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Genomics-Guided Discovery of Thailanstatins A, B, and C As Pre-mRNA Splicing Inhibitors and Antiproliferative Agents from Burkholderia thailandensisMSMB43
- Source :
- Journal of Natural Products; 20240101, Issue: Preprints
- Publication Year :
- 2024
-
Abstract
- Mining the genome sequence of Burkholderia thailandensisMSMB43 revealed a cryptic biosynthetic gene cluster resembling that of FR901464 (4), a prototype spliceosome inhibitor produced by Pseudomonassp. No. 2663. Transcriptional analysis revealed a cultivation condition in which a regulatory gene of the cryptic gene cluster is adequately expressed. Consequently, three new compounds, named thailanstatins A (1), B (2), and C (3), were isolated from the fermentation broth of B. thailandensisMSMB43. Thailanstatins are proposed to be biosynthesized by a hybrid polyketide synthase–nonribosomal peptide synthetase pathway. They differ from 4by lacking an unstable hydroxyl group and by having an extra carboxyl moiety; those differences endow thailanstatins with a significantly greater stability than 4as tested in phosphate buffer at pH 7.4. In vitroassays showed that thailanstatins inhibit pre-mRNA splicing as potently as 4, with half-maximal inhibitory concentrations in the single to sub-μM range. Cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range. This work provides new chemical entities for research and development and new structure–activity information for chemical optimization of related spliceosome inhibitors.
Details
- Language :
- English
- ISSN :
- 01633864 and 15206025
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Natural Products
- Publication Type :
- Periodical
- Accession number :
- ejs29979785
- Full Text :
- https://doi.org/10.1021/np300913h