Azinomycin B

Azinomycin B

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Category Antibiotics
Catalog number BBF-00242
CAS
Molecular Weight 623.61
Molecular Formula C31H33N3O11

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Description

Azinomycin B is produced by the strain of Streptomyces griseofuscus. It was highly cytotoxic, and the cytotoxicity of A and B to L5178Y cell IC50 was 0.07 g/mL and 0.11 g/mL, respectively.

Specification

Synonyms CARZINOPHILIN A; Cardinophyllin
IUPAC Name [(1S)-2-[[(1E)-1-[(3R,4R,5S)-3-acetyloxy-4-hydroxy-1-azabicyclo[3.1.0]hexan-2-ylidene]-2-[[(Z)-1-hydroxy-3-oxobut-1-en-2-yl]amino]-2-oxoethyl]amino]-1-[(2S)-2-methyloxiran-2-yl]-2-oxoethyl] 3-methoxy-5-methylnaphthalene-1-carboxylate
Canonical SMILES CC1=C2C=C(C=C(C2=CC=C1)C(=O)OC(C(=O)NC(=C3C(C(C4N3C4)O)OC(=O)C)C(=O)NC(=CO)C(=O)C)C5(CO5)C)OC
InChI InChI=1S/C31H33N3O11/c1-14-7-6-8-18-19(14)9-17(42-5)10-20(18)30(41)45-27(31(4)13-43-31)29(40)33-23(28(39)32-21(12-35)15(2)36)24-26(44-16(3)37)25(38)22-11-34(22)24/h6-10,12,22,25-27,35,38H,11,13H2,1-5H3,(H,32,39)(H,33,40)/b21-12-,24-23+/t22-,25+,26+,27+,31-,34?/m0/s1
InChI Key QIKVYJOCQXXRSJ-PKDLRSQSSA-N

Properties

Appearance Colorless Amorphous Solid
Melting Point 190 °C

Reference Reading

1. Identification of a novel structure-specific endonuclease AziN that contributes to the repair of azinomycin B-mediated DNA interstrand crosslinks
Xiaorong Chen, Yuedi Sun, Shan Wang, Kun Ying, Le Xiao, Kai Liu, Xiuli Zuo, Jing He Nucleic Acids Res. 2020 Jan 24;48(2):709-718. doi: 10.1093/nar/gkz1067.
DNA interstrand crosslinks (ICLs) induced by the highly genotoxic agent azinomycin B (AZB) can cause severe perturbation of DNA structure and even cell death. However, Streptomyces sahachiroi, the strain that produces AZB, seems almost impervious to this danger because of its diverse and distinctive self-protection machineries. Here, we report the identification of a novel endonuclease-like gene aziN that contributes to drug self-protection in S. sahachiroi. AziN expression conferred AZB resistance on native and heterologous host strains. The specific binding reaction between AziN and AZB was also verified in accordance with its homology to drug binding proteins, but no drug sequestering and deactivating effects could be detected. Intriguingly, due to the high affinity with the drug, AziN was discovered to exhibit specific recognition and binding capacity with AZB-mediated ICL structures, further inducing DNA strand breakage. Subsequent in vitro assays demonstrated the structure-specific endonuclease activity of AziN, which cuts both damaged strands at specific sites around AZB-ICLs. Unravelling the nuclease activity of AziN provides a good entrance point to illuminate the complex mechanisms of AZB-ICL repair.
2. Dimeric and trimeric derivatives of the azinomycin B chromophore show enhanced DNA binding
Milena Balazy, Alejandra Fausto, Christina Voskanian, Bianca Chavez, Harmanpreet Panesar, Thomas G Minehan Org Biomol Chem. 2017 May 31;15(21):4522-4526. doi: 10.1039/c7ob00944e.
To explore the utility of the azinomycin B chromophore as a platform for the development of major-groove binding small molecules, we have prepared a series of 3-methoxy-5-methylnaphthalene derivatives containing diamine, triamine, and carbohydrate linker moieties. All bis- and tris-azinomycin derivatives are intercalators that display submicromolar binding affinities for calf-thymus DNA, as revealed by viscometry measurements and fluorescent intercalator displacement (FID) assays, respectively. Although the tightest binding ligand 1d (Ka = 2.42 × 107 M-1) has similar affinities for sequence diverse polynucleotides, competition binding studies with methylated phage DNA and known major and minor groove binding small molecules suggest that the tether moiety linking the naphthalene chromophores may occupy the major groove of DNA.
3. Characterization of a novel DNA glycosylase from S. sahachiroi involved in the reduction and repair of azinomycin B induced DNA damage
Shan Wang, Kai Liu, Le Xiao, LiYuan Yang, Hong Li, FeiXue Zhang, Lei Lei, ShengQing Li, Xu Feng, AiYing Li, Jing He Nucleic Acids Res. 2016 Jan 8;44(1):187-97. doi: 10.1093/nar/gkv949. Epub 2015 Sep 22.
Azinomycin B is a hybrid polyketide/nonribosomal peptide natural product and possesses antitumor activity by interacting covalently with duplex DNA and inducing interstrand crosslinks. In the biosynthetic study of azinomycin B, a gene (orf1) adjacent to the azinomycin B gene cluster was found to be essential for the survival of the producer, Streptomyces sahachiroi ATCC33158. Sequence analyses revealed that Orf1 belongs to the HTH_42 superfamily of conserved bacterial proteins which are widely distributed in pathogenic and antibiotic-producing bacteria with unknown functions. The protein exhibits a protective effect against azinomycin B when heterologously expressed in azinomycin-sensitive strains. EMSA assays showed its sequence nonspecific binding to DNA and structure-specific binding to azinomycin B-adducted sites, and ChIP assays revealed extensive association of Orf1 with chromatin in vivo. Interestingly, Orf1 not only protects target sites by protein-DNA interaction but is also capable of repairing azinomycin B-mediated DNA cross-linking. It possesses the DNA glycosylase-like activity and specifically repairs DNA damage induced by azinomycin B through removal of both adducted nitrogenous bases in the cross-link. This bifunctional protein massively binds to genomic DNA to reduce drug attack risk as a novel DNA binding protein and triggers the base excision repair system as a novel DNA glycosylase.

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