Tianqing Pharmaceutical Group Co.,Ltd, Jiangsu, China.
  • 7 School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, 24 Weihui Road, Yangling, 712100, Shaanxi, PR China. Electronic address: hujiadong@aliyun.com.
  • 8 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: jinminggao@nwafu.edu.cn.
PMID: 37660484 DOI: 10.1016/j.ejmech.2023.115776
Abstract

A series of tetrahydro-β-carboline (THβC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THβC analogues were highly potent (IC50 < 5 nM) and selective against HDAC6 Enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon Cancer, melanoma, and breast Cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.

Keywords

Antiproliferative; HDAC6 inhibitor; Selectivity; Synthesis; THβC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149497
    HDAC6抑制剂
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