Document Detail


Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43.
MedLine Citation:
PMID:  23517093     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Xiangyang Liu; Sreya Biswas; Michael G Berg; Christopher M Antapli; Feng Xie; Qi Wang; Man-Cheng Tang; Gong-Li Tang; Lixin Zhang; Gideon Dreyfuss; Yi-Qiang Cheng
Related Documents :
1904283 - Expression of c-jun during macrophage differentiation of hl-60 cells.
10918063 - Phorbol ester-induced expression of airway squamous cell differentiation marker, sprr1b...
2109683 - Gonadotropin induction of c-fos and c-myc expression and deoxyribonucleic acid synthesi...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-21
Journal Detail:
Title:  Journal of natural products     Volume:  76     ISSN:  1520-6025     ISO Abbreviation:  J. Nat. Prod.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-06-28     Completed Date:  2013-08-13     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  7906882     Medline TA:  J Nat Prod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  685-93     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  isolation & purification*,  pharmacology*
Burkholderia / chemistry*
Drug Screening Assays, Antitumor
Genomics
Humans
Multigene Family
Pseudomonas / chemistry
Pyrans / chemistry,  isolation & purification*,  pharmacology*
RNA Precursors / drug effects
Spiro Compounds / chemistry,  isolation & purification
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
R01 CA152212/CA/NCI NIH HHS; R01CA152212/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/FR 901464; 0/Pyrans; 0/RNA Precursors; 0/Spiro Compounds; 0/thailanstatin A; 0/thailanstatin B; 0/thailanstatin C
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Re: Laparoscopy in the surgical treatment of rectal cancer in Germany 2000-2009.
Next Document:  Phase Characterization, Thermal Stability, High-Temperature Transport Properties, and Electronic Str...