2. Academic Validation
  3. Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors

Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors

  • Bioorg Med Chem. 2017 Mar 15;25(6):1939-1948. doi: 10.1016/j.bmc.2017.02.014.
Tingting Liu 1,  Yichao Wan 2,  Renshuai Liu 1,  Lin Ma 1,  Minyong Li 1,  Hao Fang 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
  • 2 Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, PR China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: haofangcn@sdu.edu.cn.
PMID: 28233676 DOI: 10.1016/j.bmc.2017.02.014
Abstract

The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for Cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XL protein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Ki value of 0.26μM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XL protein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.

Keywords

Anti-tumor; Bcl-2/Mcl-1; Indole-3-carboxylic acid-based derivatives; Inhibitors.

Figures