Discovery of Tröger's base analogues as selective inhibitors against human breast cancer cell line: Design, synthesis and cytotoxic evaluation

•Synthesis of Tröger's base analogues for cytotoxicity on cancer cell lines.•Functionalization of aromatic core and methylene bridge.•Selective cytotoxicity against MDAMB-231 compared to A549 and SK-N-SH cell lines.•Achieved better activity than doxorubicin in the second phase.

A library of structurally diverse Tröger's base analogues has been constructed via unusual amination of methylene bridge employing Vilsmeier–Haack conditions as well as by the incorporation of five and six membered heterocycles on the aromatic core of Tröger's base framework. The constructed structurally diverse frameworks were evaluated for their cytotoxic activities against a panel of three human cancer lines A549 (lung adenocarcinoma), MDAMB-231 (breast) and SK-N-SH (neuroblastoma). From the activity profile obtained, a redesign of Tröger's base analogues led to the construction of more potent molecular entities. The study led to development of a series of compounds with MDAMB-231 cell line specific cytotoxicity. Of the 30 compounds synthesized and evaluated, 7 compounds were found to possess cytotoxicity that is equivalent or better than standard drug doxorubicin against MDAMB-231 cell line while only one compound was found to be active against SK-N-SH cell line.

Graphical abstractDesign and synthesis of methylene bridge and aromatic core substituted Tröger's base analogues were made. Better cytotoxic activity compared to doxorubicin was observed against breast cancer MDAMB-231 cell line.Figure optionsDownload full-size imageDownload as PowerPoint slide