Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent

  • Sci Rep. 2024 Apr 1;14(1):7628. doi: 10.1038/s41598-024-58196-3.
Keita Kojima  1 ,  Hiroaki Konishi  2 ,  Kyoka Momosaki  1 ,  Yuya Komatani  1 ,  Akira Katsuyama  1  3  4 ,  Koji Nakagawa  5 ,  Kayoko Kanamitsu  6 ,  Fumika Yakushiji  1  3  4 ,  Mikihiro Fujiya  2  7 ,  Satoshi Ichikawa  8  9  10
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
  • 2. Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Asahikawa, Hokkaido, 078-8510, Japan.
  • 3. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
  • 4. Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Sapporo, 060-0812, Japan.
  • 5. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu-cho, Ishikari-gun, Hokkaido, 061-0293, Japan.
  • 6. Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 7. Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan.
  • 8. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan. [email protected].
  • 9. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan. [email protected].
  • 10. Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Sapporo, 060-0812, Japan. [email protected].
PMID: 38561454 DOI: 10.1038/s41598-024-58196-3
Abstract

Colorectal Cancer is the third most commonly diagnosed Cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon Cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human Cancer cell lines, were synthesized, and their biological activities against human colon Cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon Cancer.

Products