Diazepinomicin
(Synonyms: ECO-4601; TLN-4601; BU 4664L) 目录号 : GC35859Diazepinomicin (TLN-4601) 是Micromonospora sp 的次生代谢产物,可抑制EGF 诱导的 Ras-ERK MAPK 信号通路,可诱导凋亡。是一种可用于 K-Ras 突变型的抗肿瘤药物。
Cas No.:733035-26-2
Sample solution is provided at 25 µL, 10mM.
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Diazepinomicin (TLN-4601) is a secondary metabolite produced by Micromonospora sp. Diazepinomicin (TLN-4601) inhibits the EGF-induced Ras-ERK MAPK signaling pathway and induces apoptosis. An anti-tumor agent for K-Ras mutant models[1]. Diazepinomicin (TLN-4601) inhibits the EGF-induced Ras-ERK MAPK signaling pathway post Ras prenylation and prior to MEK activation[1].
[1]. Campbell PM, et al. TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling. J Mol Signal. 2010 Nov 2;5:18.
Cas No. | 733035-26-2 | SDF | |
别名 | ECO-4601; TLN-4601; BU 4664L | ||
Canonical SMILES | O=C1C2=CC=CC(O)=C2NC3=C(O)C=C(O)C=C3N1C/C=C(C)/CC/C=C(C)/CC/C=C(C)\C | ||
分子式 | C28H34N2O4 | 分子量 | 462.58 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C, protect from light, stored under nitrogen |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.1618 mL | 10.8089 mL | 21.6179 mL |
5 mM | 0.4324 mL | 2.1618 mL | 4.3236 mL |
10 mM | 0.2162 mL | 1.0809 mL | 2.1618 mL |
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1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Antioxidant and anti-protease activities of Diazepinomicin from the sponge-associated Micromonospora strain RV115
Mar Drugs 2012 Oct;10(10):2208-2221.PMID:23170078DOI:10.3390/md10102208.
Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of Diazepinomicin was demonstrated. Moreover, Diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, Diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC₅₀ of 70-90 µM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC₅₀ of 13.5 µM. These results showed unprecedented antioxidant and anti-protease activities of Diazepinomicin, thus further highlighting its potential as a future drug candidate.
Diazepinomicin, a new antimicrobial alkaloid from a marine Micromonospora sp
J Nat Prod 2004 Aug;67(8):1431-3.PMID:15332871DOI:10.1021/np040042r.
The structure of a new dibenzodiazepine alkaloid, Diazepinomicin (1), isolated from the culture of a marine actinomycete of the genus Micromonospora was characterized using spectroscopic methods. Diazepinomicin represents a unique molecular class composed of a dibenzodiazepine core linked to a farnesyl side chain.
Biosynthesis of Diazepinomicin/ECO-4601, a Micromonospora secondary metabolite with a novel ring system
J Nat Prod 2008 Sep;71(9):1585-90.PMID:18722414DOI:10.1021/np800376n.
The novel microbial metabolite Diazepinomicin/ECO-4601 (1) has a unique tricyclic dibenzodiazepinone core, which was unprecedented among microbial metabolites. Labeled feeding experiments indicated that the carbocyclic ring and the ring nitrogen of tryptophan could be incorporated via degradation to the 3-hydroxyanthranilic acid, forming ring A and the nonamide nitrogen of 1. Genomic analysis of the biosynthetic locus indicated that the farnesyl side chain was mevalonate derived, the 3-hydroxyanthranilic acid moiety could be formed directly from chorismate, and the third ring was constructed via 3-amino-5-hydroxybenzoic acid. Successful incorporation of 4,6-D2-3-hydroxyanthranilic acid into ring A of 1 via feeding experiments supports the genetic analysis and the allocation of the locus to this biosynthesis. These studies highlight the enzymatic complexity needed to produce this structural type, which is rare in nature.
Unusual N-prenylation in Diazepinomicin biosynthesis: the farnesylation of a benzodiazepine substrate is catalyzed by a new member of the ABBA prenyltransferase superfamily
PLoS One 2013 Dec 23;8(12):e85707.PMID:24376894DOI:10.1371/journal.pone.0085707.
The bacterium Micromonospora sp. RV115, isolated from a marine sponge, produces the unusual metabolite Diazepinomicin, a prenylated benzodiazepine derivative. We have cloned the prenyltransferase gene dzmP from this organism, expressed it in Escherichia coli, and the resulting His8-tagged protein was purified and investigated biochemically. It was found to catalyze the farnesylation of the amide nitrogen of dibenzodiazepinone. DzmP belongs to the ABBA prenyltransferases and is the first member of this superfamily which utilizes farnesyl diphosphate as genuine substrate. All previously discovered members utilize either dimethylallyl diphosphate (C5) or geranyl diphosphate (C10). Another putative Diazepinomicin biosynthetic gene cluster was identified in the genome of Streptomyces griseoflavus Tü4000, suggesting that the formation of Diazepinomicin is not restricted to the genus Micromonospora. The gene cluster contains a gene ssrg_00986 with 61.4% identity (amino acid level) to dzmP. The gene was expressed in E. coli, and the purified protein showed similar catalytic properties as DzmP. Both enzymes also accepted other phenolic or phenazine substrates. ABBA prenyltransferases are useful tools for chemoenzymatic synthesis, due to their nature as soluble, stable biocatalysts. The discovery of DzmP and Ssrg_00986 extends the isoprenoid substrate range of this superfamily. The observed prenylation of an amide nitrogen is an unusual biochemical reaction.
Evaluating indole-related derivatives as precursors in the directed biosynthesis of Diazepinomicin analogues
J Nat Prod 2009 Mar 27;72(3):496-9.PMID:19199816DOI:10.1021/np800664u.
The effectiveness of precursor-directed biosynthesis to generate Diazepinomicin (1) analogues with varied ring-A substitutents was investigated by feeding commercially available, potential ring-A precursors such as fluorinated tryptophans, halogenated anthranilates, and various substituted indoles into growing actinomycete culture DPJ15 (genus Micromonospora). Two new monofluorinated Diazepinomicin analogues (2 and 3) were identified and characterized by spectroscopic methods. Both derivatives showed modest antibacterial activity against the Gram-positive coccus Staphylococcus aureus with MIC values in the range 8-32 microg/mL.