Generation of halogenated angucyclinones with cytotoxicity activities against human cancer cell lines based on biosynthesis and chemical conversion

Halogen substituents play a crucial role in the structural diversity and biological activity of natural products, and the synthesis of halogenated molecules remains an area of significant research interest. This study describes the generation of 15 new halogenated angucyclinones through the incorporation of halogen-containing phenylamines into a biosynthetic C-ring-cleaved angucyclinone under mild conditions. The newly synthesized compounds feature halogen substituents encompassing all four halogen atoms (F, Cl, Br, I), with some compounds containing multiple halogen types. Structural elucidation was accomplished through ultraviolet (UV), infrared spectroscopy (IR), mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopic analyses, expanding the structural diversity of angucyclinone-type polyketides. Cytotoxicity evaluations revealed that eight compounds demonstrated moderate cytotoxic activities against four human tumor cell lines, with half maximal inhibitory concentration (IC₅₀) values ranging from 3.35 ± 0.37 to 16.02 ± 6.60 μmol·L⁻¹. These findings highlight the significant potential of combining biosynthetic and chemical approaches in generating bioactive halogenated molecules.