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Thailanstatin A - CAS 1426953-21-0 Catalog number: BADC-00707
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Thailanstatin A is a splicesosome inhibitor that acts via suppressing RNA-polymerase II. It is effective against cancers, and can be used as a payload for ADCs.
Category
ADCs Cytotoxin
Product Name
Thailanstatin A
CAS
1426953-21-0
Catalog Number
BADC-00707
Molecular Formula
C28H41NO9
Molecular Weight
535.63
Ordering Information
| Catalog Number | Size | Price | Quantity |
|---|---|---|---|
| BADC-00707 | 5 mg | $299 | |
| BADC-00707 | 10 mg | $629 |
Description
Thailanstatin A is a splicesosome inhibitor that acts via suppressing RNA-polymerase II. It is effective against cancers, and can be used as a payload for ADCs.
Synonyms
1,6-Dioxaspiro[2.5]octane-5-acetic acid, 7-[(1E,3E)-5-[(2S,3S,5R,6R)-5-[[(2Z,4S)-4-(acetyloxy)-1-oxo-2-penten-1-yl]amino]tetrahydro-3,6-dimethyl-2H-pyran-2-yl]-3-methyl-1,3-pentadien-1-yl]-8-hydroxy-, (3R,5S,7R,8R)-
IUPAC Name
2-[(3R,4R,5R,7S)-5-[(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-hydroxy-1,6-dioxaspiro[2.5]octan-7-yl]acetic acid
Canonical SMILES
CC1CC(C(OC1CC=C(C)C=CC2C(C3(CC(O2)CC(=O)O)CO3)O)C)NC(=O)C=CC(C)OC(=O)C
InChI
InChI=1S/C28H41NO9/c1-16(7-10-24-27(34)28(15-35-28)14-21(38-24)13-26(32)33)6-9-23-17(2)12-22(19(4)37-23)29-25(31)11-8-18(3)36-20(5)30/h6-8,10-11,17-19,21-24,27,34H,9,12-15H2,1-5H3,(H,29,31)(H,32,33)/b10-7+,11-8-,16-6+/t17-,18-,19+,21+,22+,23-,24+,27+,28+/m0/s1
InChIKey
GJKQDOMCDFJANR-FUDLAKRJSA-N
Density
1.2±0.1 g/cm3
Solubility
Soluble in DMSO
In Vitro
Thailanstatin A (DU-145, NCI-H232A, MDA-MB-231 and SKOV-3 cells) exhibits potent antiproliferative activities with GI50s in the single nM range (1.11-2.69 nM).
Appearance
Solid
Purity
95%
Shipping
-20°C (International: -20°C)
Storage
Store at -20°C
Boiling Point
757.3±60.0°C at 760 mmHg
1. Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs
Monette Aujay, Stefan Munneke, Santhosh Reddy Rekula, Christine Gu, K C Nicolaou, Paul M Jung, Joseph Lyssikatos, Hetal Sarvaiya, Regina M Reilly, Joseph Sandoval, S Mothish Kumar, James W Purcell, Lloyd T Lam, Julia Gavrilyuk, Andrew C Phillips, Ananda Rao Podilapu, Mikhail Hammond, Ryan P Matuszak J Org Chem . 2021 Feb 5;86(3):2499-2521. doi: 10.1021/acs.joc.0c02643.
Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.
2. Biosynthetic engineering and fermentation media development leads to gram-scale production of spliceostatin natural products in Burkholderia sp
Li-Ping Chang, Greg L Steele, Christopher J O Donnell, Alessandra S Eustáquio, Frank E Koehn Metab Eng . 2016 Jan;33:67-75. doi: 10.1016/j.ymben.2015.11.003.
A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/α-ketoglutarate-dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an l-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40-fold, going from the starting ~60 mg/L to 2.5 g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy.
3. Total Synthesis of Thailanstatin A
K C Nicolaou, Manas R Pattanayak, S Mothish Kumar, Derek Rhoades, Manjunath Lamani J Am Chem Soc . 2016 Jun 22;138(24):7532-5. doi: 10.1021/jacs.6b04781.
The total synthesis of the spliceosome inhibitor thailanstatin A has been achieved in a longest linear sequence of nine steps from readily available starting materials. A key feature of the developed synthetic strategy is the implementation of a unique, biomimetic asymmetric intramolecular oxa-Michael reaction/hydrogenation sequence that allows diastereodivergent access to highly functionalized tetrahydropyrans, which can be used for the synthesis of designed analogues of this bioactive molecule.
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