Hymeglusin
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| Category | Antibiotics |
| Catalog number | BBF-03480 |
| CAS | 29066-42-0 |
| Molecular Weight | 324.41 |
| Molecular Formula | C18H28O5 |
| Purity | ≥95% |
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Description
It is a β-lactone antibiotic produced by the strain of Cephalosporium sp. It has a strong inhibitory effect on hydroxymethyl glutaryl coenzyme A (HMG-CoA) synthase.
Specification
| Synonyms | Antibiotic 1233A; 1233A; Antibiotic F 244; (R,R)-Hymeglusin; 2,4-Undecadienoic acid, 11-(3-(hydroxymethyl)-4-oxo-2-oxetanyl)-3,5,7-trimethyl-, (2R-(2-alpha(2E,4E,7R*),3-beta))-; Antibiotic L 659699 |
| Storage | Store at-20°C |
| IUPAC Name | (2E,4E,7R)-11-[(2R,3R)-3-(hydroxymethyl)-4-oxooxetan-2-yl]-3,5,7-trimethylundeca-2,4-dienoic acid |
| Canonical SMILES | CC(CCCCC1C(C(=O)O1)CO)CC(=CC(=CC(=O)O)C)C |
| InChI | InChI=1S/C18H28O5/c1-12(8-13(2)9-14(3)10-17(20)21)6-4-5-7-16-15(11-19)18(22)23-16/h9-10,12,15-16,19H,4-8,11H2,1-3H3,(H,20,21)/b13-9+,14-10+/t12-,15-,16-/m1/s1 |
| InChI Key | ODCZJZWSXPVLAW-KXCGKLMDSA-N |
Properties
| Appearance | Crystalline Solid |
| Boiling Point | 516.6°C at 760 mmHg |
| Melting Point | 76-77°C |
| Density | 1.101 g/cm3 |
| Solubility | Soluble in DMSO, Chloroform, Methanol |
Reference Reading
1. Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia
Liang Zhao, Zhiqin Wang, Huan Li, Shuanghui Yang, Cheng Zhou Front Oncol . 2022 Jun 29;12:864430. doi: 10.3389/fonc.2022.864430.
Venetoclax is used for the priority treatment of elderly patients with acute myeloid leukemia (AML). Resistance or intolerance to venetoclax offsets its clinical benefits in some patients. Combination strategies with other drugs are promising alternatives to overcome the current complications associated with venetoclax use. Hymeglusin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), regulates the mevalonate pathway, which is vital for AML growth and chemosensitivity. The effects of the combination of venetoclax and hymeglusin on AML were explored in this study. The correlations between HMGCS1 and apoptosis-related genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 and The Cancer Genome Atlas databases. Apoptosis and cell viability were detected in HL-60 and KG-1 cells after treatment with gradient concentrations of venetoclax or hymeglusin. The transcriptomic profiles of HL-60 and KG-1 cells were comparedviaRNA-Seq analysis. The effects of venetoclax and hymeglusin on apoptosis were validated in primary cells. The results showed that HMGCS1 expression was closely associated with apoptosis-related genes based on the data from large clinical databases. B cell lymphoma (BCL)-2 expression was elevated in AML and negatively associated with overall survival. Hymeglusin decreased BCL2 expression levels in HL-60 and KG-1 cells. Venetoclax and hymeglusin inhibited cell viability in both cell lines, but induced apoptosis in HL-60 cells. This discrepancy in sensitivity to hymeglusin may be attributed to the positive increase in the expression levels of HMGCS1 and multiple upregulated pro-leukemia genes in KG-1 cells. Combination treatment with venetoclax and hymeglusin significantly increased the apoptotic rates compared to single-agent treatment in both AML cell lines and primary AML cells. Furthermore, the combination strategy did not result in remarkably enhanced toxicity in normal mononuclear cells. Collectively, hymeglusin enhanced the effects of venetoclax on apoptosis. This combination strategy showed enhanced antileukemic activity with acceptable toxicity in AML.
2. HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis
Xuejun Xu, Hui Zeng, Xinya Jiang, Jue Li, Qun He, Peng Fang, Huien Zhan, Cheng Zhou, Juan Du, Yi Liu, Hui Liang Biomed Pharmacother . 2021 May;137:111378. doi: 10.1016/j.biopha.2021.111378.
Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.
3. Opportunities and Limitations for Assigning Relative Configurations of Antibacterial Bislactones using GIAO NMR Shift Calculations
Joseph O Falkinham Iii, Christopher D Roberts, Nicholas H Oberlies, Laura Flores-Bocanegra, Huzefa A Raja, Sonja L Knowles, Kimberly N Heath-Borrero, Joanna E Burdette, Mario Augustinović, Cedric J Pearce J Nat Prod . 2021 Apr 23;84(4):1254-1260. doi: 10.1021/acs.jnatprod.0c01309.
Four new bislactones, dihydroacremonol (1), clonostachyone (2), acremodiol B (3), and acremodiol C (4), along with one known compound, hymeglusin (5), were isolated from cultures of two fungal strains (MSX59876 and MSX59260). Both strains were identified based on phylogenetic analysis of molecular data asClonostachysspp.; yet, they biosynthesized a suite of related, but different, secondary metabolites. Given the challenges associated with elucidating the structures and configurations of bislactones, GIAO NMR calculations were tested as a complement to traditional NMR and HRESIMS experiments. Fortuitously, the enantiomer of the new natural product (4) was known as a synthetic compound, and the predicted configuration from GIAO NMR calculations (i.e., for the relative configuration) and optical rotation calculations (i.e., for the absolute configuration) matched those of the synthesis product. These results engendered confidence in using similar procedures, particularly the mixture of GIAO NMR shift calculations coupled with an orthogonal technique, to predict the configuration of1-3; however, there were important limitations, which are discussed for each of these. The metabolites displayed antimicrobial activities, with compounds1and4being the most potent againstStaphylococcus aureuswith MICs of 1 and 4 μg/mL, respectively.
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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
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Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
