Synthesis of raloxifene-like quinoxaline derivatives by intramolecular electrophilic cyclization with disulfides

Yuhi Umezu; Eito Horiyama; Yuto Nakai; Masayuki Ninomiya; Atsuyoshi Nishina; Mamoru Koketsu

doi:10.1016/j.bmcl.2023.129415

Synthesis of raloxifene-like quinoxaline derivatives by intramolecular electrophilic cyclization with disulfides

Bioorg Med Chem Lett. 2023 Sep 1:93:129415. doi: 10.1016/j.bmcl.2023.129415. Epub 2023 Aug 1.

Authors

Yuhi Umezu¹, Eito Horiyama¹, Yuto Nakai¹, Masayuki Ninomiya², Atsuyoshi Nishina³, Mamoru Koketsu⁴

Affiliations

¹ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
² Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
³ Department of Applied Chemistry, College of Science and Technology, Nihon University, 1-5-1 Kandasurugadai, Chiyoda, Tokyo 101-0062, Japan; School of Health and Nutrition, Tokai Gakuen University, 2-901 Nakahira, Tenpaku-ku, Nagoya, Aichi 468-8514, Japan.
⁴ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: koketsu.mamoru.e0@f.gifu-u.ac.jp.

PMID: 37532107
DOI: 10.1016/j.bmcl.2023.129415

Abstract

The intramolecular electrophilic cyclization of alkynes with disulfides to form thieno[2,3-b]quinoxaline structures and to introduce thioether substituents afforded quinoxaline derivatives (7a-7d, 8a-8d). Among obtained eight derivatives, the raloxifene analogues (7c, 8b) showed specifically high cytotoxicity against breast cancer cells (SK-BR-3), and raloxifene analogues (8a) showed the highest cytotoxicity against human leukemia cells (HL-60). None of the raloxifene analogues (7a-7d, 8a-8d) showed cytotoxicity against human lung fibroblasts (WI-38), which are normal cells.

Keywords: Disulfide; HL-60; Intramolecular electrophilic cyclization; SK-BR-3; Thieno[2,3–b]quinoxaline.

MeSH terms

Cyclization
Disulfides
Humans
Quinoxalines* / pharmacology
Raloxifene Hydrochloride* / pharmacology

Substances

Quinoxalines
Raloxifene Hydrochloride
Disulfides