Re-engineering and synthesis of cytotoxic 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride

Abstract

A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8-tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH₄. All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced.

Graphical Abstract

Keywords:

• Aryl alkylenedioxy synthons
• benzo[c]phenanthridiniums
• quaternary sanguinarine analogs
• synthetic method
• growth inhibitory activity
• cancer cell lines

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by grant from CAMS Initiation Fund for Innovative Medicine [grant number 2016-I2M-1-010].