GEX1Q1
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| Category | Antibiotics |
| Catalog number | BBF-03583 |
| CAS | |
| Molecular Weight | 454.60 |
| Molecular Formula | C25H42O7 |
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Description
It is originally isolated from Streptomyces sp. GEX1. GEX1Q1 has no antibacterial activity but has cytotoxicity to some cancer cells.
Specification
| IUPAC Name | 2-[(2R,5S,6S)-4-hydroxy-6-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R,4R)-4-hydroxy-3-methoxypentan-2-yl]-2-methyloxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-5-methyloxan-2-yl]acetic acid |
| Canonical SMILES | CC1C(CC(OC1C(=CC=CC(C)CC2(C(O2)C(C)C(C(C)O)OC)C)C)CC(=O)O)O |
| InChI | InChI=1S/C25H42O7/c1-14(13-25(6)24(32-25)17(4)23(30-7)18(5)26)9-8-10-15(2)22-16(3)20(27)11-19(31-22)12-21(28)29/h8-10,14,16-20,22-24,26-27H,11-13H2,1-7H3,(H,28,29)/b9-8+,15-10+/t14-,16+,17-,18-,19-,20?,22-,23-,24-,25-/m1/s1 |
| InChI Key | HMVDRJCEIAATNJ-ZNLFPWLXSA-N |
Properties
| Appearance | Colorless Oily Matter |
| Antibiotic Activity Spectrum | neoplastics (Tumor) |
| Boiling Point | 609.1±55.0°C at 760 mmHg |
| Density | 1.1±0.1 g/cm3 |
Reference Reading
1. Molecular mechanisms by which splice modulator GEX1A inhibits leukaemia development and progression
Mark Sellin, Ryan Mack, Matthew C Rhodes, Lei Zhang, Stephanie Berg, Kanak Joshi, Shanhui Liu, Wei Wei, Peter Breslin S J, Peter Larsen, Richard E Taylor, Jiwang Zhang Br J Cancer. 2022 Jul;127(2):223-236. doi: 10.1038/s41416-022-01796-5. Epub 2022 Apr 14.
Introduction: Splice modulators have been assessed clinically in treating haematologic malignancies exhibiting splice factor mutations and acute myeloid leukaemia. However, the mechanisms by which such modulators repress leukaemia remain to be elucidated. Objectives: The primary goal of this assessment was to assess the molecular mechanism by which the natural splice modulator GEX1A kills leukaemic cells in vitro and within in vivo mouse models. Methods: Using human leukaemic cell lines, we assessed the overall sensitivity these cells have to GEX1A via EC50 analysis. We subsequently analysed its effects using in vivo xenograft mouse models and examined whether cell sensitivities were correlated to genetic characteristics or protein expression levels. We also utilised RT-PCR and RNAseq analyses to determine splice change and RNA expression level differences between sensitive and resistant leukaemic cell lines. Results: We found that, in vitro, GEX1A induced an MCL-1 isoform shift to pro-apoptotic MCL-1S in all leukaemic cell types, though sensitivity to GEX1A-induced apoptosis was negatively associated with BCL-xL expression. In BCL-2-expressing leukaemic cells, GEX1A induced BCL-2-dependent apoptosis by converting pro-survival BCL-2 into a cell killer. Thus, GEX1A + selective BCL-xL inhibition induced synergism in killing leukaemic cells, while GEX1A + BCL-2 inhibition showed antagonism in BCL-2-expressing leukaemic cells. In addition, GEX1A sensitised FLT3-ITD+ leukaemic cells to apoptosis by inducing aberrant splicing and repressing the expression of FLT3-ITD. Consistently, in in vivo xenografts, GEX1A killed the bulk of leukaemic cells via apoptosis when combined with BCL-xL inhibition. Furthermore, GEX1A repressed leukaemia development by targeting leukaemia stem cells through inhibiting FASTK mitochondrial isoform expression across sensitive and non-sensitive leukaemia types. Conclusion: Our study suggests that GEX1A is a potent anti-leukaemic agent in combination with BCL-xL inhibitors, which targets leukaemic blasts and leukaemia stem cells through distinct mechanisms.
2. Total synthesis of (+)-herboxidiene/GEX 1A
Alejandro Gómez-Palomino, Miquel Pellicena, Katrina Krämer, Pedro Romea, Fèlix Urpí, Gabriel Aullón, José M Padrón Org Biomol Chem. 2017 Feb 22;15(8):1842-1862. doi: 10.1039/c7ob00072c.
A total synthesis of (+)-herboxidiene/GEX 1A has been accomplished from (R)- and (S)-lactate esters in a highly efficient manner. Key steps of the synthesis involve substrate-controlled titanium-mediated aldol reactions from chiral lactate-derived ethyl ketones, an oxa-Michael cyclization, an Ireland-Claisen rearrangement, and a Suzuki coupling. Furthermore, computational studies of the oxa-Michael reaction have unveiled the dramatic influence of intramolecular hydrogen bonds on the stereochemical outcome of such cyclizations, whereas biological analyses have clearly proved the important cytoxicity of (+)-herboxidiene/GEX 1A.
3. Chemical Inhibition of Pre-mRNA Splicing in Living Saccharomyces cerevisiae
Sarah R Hansen, Brandon J Nikolai, Peyton J Spreacker, Tucker J Carrocci, Aaron A Hoskins Cell Chem Biol. 2019 Mar 21;26(3):443-448.e3. doi: 10.1016/j.chembiol.2018.11.008. Epub 2019 Jan 10.
The spliceosome mediates precursor mRNA splicing in eukaryotes, including the model organism Saccharomyces cerevisiae (yeast). Despite decades of study, no chemical inhibitors of yeast splicing in vivo are available. We have developed a system to efficiently inhibit splicing and block proliferation in living yeast cells using compounds that target the human spliceosome protein SF3B1. Potent inhibition is observed in yeast expressing a chimeric protein containing portions of human SF3B1. However, only a single point mutation in the yeast homolog of SF3B1 is needed for selective inhibition of splicing by pladienolide B, herboxidiene, or meayamycin in liquid culture. Mutations that enable inhibition also improve splicing of branch sites containing mismatches between the intron and small nuclear RNA-suggesting a link between inhibitor sensitivity and usage of weak branch sites in humans. This approach provides powerful new tools for manipulating splicing in live yeast and studies of spliceosome inhibitors.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
