Enfumafungin
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| Category | Bioactive by-products |
| Catalog number | BBF-05724 |
| CAS | 260979-95-1 |
| Molecular Weight | 708.88 |
| Molecular Formula | C38H60O12 |
| Purity | ≥98% |
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Description
Enfumafungin is a triterpene glycoside and hemiacetal isolated from a fermentation of Hormonema sp. Enfumafungin is an antifungal agent that acts on fungal cell walls as an inhibitor of (1,3)-beta-D-glucan synthase. It is specific for yeast and fungi (excluding Cryptococcus) and does not inhibit the growth of Bacillus subtilis.
Specification
| Synonyms | 4H-1,4a-Propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid, 14-(acetyloxy)-8-[(1R)-1,2-dimethylpropyl]-15-(β-D-glucopyranosyloxy)-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-4-hydroxy-1,6a,8,10a-tetramethyl-, (1S,4aR,6aS,7R,8R,10aR,10bR,12aS,14R,15R)- |
| Storage | Store at -20°C |
| IUPAC Name | (1R,5S,6R,7R,10R,11R,14S,15S,20R,21R)-20-acetyloxy-18-hydroxy-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid |
| Canonical SMILES | CC(C)C(C)C1(CCC2(C3CCC4C5(COC(C4(C3=CCC2(C1C(=O)O)C)CC(C5OC6C(C(C(C(O6)CO)O)O)O)OC(=O)C)O)C)C)C |
| InChI | InChI=1S/C38H60O12/c1-18(2)19(3)34(5)13-14-36(7)21-9-10-25-35(6)17-47-33(46)38(25,22(21)11-12-37(36,8)29(34)31(44)45)15-23(48-20(4)40)30(35)50-32-28(43)27(42)26(41)24(16-39)49-32/h11,18-19,21,23-30,32-33,39,41-43,46H,9-10,12-17H2,1-8H3,(H,44,45)/t19-,21+,23-,24-,25+,26-,27+,28-,29-,30+,32+,33?,34-,35-,36-,37+,38+/m1/s1 |
| InChI Key | IAOFPTKYKOAKGZ-CRWQHXLTSA-N |
Properties
| Antibiotic Activity Spectrum | Fungi |
| Boiling Point | 813.5±65.0°C (Predicted) |
| Density | 1.31±0.1 g/cm3 (Predicted) |
| Solubility | Soluble in DMSO |
Reference Reading
1. Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases
Qun Yue, Li Chen, Yan Li, Kenichi Yokoyama, Zhiqiang An, Eric Kuhnert, Gerald F Bills, Russell J Cox, Nan Lan Environ Microbiol . 2018 Sep;20(9):3325-3342. doi: 10.1111/1462-2920.14333.
Enfumafungin is a glycosylated fernene-type triterpenoid produced by the fungus Hormonema carpetanum. Its potent antifungal activity, mediated by its interaction with β-1,3-glucan synthase and the fungal cell wall, has led to its development into the semi-synthetic clinical candidate, ibrexafungerp (=SCY-078). We report on the preliminary identification of the enfumafungin biosynthetic gene cluster (BGC) based on genome sequencing, phylogenetic reconstruction, gene disruption, and cDNA sequencing studies. Enfumafungin synthase (efuA) consists of a terpene cyclase domain (TC) fused to a glycosyltransferase (GT) domain and thus represents a novel multifunctional enzyme. Moreover, the TC domain bears a phylogenetic relationship to bacterial squalene-hopene cyclases (SHC) and includes a typical DXDD motif within the active centre suggesting that efuA evolved from SHCs. Phylogenetic reconstruction of the GT domain indicated that this portion of the fusion gene originated from fungal sterol GTs. Eleven genes flanking efuA are putatively involved in the biosynthesis, regulation, transport and self-resistance of enfumafungin and include an acetyltransferase, three P450 monooxygenases, a dehydrogenase, a desaturase and a reductase. A hypothetical scheme for enfumafungin assembly is proposed in which the E-ring is oxidatively cleaved to yield the four-ring system of enfumafungin. EfuA represents the first member of a widespread lineage of fungal SHCs.
2. Cell Wall-Modifying Antifungal Drugs
David S Perlin Curr Top Microbiol Immunol . 2020;425:255-275. doi: 10.1007/82_2019_188.
Antifungal therapy is a critical component of patient management for invasive fungal diseases. Yet, therapeutic choices are limited as only a few drug classes are available to treat systemic disease, and some infecting strains are resistant to one or more drug classes. The ideal antifungal inhibits a fungal-specific essential target not present in human cells to avoid off-target toxicities. The fungal cell wall is an ideal drug target because its integrity is critical to cell survival and a majority of biosynthetic enzymes and wall components is unique to fungi. Among currently approved antifungal agents and those in clinical development, drugs targeting biosynthetic enzymes of the cell wall show safe and efficacious antifungal properties, which validates the cell wall as a target. The echinocandins, which inhibit β-1,3-glucan synthase, are recommended as first-line therapy for Candida infections. Newer cell wall-active drugs in clinical development encompass next-generation glucan synthase inhibitors including a novel echinocandin and an enfumafungin, an inhibitor of Gwt1, a key component of GPI anchor protein biosynthesis, and a classic inhibitor of chitin biosynthesis. As the cell wall is rich in potential drug discovery targets, it is primed to help deliver the next generation of antifungal drugs.
3. MK-5204: An orally active β-1,3-glucan synthesis inhibitor
Andrew M Galgoci, Jasminka Dragovic, Weiming Fan, George K Abruzzo, Amy M Flattery, Andrew S Misura, Shu Lee, Dongfang Meng, Jennifer Nielsen Kahn, Kingsley Nelson, Mark L Greenlee, James M Balkovec, Hao Liu, Mary Motyl, Robin Kirwan, Charles J Gill, Robert R Wilkening, Kenneth J Wildonger, Michael Peel, James M Apgar, Maryann Powles, Fred Racine, Dann L Parker Jr, Robert A Giacobbe, Ahmed Mamai, Paul Liberator, Ming-Jo Hsu, Donald Sperbeck Bioorg Med Chem Lett . 2020 Sep 1;30(17):127357. doi: 10.1016/j.bmcl.2020.127357.
Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.
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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 ╳
