Belactosin A

Belactosin A

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Category Antibiotics
Catalog number BBF-00275
CAS
Molecular Weight 369.41
Molecular Formula C17H27N3O6

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Description

Belactosin A is produced by the strain of Streptomyces sp. No antibacterial activity. A inhibits the IC50 of HeLa S3 cells is 51μmol/L.

Specification

Synonyms (alphaS,1S)-alpha-(L-Alanylamino)-2beta-[[[(2R)-3alpha-[(S)-sec-butyl]-4-oxooxetane-2beta-yl]carbonyl]amino]cyclopropane-1beta-propionic acid
IUPAC Name (2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]propanoic acid
Canonical SMILES CCC(C)C1C(OC1=O)C(=O)NC2CC2CC(C(=O)O)NC(=O)C(C)N
InChI InChI=1S/C17H27N3O6/c1-4-7(2)12-13(26-17(12)25)15(22)19-10-5-9(10)6-11(16(23)24)20-14(21)8(3)18/h7-13H,4-6,18H2,1-3H3,(H,19,22)(H,20,21)(H,23,24)/t7-,8-,9-,10-,11-,12-,13+/m0/s1
InChI Key ZSYIAUXMQLVKIL-BLTCOFLISA-N

Properties

Appearance White Powder
Antibiotic Activity Spectrum neoplastics (Tumor)
Melting Point 184-185 °C

Reference Reading

1. Discovery of a Cryptic Nitro Intermediate in the Biosynthesis of the 3-( trans-2'-Aminocyclopropyl)alanine Moiety of Belactosin A
Alicia Engelbrecht, Felix Wolf, Annika Esch, Andreas Kulik, Sergei I Kozhushkov, Armin de Meijere, Chambers C Hughes, Leonard Kaysser Org Lett. 2022 Jan 21;24(2):736-740. doi: 10.1021/acs.orglett.1c04205. Epub 2022 Jan 6.
Belactosin A, a β-lactone proteasome inhibitor, contains a unique 3-(trans-2'-aminocyclopropyl)alanine moiety. We recently identified the biosynthetic gene cluster of the belactosin series from Streptomyces sp. UCK14. To shed light on the formation of the aminocyclopropylalanine, we established a heterologous pathway expression, constructed a set of gene deletion mutants, and performed feeding studies for a chemical complementation that include the incorporation of stable isotope-labeled precursors. We thereby show that, in the biosynthesis of this building block, a cryptic nitrocyclopropylalanine intermediate is generated from l-lysine. The subsequent reduction of the N-oxygenated precursor to the corresponding amine is mediated by the molybdopterin-dependent enzyme BelN.
2. Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A
Shuhei Kawamura, Yuka Unno, Takatsugu Hirokawa, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto Chem Commun (Camb). 2014 Mar 7;50(19):2445-7. doi: 10.1039/c3cc48818g. Epub 2014 Jan 22.
Rational scaffold hopping of a natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC50 = 26-393 nM).
3. Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones
Shuhei Kawamura, Yuka Unno, Akira Asai, Mitsuhiro Arisawa, Satoshi Shuto Bioorg Med Chem. 2014 Jun 15;22(12):3091-5. doi: 10.1016/j.bmc.2014.04.032. Epub 2014 Apr 24.
Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure-activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable β-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient α,β-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome.

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It is commonly abbreviated as: C1V1 = C2V2

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Tip: Chemical formula is case sensitive. C22H30N4O c22h30n40
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