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Updated: Jul 13, 2025

Author Spotlight: Discovering New Alkaloids in Plants with Advanced Mass Spectrometry Techniques
Published on: March 8, 2024
Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space
Jianing Xie1, Axel Pahl1,2, Adrian Krzyzanowski1,3
1Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
Abstract:
Monoterpene indole alkaloids (MIAs) are endowed with high structural and spatial complexity and characterized by diverse biological activities. Given this complexity-activity combination in MIAs, rapid and efficient access to chemical matter related to and with complexity similar to these alkaloids would be highly desirable, since such compound classes might display novel bioactivity. We describe the design and synthesis of a pseudo-natural product (pseudo-NP) collection obtained by the unprecedented combination of MIA fragments through complexity-generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatic analyses revealed that both the pseudo-NPs and the MIAs reside in a unique and common area of chemical space with high spatial complexity-density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo-NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo-NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with.
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