3-epi-Deoxynegamycin
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| Category | Mycotoxins |
| Catalog number | BBF-01353 |
| CAS | |
| Molecular Weight | 232.28 |
| Molecular Formula | C9H20N4O3 |
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Description
3-epi-Deoxynegamycin is produced by the strain of Streptomyces goshikiensis. Its antibacterial activity against most gram-positive bacteria is half that of negative mycin, and its anti-gram-negative bacteria activity is a little weak.
Specification
| IUPAC Name | 2-[[[(3S)-3,6-diaminohexanoyl]amino]-methylamino]acetic acid |
| Canonical SMILES | CN(CC(=O)O)NC(=O)CC(CCCN)N |
| InChI | InChI=1S/C9H20N4O3/c1-13(6-9(15)16)12-8(14)5-7(11)3-2-4-10/h7H,2-6,10-11H2,1H3,(H,12,14)(H,15,16)/t7-/m0/s1 |
| InChI Key | GMDVGRCKPKMEFK-ZETCQYMHSA-N |
Properties
| Appearance | Colorless Hygroscopic Powder |
| Antibiotic Activity Spectrum | Gram-positive bacteria; Gram-negative bacteria |
| Melting Point | 93-105°C |
Reference Reading
1. Structure-Activity Relationship Studies of 3-epi-Deoxynegamycin Derivatives as Potent Readthrough Drug Candidates
Keisuke Hamada, Akihiro Taguchi, Masaya Kotake, Suguru Aita, Saori Murakami, Kentaro Takayama, Fumika Yakushiji, Yoshio Hayashi ACS Med Chem Lett. 2015 May 11;6(6):689-94. doi: 10.1021/acsmedchemlett.5b00121. eCollection 2015 Jun 11.
(+)-Negamycin (1), a natural dipeptidic antibiotic bearing a hydrazide structure, exhibits a readthrough activity toward the nonsense mutation of the dystrophin gene and restores dystrophin expression in muscles of Duchenne muscular dystrophy model mdx mice. Herein to develop more potent readthrough compounds, we performed a structure-activity relationship (SAR) study of 3-epi-deoxynegamycin (2), which is also another natural readthrough compound with little antimicrobial activity, focusing on the main carbon chain length. We found that one carbon atom shorter derivative 9b shows a higher readthrough activity than 1 and 2. Further derivatization at the carboxylic acid part of 9b demonstrates that its meta-chlorobenzyl ester derivative 17e, which has a higher ClogP value, exhibits a more potent readthrough activity than 9b. Interestingly, in the cell-free protein expression system, the readthrough activity of 17e drastically decreases compared to that in the cell-based assay. These results suggest that benzyl ester-type derivatives enhance the hydrophobicity and function as prodrugs to produce active compound 9b in living cell systems.
2. Structure-Activity Relationship Study of Leucyl-3- epi-deoxynegamycin for Potent Premature Termination Codon Readthrough
Akihiro Taguchi, Keisuke Hamada, Masataka Shiozuka, Misaki Kobayashi, Saori Murakami, Kentaro Takayama, Atsuhiko Taniguchi, Takeo Usui, Ryoichi Matsuda, Yoshio Hayashi ACS Med Chem Lett. 2017 Sep 29;8(10):1060-1065. doi: 10.1021/acsmedchemlett.7b00269. eCollection 2017 Oct 12.
(+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure-activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.
3. Chemotherapeutics overcoming nonsense mutation-associated genetic diseases: medicinal chemistry of negamycin
Akihiro Taguchi, Keisuke Hamada, Yoshio Hayashi J Antibiot (Tokyo). 2018 Feb;71(2):205-214. doi: 10.1038/ja.2017.112. Epub 2017 Sep 27.
Nonsense mutations caused by the presence of an in-frame premature termination codon (PTC) account for ~10% of gene lesions that together cause over 1800 inherited human diseases. One approach to treating genetic diseases that stem from PTCs is selective promotion of translational readthrough in a PTC using 'readthrough compounds' that can lead to partial restoration of full-length functional protein expression. (+)-Negamycin, a natural dipeptide-like antibiotic, may restore some dystrophin expression in the skeletal muscles of mice with Duchenne muscular dystrophy, and this compound has been recognized as a potential therapeutic agent for diseases caused by nonsense mutations. In an effort to develop new candidate molecules with improved activities, we established the efficient total synthesis in eight steps of (+)-negamycin using both achiral and chiral starting material. These routes provided a deamino derivative with in vivo readthrough activity with potential for long-term treatment. In a separate approach, we discovered two natural negamycin analogs, 3-epi-deoxynegamycin and its leucine derivative, which are potent readthrough compounds effective against nonsense mutations of eukaryotes but not prokaryotes. These compounds fail to display antimicrobial activity. More potent derivatives, whose structure is derived from 3-epi-deoxynegamycin, were identified and their chemistry is discussed in this review.
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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 ╳
