1. Genomics-Guided Discovery of Thailanstatins A, B, and C As Pre-mRNA Splicing Inhibitors and Antiproliferative Agents from Burkholderia thailandensisMSMB43
- Author
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Liu, Xiangyang, Biswas, Sreya, Berg, Michael G., Antapli, Christopher M., Xie, Feng, Wang, Qi, Tang, Man-Cheng, Tang, Gong-Li, Zhang, Lixin, Dreyfuss, Gideon, and Cheng, Yi-Qiang
- 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.
- Published
- 2024
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