(R)-N4- 羟基-N1-((S)-1-((S)-2-(羟甲基)吡咯烷-1-基)-3-甲基-1-氧代丁-2-基)-2-戊基琥珀酰胺

用途

Actinonin ((-)-Actinonin) 是一种由放线菌产生的天然抗菌剂。Actinonin 抑制氨肽酶 M,氨肽酶 N 和亮氨酸氨肽酶。Actinonin 是一种有效的可逆肽去甲酰基酶 (PDF) 抑制剂,Ki 为 0.28 nM。Actinonin 还抑制 MMP-1,MMP-3,MMP-8,MMP-9 和 hmeprin α 的 Ki 值分别为 300 nM,1,700 nM,190 nM,330 nM 和 20 nM。Actinonin 是一种凋亡诱导剂,具有抗增殖和抗肿瘤活性。

名称

[ CAS 号 ]:
13434-13-4

[ 中文名 ]:
放线酰胺素

[ 英文名 ]:
ACTINONIN

[英文别名 ]:

Actinonine
MFCD00080257
hylpropyl)carbamoyl)

生物活性

[ 描述 ]:

[ 相关类别 ]:

信号通路 >> 细胞凋亡 >> 细胞凋亡

研究领域 >> 癌症

研究领域 >> 感染

信号通路 >> 代谢酶/蛋白酶 >> 氨肽酶

信号通路 >> 代谢酶/蛋白酶 >> MMP

信号通路 >> 抗感染 >> 细菌

[ 靶点 ]

Ki: 0.28 nM (Peptide deformylase (PDF))[2], 300 nM (MMP-1), 1,700 nM (MMP-3), 190 nM (MMP-8), 330 nM (MMP-9)[3], and 20 nM (hmeprin α)[5] Apoptosis[1] Aminopeptidase M, Aminopeptidase N and Leucine aminopeptidase[1]

[体外研究]

肌动蛋白抑制多种肿瘤细胞系的生长。Raji细胞、MDA-MB-468细胞、PC3细胞、SK-LC-19细胞、Hela细胞、HT-1080细胞和AL67细胞的IC50分别为4、6.9、12.8、16.6、27.4、15.7和49.3μM[1]。HsPDF是肌动蛋白的重要靶点,其在线粒体中的抑制作用导致肿瘤细胞死亡。肌动蛋白对细胞的治疗以时间和剂量依赖的方式导致肿瘤特异性线粒体膜去极化和ATP耗竭[1]。肌动蛋白是来自金黄色葡萄球菌和大肠杆菌的三种形式(锌、镍和铁)的肽变形酶的有效抑制剂。在分析条件下,锌PDF(大肠杆菌)、镍PDF(大肠杆菌)、铁PDF(大肠杆菌)和镍PDF(金黄色葡萄球菌)的肌动蛋白IC50值分别为90、3、0.8和11nm[2]。肌动蛋白对革兰氏阳性菌有活性,包括金黄色葡萄球菌(MIC值为8-16微克/毫升)、化脓性链球菌(MIC值为8微克/毫升)和表皮链球菌(MIC值为2-4微克/毫升)。肌动蛋白还对严格的革兰氏阴性菌具有活性,如流感嗜血杆菌(MIC值为1-2微克/毫升)、卡他莫拉菌(MIC值为0.5微克/毫升)和淋病奈瑟菌(MIC值为1-4微克/毫升)。肌动蛋白对H.influezae acr(MIC值为0.13μg/mL)和E.coli acr(MIC值为0.25μg/mL)外排泵突变体非常有效[2]。

[体内研究]

肌动蛋白已安全地作为抗生素给小鼠使用,剂量高达400毫克/千克。Actinonin对正常组织没有明显的毒性,尽管它在体外具有抗肿瘤活性。值得注意的是,肌动蛋白在裸鼠CWR22人前列腺肿瘤异种移植模型中显示出显著的抗肿瘤活性。在治疗过程中,动物没有毒性迹象(1)。

[参考文献]

[1]. Lee MD, et al. Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics. J Clin Invest. 2004 Oct;114(8):1107-16.

[2]. Chen DZ, et al. Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry. 2000 Feb 15;39(6):1256-62.

[3]. Wahl, R.C., et al. Hydroxamate inhibitors of human gelatinase B (92 kDa). Bioorganic & Medicinal Chemistry Letters 5(4), 349-352 (1995).

[4]. Duke SO, et al. Modes of action of microbially-produced phytotoxins. Toxins (Basel). 2011 Aug;3(8):1038-64.

[5]. Kruse MN, et al. Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J. 2004 Mar 1;378(Pt 2):383-9.

物理化学性质

[ 密度 ]:
1.1±0.1 g/cm3

[ 熔点 ]:
137-139ºC

[ 分子式 ]:
C₁₉H₃₅N₃O₅

[ 分子量 ]:
385.498

[ 精确质量 ]:
385.257660

[ PSA ]:
118.97000

[ LogP ]:
0.59

[ 外观性状 ]:
灰白色固体

[ 折射率 ]:
1.513

[ 储存条件 ]:
−20°C

MSDS

详细MSDS(安全技术说明书)

毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: RG9900700

CHEMICAL NAME :: Octanohydroxamic acid, 3-((1-((2-(hydroxymethyl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl) carbamoyl)-

CAS REGISTRY NUMBER :: 13434-13-4

LAST UPDATED :: 199512

DATA ITEMS CITED :: 3

MOLECULAR FORMULA :: C19-H35-N3-O5

MOLECULAR WEIGHT :: 385.57

WISWESSER LINE NOTATION :: T5NTJ AVYY1&1&MVY5&1VMQ B1Q

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >250 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: JANTAJ Journal of Antibiotics. (Japan Antibiotics Research Assoc., 2-20-8 Kamiosaki, Shinagawa-ku, Tokyo, 141, Japan) V.2-5, 1948-52; V.21- 1968- Volume(issue)/page/year: 38,1629,1985

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 400 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: 85FZAT "Index of Antibiotics from Actinomycetes," Umezawa, H. et al., eds., Tokyo, Univ. of Tokyo Press, 1967 Volume(issue)/page/year: -,102,1967

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Unreported

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >400 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: EPXXDW European Patent Application. (U.S. Patent and Trademark Office, Foreign Patents, Washington, DC 20231) Volume(issue)/page/year: #167936

安全信息

[ 个人防护装备 ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ 安全声明 (欧洲) ]:
S22-S24/25

[ 危险品运输编码 ]:
NONH for all modes of transport

[ WGK德国 ]:
3

[ RTECS号 ]:
RG9900700

文献

Proteome-wide analysis of the amino terminal status of Escherichia coli proteins at the steady-state and upon deformylation inhibition.

Proteomics 15 , 2503-18, (2015)

A proteome wide analysis was performed in Escherichia coli to identify the impact on protein N-termini of actinonin, an antibiotic specifically inhibiting peptide deformylase (PDF). A strategy and too...

Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness.

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Mitochondrial ribosomes synthesize a subset of hydrophobic proteins required for assembly of the oxidative phosphorylation complexes. This process requires temporal and spatial coordination and regula...

Concanavalin-A-induced autophagy biomarkers requires membrane type-1 matrix metalloproteinase intracellular signaling in glioblastoma cells.

Glycobiology 22(9) , 1245-55, (2012)

Pre-clinical trials for cancer therapeutics support the anti-neoplastic properties of the lectin from Canavalia ensiformis (Concanavalin-A, ConA) in targeting apoptosis and autophagy in a variety of c...

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