1. Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43.
- Author
-
Liu X, Biswas S, Berg MG, Antapli CM, Xie F, Wang Q, Tang MC, Tang GL, Zhang L, Dreyfuss G, and Cheng YQ
- Subjects
- Antineoplastic Agents chemistry, Drug Screening Assays, Antitumor, Genomics, Humans, Multigene Family, Pseudomonas chemistry, Pyrans chemistry, RNA Precursors drug effects, Spiro Compounds chemistry, Spiro Compounds isolation & purification, Structure-Activity Relationship, Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Burkholderia chemistry, Pyrans isolation & purification, Pyrans pharmacology
- Abstract
Mining the genome sequence of Burkholderia thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster resembling that of FR901464 (4), a prototype spliceosome inhibitor produced by Pseudomonas sp. 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. thailandensis MSMB43. Thailanstatins are proposed to be biosynthesized by a hybrid polyketide synthase-nonribosomal peptide synthetase pathway. They differ from 4 by lacking an unstable hydroxyl group and by having an extra carboxyl moiety; those differences endow thailanstatins with a significantly greater stability than 4 as tested in phosphate buffer at pH 7.4. In vitro assays 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
- 2013
- Full Text
- View/download PDF