Synthesis and anti-tumor activities in human leukemia-derived cells of polyenylpyrroles with a methyl group at the conjugated polyene terminus

Tomoya Higashi; Chihiro Yoshida; Yoshifumi Hachiro; Chihiro Nakata; Azusa Takechi; Takuya Yagi; Kazuya Miyashita; Nobuo Kitada; Rika Obata; Takashi Hirano; Takahiko Hara; Shojiro A Maki

doi:10.1016/j.bmcl.2023.129471

Synthesis and anti-tumor activities in human leukemia-derived cells of polyenylpyrroles with a methyl group at the conjugated polyene terminus

Bioorg Med Chem Lett. 2023 Oct 15:95:129471. doi: 10.1016/j.bmcl.2023.129471. Epub 2023 Sep 15.

Authors

Affiliations

¹ Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu-shi, Tokyo 182-8585, Japan; Center for Neuroscience and Biomedical Engineering, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu-shi, Tokyo 182-8585, Japan.
² Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
³ Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Graduate School of Science, Department of Biological Science, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
⁴ Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁵ Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu-shi, Tokyo 182-8585, Japan.
⁶ Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Graduate School of Science, Department of Biological Science, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
⁷ Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu-shi, Tokyo 182-8585, Japan; Center for Neuroscience and Biomedical Engineering, The University of Electro-Communications, 1-5-1 Chofugaoka, Chofu-shi, Tokyo 182-8585, Japan. Electronic address: s-maki@uec.ac.jp.

PMID: 37717362
DOI: 10.1016/j.bmcl.2023.129471

Abstract

To develop novel drugs for treating T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) which are highly malignant hematological tumors, a series of analogs having a polyenylpyrrole structure of natural compounds (rumbrin and auxarconjugatin B) were synthesized and investigated their structure-activity relationships (SAR) of in vitro anti-T-ALL and anti-AML activities. We obtained three findings: (1) introduction of a methyl group at the conjugated polyene terminus enhanced anti-T-ALL activity, (2) analogs with a 3-chloropyrrole moiety had even higher selectivity for T-ALL cells, and (3) some analogs were effective against AML-derived cells. Among the studied compounds, 3-chloro-2-(8-ethoxycarbonylnona-1,3,5,7-tetraenyl) pyrrole 4e was the most promising candidate of T-ALL- and AML-treating drug. This study provides useful structural information for designing novel drugs treating T-ALL and AML.

Keywords: AML; Auxarconjugatin B; Polyenylpyrrole; Rumbrin; T-ALL.