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

Keita Kojima; Hiroaki Konishi; Kyoka Momosaki; Yuya Komatani; Akira Katsuyama; Koji Nakagawa; Kayoko Kanamitsu; Fumika Yakushiji; Mikihiro Fujiya; Satoshi Ichikawa

doi:10.1038/s41598-024-58196-3

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.

Authors

Keita Kojima¹, Hiroaki Konishi², Kyoka Momosaki¹, Yuya Komatani¹, Akira Katsuyama^{1

3

4}, Koji Nakagawa⁵, Kayoko Kanamitsu⁶, 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. ichikawa@pharm.hokudai.ac.jp.
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. ichikawa@pharm.hokudai.ac.jp.
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. ichikawa@pharm.hokudai.ac.jp.

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.

MeSH terms

Animals
Colonic Neoplasms* / drug therapy
Echinomycin* / pharmacology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Mice

Substances

Echinomycin
Hypoxia-Inducible Factor 1, alpha Subunit

Abstract

MeSH terms

Substances

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