Natural products (NPs) and their derivatives play a pivotal role in drug discovery due to their complexity and diversity. The strategies to rapidly generate NP-like compounds offer unique opportunities to access bioactive compounds. Here we present a new approach, precursor-assisted biosynthesis (PAB), for the creation of NP-like compounds by combination of artificial supplementation of common precursors and divergent post-modifications of precursor-deficient fungi. This method was applied to construct a meroterpenoid-like compound collection containing 43 compounds with diverse molecular scaffolds. Extensive bioactive screening of the collection revealed novel STING (stimulator of interferon genes) inhibitors, cytotoxic and antifungal compounds. This result indicates that PAB is an effective methodology for producing compound collections for the purpose of drug discovery.
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Construction of a meroterpenoid-like compound collection by precursor-assisted biosynthesis.
Org Biomol Chem
August 2020
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Natural products (NPs) and their derivatives play a pivotal role in drug discovery due to their complexity and diversity. The strategies to rapidly generate NP-like compounds offer unique opportunities to access bioactive compounds. Here we present a new approach, precursor-assisted biosynthesis (PAB), for the creation of NP-like compounds by combination of artificial supplementation of common precursors and divergent post-modifications of precursor-deficient fungi.
View Article and Find Full Text PDFConstruction of a Meroterpenoid-Like Compounds Library Based on Diversity-Enhanced Extracts.
Chemistry
January 2019
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aza-Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Article Synopsis
- The paper discusses the decline in pharmaceutical research on natural products due to challenges in obtaining novel compounds.
- It presents the creation of a library of 25 diverse meroterpenoid-like compounds using a combination of natural product chemistry and diversity-oriented synthesis.
- Pharmacological screening of these compounds showed potential for new anti-osteoporotic and anti-lymphoma/leukemia drugs, highlighting the effectiveness of diversity-enhanced extracts in drug discovery.
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Natural products from marine animals show high potential for the development of new medicines, but drug development based on these compounds is commonly hampered by their low natural abundance. Since many of these metabolites are suspected or known to be produced by uncultivated bacterial symbionts, the rapidly growing diversity of sequenced prokaryotic genomes offers the opportunity to identify alternative, culturable sources of natural products computationally. In this work, we investigated the potential of using this sequenced resource to facilitate the production of meroterpenoid-like compounds related to those from marine sources.
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