title: Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43.
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.
authors.affiliation: Department of Biological Sciences and Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Liu
authors.forename: Sreya
authors.initials: S
authors.lastname: Biswas
authors.forename: Michael G
authors.initials: MG
authors.lastname: Berg
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Antapli
authors.forename: Feng
authors.initials: F
authors.lastname: Xie
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Man-Cheng
authors.initials: MC
authors.lastname: Tang
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Tang
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gideon
authors.initials: G
authors.lastname: Dreyfuss
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019117:Burkholderia / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D023281:Genomics; D006801:Humans; D005810:Multigene Family; D011549:Pseudomonas / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012322:RNA Precursors / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C104486:FR 901464; D011714:Pyrans; D012322:RNA Precursors; D013141:Spiro Compounds; C582010:thailanstatin A; C582011:thailanstatin B; C582012:thailanstatin C