Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume -, Issue -, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202310222
Keywords
Alkaloids; Chemical Evolution; Cheminformatics; Morphological Profiling; Spatial Complexity
Categories
Ask authors/readers for more resources
Monoterpene indole alkaloids (MIAs) exhibit high structural and spatial complexity, along with diverse biological activities. A pseudo-natural product (pseudo-NP) collection has been designed and synthesized by combining MIA fragments through complexity-generating transformations, occupying a unique chemical space with high spatial complexity-density similar to MIAs and showing bioactivities inhibiting DNA synthesis and tubulin modulation. These findings suggest potential novel bioactive compounds inspired by MIAs.
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. The structures of monoterpene indole alkaloid natural products have been subjected to chemical evolution to afford a collection of pseudo-natural products. The novel structural classes match the unique chemical space that is highlighted by the high spatial complexity-density of the parent natural product class and are enriched with bioactivities inhibiting DNA synthesis and tubulin polymerization.image
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available