Thailanstatin B

Thailanstatin B

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Category New Products
Catalog number BBF-05705
CAS 1426953-23-2
Molecular Weight 572.1
Molecular Formula C28H42ClNO9

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Description

Thailanstatin B is a pre-mRNA splicing inhibitor. Thailanstatin B is used as a cytotoxin for ADCs.

Specification

Synonyms EX-A5053
IUPAC Name 2-[(2S,4S,5R,6R)-6-[(1E,3E)-5-[(2S,3S,5R,6R)-5-[[(Z,4S)-4-acetyloxypent-2-enoyl]amino]-3,6-dimethyloxan-2-yl]-3-methylpenta-1,3-dienyl]-4-(chloromethyl)-4,5-dihydroxyoxan-2-yl]acetic acid
Canonical SMILES CC1CC(C(OC1CC=C(C)C=CC2C(C(CC(O2)CC(=O)O)(CCl)O)O)C)NC(=O)C=CC(C)OC(=O)C
InChI InChI=1S/C28H42ClNO9/c1-16(7-10-24-27(35)28(36,15-29)14-21(39-24)13-26(33)34)6-9-23-17(2)12-22(19(4)38-23)30-25(32)11-8-18(3)37-20(5)31/h6-8,10-11,17-19,21-24,27,35-36H,9,12-15H2,1-5H3,(H,30,32)(H,33,34)/b10-7+,11-8-,16-6+/t17-,18-,19+,21+,22+,23-,24+,27+,28+/m0/s1
InChI Key GAXKYFBEYVVCBB-FUDLAKRJSA-N

Reference Reading

1. Total Syntheses of Thailanstatins A-C, Spliceostatin D, and Analogues Thereof. Stereodivergent Synthesis of Tetrasubstituted Dihydro- and Tetrahydropyrans and Design, Synthesis, Biological Evaluation, and Discovery of Potent Antitumor Agents
K C Nicolaou, Derek Rhoades, S Mothish Kumar J Am Chem Soc. 2018 Jul 5;140(26):8303-8320. doi: 10.1021/jacs.8b04634. Epub 2018 Jun 26.
Efficient and selective total syntheses of spliceosome modulating natural products thailanstatins A-C and spliceostatin D are reported. A number of stereoselective methods for the construction of various tetrasubstituted dihydro- and tetrahydropyrans were developed as a prerequisite for the syntheses of these naturally occurring molecules and variations thereof. The pyran-forming reactions utilize a Heck/Saegusa-Ito cascade sequence to generate hydroxy α,β,γ,δ-unsaturated aldehyde precursors followed by a catalyst-controlled oxa-Michael cyclization to furnish tetrasubstituted dihydropyrans with high stereocontrol. Subsequent optimized homogeneous or heterogeneous hydrogenations of these dihydropyran systems afford their tetrahydropyran counterparts, also in a highly stereoselective manner. The synthesized thailanstatins and related analogues were biologically evaluated for their cytotoxic properties, leading to the identification of a number of compounds with exceptionally potent antitumor activities suitable for further development as potential antibody-drug conjugate payloads, single drugs, or drug combinations for cancer therapies. Important structure-activity relationships within the thailanstatin family and structurally related compounds are discussed and are expected to be path-pointing for future studies.
2. Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43
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 J Nat Prod. 2013 Apr 26;76(4):685-93. doi: 10.1021/np300913h. Epub 2013 Mar 21.
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.
3. Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma
Ankur Jain, Xiangyang Liu, Robert J Wordinger, Thomas Yorio, Yi-Qiang Cheng, Abbot F Clark Invest Ophthalmol Vis Sci. 2013 May 3;54(5):3137-42. doi: 10.1167/iovs.12-11480.
Purpose: Elevated intraocular pressure (IOP) is a major risk factor in glaucoma. Various changes in the trabecular meshwork (TM) are responsible for elevated IOP. Glucocorticoids (GCs) increase IOP and mediate biochemical changes in the TM, similar to those associated with primary open-angle glaucoma (POAG). There are differences in steroid responsiveness among the population. Approximately 40% of individuals significantly elevate IOP (i.e., responders) upon GC administration, while others do not (i.e., nonresponders). The responders are at higher risk of developing POAG compared to the nonresponders. In addition, almost all POAG patients are steroid responders. GC responsiveness is regulated by the relative levels of the active GC receptor alpha (GRα) and the alternatively spliced dominant negative regulator isoform GRβ. Glaucomatous TM cell strains have a lower GRβ-GRα ratio compared to normal TM cells, making them more sensitive to GCs. Our purpose was to investigate the role of a special class of natural products called thailanstatins (TSTs) in GR alternative splicing and GC response in cultured human TM cells. Methods: Quantitative RT-PCR and Western immunoblotting were used to study the effect of TSTs on GRβ-GRα ratios in human TM cell strains. Effects of TSTs on dexamethasone (DEX) responsiveness were assessed by GRE-luciferase reporter activity assay and fibronectin (FN) induction in TM cells. Results: TSTs increased the GRβ-GRα ratio in TM cells. Increased GRβ-GRα ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity. Conclusions: TSTs modulate the GR splicing process to enhance GRβ levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.

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