Design, synthesis and SARs of novel telomerase inhibitors based on BIBR1532

Bioorg Chem. 2020 Sep:102:104077. doi: 10.1016/j.bioorg.2020.104077. Epub 2020 Jul 7.

Abstract

Telomerase has become one of the new popular targets for the development of anti-tumor drugs. Based on the structural characteristics of the BIBR1532 which has entered the stage of clinical research, six series total of 64 new compounds with diverse structural characteristics were designed and synthesized. The inhibitory activity against SGC-7901, MGC-803, SMMC-7721, A375 and GES cell lines and their telomerase inhibitory activity were tested. Among them, eight compounds showed good activity against cancer cells, among them compounds 56, 57 and 59 also showed low toxicity. Some of them showed excellent telomerase inhibitory activity with IC50 values ranging from 0.62 μM to 8.87 μM. Based on above, in depth structure-activity relationships were summarized, the compounds by replacing methyl group with cyanide and retaining amide moiety had good anti-tumor activity, moderate cytotoxicity, and better telomerase inhibitory activity. The results should be used for reference in BIBR1532-based structural optimization for further development of small molecule telomerase inhibitors.

Keywords: BIBR1532; Design; Synthesis; TERT inhibitor; Telomerase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobenzoates / chemical synthesis*
  • Aminobenzoates / pharmacology
  • Aminobenzoates / therapeutic use*
  • Drug Design
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use*
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors*

Substances

  • Aminobenzoates
  • BIBR 1532
  • Enzyme Inhibitors
  • Naphthalenes
  • Telomerase