11-Azaartemisinin derivatives bearing halogenated aromatic moieties: Potent anticancer agents with high tumor selectivity

• Published in: Bioorganic & medicinal chemistry letters 2024-11, Vol.113, p.129969, Article 129969
• Main Authors: Nguyen, Dung Tien, Ngo, Thuong Hanh, Tran, Mai Thanh, Nguyen, Hao Thi Thanh, Ho, Hien Thanh, Nguyen, Dat Van, Nguyen, Tinh Thi, Ly, Khang Duc, Nguyen, Thao Thi, Vuong, Tam Thi, Tran, Hung-Vu
• Format: Article
• Language: English
• Subjects: 11-Azaartemisinin; Anticancer activity; Artemisinin; Click reaction; Halogenated aromatic; Structure–activity relationships; Tumor selectivity
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129969

[Display omitted] •New 11-azaartemisinin derivatives bearing halogenated aromatic moieties linked via 1,2,3‐triazole bridges were synthesized.•Six of them (8c-h) displayed good to excellent anticancer activity against KB, HepG2, and A549 human cancer cell lines.•The m-Br (8c) and m-I (8d) compounds showed superior anticancer activity compared to their o-, p-, m-Cl, and m-F analogs.•The most active m-Br compound 8c showed IC50 values of 7.7, 42.5, and 15.5 μM for KB, HepG2, and A549 cells, respectively.•The most active compound 8c showed significant tumor selectivity, up to 32-fold higher compared to Hek293 normal cells. While artemisinin and its derivatives, including 11-azaartemisinin-based compounds, have shown promising anticancer activity, the integration of halogens into aromatic structures can amplify drug potency, metabolic stability, and selectivity. Herein, we present the synthesis of new novel 11-azaartemisinin derivatives bearing halogenated aromatic moieties connected via 1,2,3‐triazole bridges and evaluate their anticancer activities against three human tumor cell lines: epidermoid carcinoma (KB), hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). Among the synthesized compounds, six of them (8c-h) displayed good to excellent antiproliferative activity in the low micromolar range across all three human cancer cell lines. In general, the m-bromide (8c) and m-iodide (8d) compounds exhibited superior anticancer activities compared to their o- and p-analogs, as well as the m-chloride and m-fluoride compounds. The most promising m-Br compound (8c) displayed 50 % inhibition of KB, HepG2, and A549 cell growth at concentrations of 7.7, 42.5, and 15.5 μM, respectively. Notably, the m-Br compound (8c) exhibited approximately 32-, 6-, and 16-fold lower activity in normal cells (Hek293) compared to KB, HepG2, and A549 tumor cells, respectively, indicating a significant tumor-selectivity.