Chemistry:Pneumocandin B0
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| IUPAC name
N-{(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1S)-3-Amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1S)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2',1'-l] [1,4,7,10,13,16]hexaazacyclohenicosin-9-yl}-10,12-dimethyltetradecanamide
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| Other names
CHEMBL269311; 135575-42-7; Pneumocandin B0; Hydroxy Echinocandin; SCHEMBL8444763
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3D model (JSmol)
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PubChem CID
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| Properties | |
| C50H80N8O17 | |
| Molar mass | 1065.229 g·mol−1 |
| Appearance | White crystalline powder |
| Density | 1.411 g.cm−3 |
| Soluble in ethanol, methanol, DMF or DMSO. Limited water solubility. | |
Refractive index (nD)
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1.629 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
| Infobox references | |
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Pneumocandin B0, also known as pneumocandin B0, pneumocandin B(0), and hydroxy echinocandin, is an organic chemical compound with the formula C50H80N8O17,[1] produced by the fungus Glarea lozoyensis.
It is a strong antifungal and inhibits the synthesis of β-(1→3)-D-glucan, which is a fundamental component in most cell walls, like the Candida albicans membrane. This is a very important activity since there is an increase in the frequency of fungal infections, accompanied by an increase in the variety of opportunistic and pathogenic fungi such as Candida.
This compound is used to synthesize caspofungin.[2]
Pneumocandin B0 can be easily confused with pneumocandin B, although they have different side chains and residues.
Production
Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate.[citation needed]
In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization.[citation needed]
The pneumocandin biosynthetic gene cluster was previously elucidated by a whole genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to exclusively produce pneumocandin B0.[citation needed]
Disruption of GLOXY4, encoding a nonheme, α-ketoglutarate-dependent oxygenase, confirmed its involvement in L-leucine cyclization to form (4S)-methyl-L-proline. The absence of (4S)-methyl-L-proline abolishes pneumocandin A0 production, and (3S)-hydroxyl-L-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0.[citation needed]
Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4.[citation needed]
This one-step genetic manipulation can rationally engineer a high-yield production strain.[3]
Special features
The echinocandins and pneumocandins are lipopeptides antifungal agents that inhibit the synthesis of β-(1→3)-D-glucan, an essential cell wall homopolysaccharide found in many pathogenic fungi.[citation needed]
Compounds with this fungal-specific target have several attractive features:
- Lack of mechanism-based toxicity
- Potential for fungicidal activity
- Activity against strains with intrinsic or acquired resistance mechanisms for existing antimycotics.[4]
Caspofungin
Caspofungin, a semisynthetic derivate of the pneumocandin B0, is the first licensed compound of a new class of antifungal agent, that are called the echinocandins. This antifungal agent attacks the fungal cell by selective inhibition of β-(1→3)-D-glucan synthase, which is not present in mammalian cells. Caspofungin represents an interesting and clinically valuable new antifungal drug that broadens the available therapeutic armamentarium for the treatment of invasive fungal infections. [5]
Semisynthetic derivatives
The antipneumocystis activities of the pneumocandins can be significantly improved through synthetic modification.
There are new semisynthetic pneumocandin B0 derivatives that have been found:
- By the addition of an aminoethyl ether at the R3 position of pneumocandin B0 resulted water-soluble and nonprodrug compounds, substantially more efficacious
- By the modification of pneumocandin B0 at the R2 position by the conversion of the hydroxyglutamine to a hydroxyornithine increases the antipneumocystis activities of the compounds by 4-fold.
These two modifications combined were synergistic, resulting in a 10-fold improvement in potency against Pneumocystis jirovecii (formerly known as Pneumocystis carinii) pneumonia.[6]
References
- ↑ "Pneumocandin Bo". Pubchem Open Chemistry Database. https://pubchem.ncbi.nlm.nih.gov/compound/5742645. Retrieved 17 October 2015.
- ↑ Bouffard, FA; Zambias, RA; Dropinski, JF; Balkovec, JM; Hammond, ML; Abruzzo, GK; Bartizal, KF; Marrinan, JA et al. (21 January 1994). "Synthesis and Antifungal Activity of Novel Cationic Pneumocandin Bo Derivatives". Journal of Medicinal Chemistry 37 (2): 222–5. doi:10.1021/jm00028a003. PMID 8295208.
- ↑ Chen, Li; Yue, Qun; Li, Yan; Niu, Xuemei; Xiang, Meichun; Wang, Wenzhao; Bills, Gerald F.; Liu, Xingzhong et al. (2015-03-01). "Engineering of Glarea lozoyensis for Exclusive Production of the Pneumocandin B0 Precursor of the Antifungal Drug Caspofungin Acetate" (in en). Applied and Environmental Microbiology 81 (5): 1550–1558. doi:10.1128/AEM.03256-14. ISSN 0099-2240. PMID 25527531. Bibcode: 2015ApEnM..81.1550C.
- ↑ Kurtz, M. B.; Douglas, C. M. (1997-01-01). "Lipopeptide inhibitors of fungal glucan synthase". Journal of Medical and Veterinary Mycology 35 (2): 79–86. doi:10.1080/02681219780000961. ISSN 0268-1218. PMID 9147267.
- ↑ Maschmeyer, Georg; Glasmacher, Axel (2005-07-01). "Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofungin" (in en). Mycoses 48 (4): 227–234. doi:10.1111/j.1439-0507.2005.01131.x. ISSN 1439-0507. PMID 15982202.
- ↑ Schmatz, DM; Powles, MA; McFadden, D; Nollstadt, K; Bouffard, FA; Dropinski, JF; Liberator, P; Andersen, J (1995). "New Semisynthetic Pneumocandins with Improved Efficacies against Pneumocystis carinii in the Rat". Antimicrob Agents Chemother 39 (6): 1320–3. doi:10.1128/aac.39.6.1320. PMID 7574523.
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