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阿洛司他丁

阿洛司他丁用途

Aloxistatin (E64d) 是可渗透细胞,不可逆的广谱半胱氨酸蛋白酶 (cysteine protease) 抑制剂。

阿洛司他丁名称

[ CAS 号 ]:
88321-09-9

[ 中文名 ]:
阿洛司他丁

[ 英文名 ]:
E-64d

[英文别名 ]:

ep453
LOXASTATIN
aloxistatin
LOXISTATIN
MFCD00132883
E-64D

阿洛司他丁生物活性

[ 描述 ]:

Aloxistatin (E64d) 是可渗透细胞,不可逆的广谱半胱氨酸蛋白酶 (cysteine protease) 抑制剂。

[ 相关类别 ]:

信号通路 >> 代谢酶/蛋白酶 >> 组织蛋白酶

研究领域 >> 神经疾病

[ 靶点 ]

Cysteine protease[1]

[体外研究]

半胱氨酸蛋白酶抑制剂Aloxistatin(E64d)抑制蛋白酶抗性朊蛋白(PrP-res)在ScNB细胞中的积累,IC50为0.5±0.11μM。对于细胞表面PrP-sen检测,PrP-sen从用磷脂酰肌醇特异性磷脂酶C(PIPLC)处理的培养基中免疫沉淀,以从细胞表面释放脉冲-35S标记的PrP-sen。在所有对照细胞的标记培养基中,氧化抑制素分别维持在15μM[1]。当与NK-92或YT 5细胞预孵育时,Aloxistatin(E64d)(特异性阻断半胱氨酸蛋白酶,但不阻断丝氨酸蛋白酶,如颗粒酶)能够完全阻断CatL底物Z-Phe-Arg-氨基甲基香豆素的更新[ 2]。 Aloxistatin(E64d)是一种广谱细胞渗透性半胱氨酸蛋白酶抑制剂[3]。

[体内研究]

向豚鼠口服施用氧氟沙星(E64d)可导致脑,脑脊液和血浆Aβ(40)和Aβ(42)的剂量依赖性减少。 Aloxistatin还可引起脑CTFβ的双相剂量依赖性降低。 Aloxistatin引起脑sAβPPα的剂量依赖性增加。对于Aloxistatin剂量为5mg/kg /天或更高剂量,平均sAβPPα水平显着高于无剂量组,其中最高的Aloxistatin剂量导致sAβPPα的最大增加比对照组高约54％。与Aβ效应类似,口服Aloxistatin给药可产生脑组织蛋白酶B活性的双相剂量依赖性降低。最小有效剂量为约1mg/kg /天,最高的Aloxistatin剂量导致脑组织蛋白酶B活性的最大降低比对照组低约91％。因此,Aloxistatin以与抑制组织蛋白酶Bβ-分泌酶活性的化合物一致的方式降低豚鼠脑组织蛋白酶B的活性[4]。 Aloxistatin(E64d)抑制大鼠AT1AR和ACE基因表达的增加。奥美沙坦或Aloxistatin的施用减少了HF大鼠心肌内冠状动脉的超氧化物产生的增加[5]。

[激酶实验]

将CTL和NK细胞（0.8×106 / mL）用抑制剂L1（10-20μM）或Aloxistatin（20-30μM）在37℃下在24孔板中处理24小时。然后将细胞用于51Cr释放测定中或裂解以在蛋白质印迹中检查穿孔素。如所示，在一些51Cr-释放测定中，在4小时反应期间还以相同浓度添加抑制剂。使用NP-40裂解缓冲液（25mM HEPES，250mM NaCl，2.5mM乙二胺四乙酸，0.1％体积/体积Nonidet P-40）制备细胞裂解物，并使用Bradford测定法测定总蛋白质浓度。加载等量的蛋白质并在8％SDS-PAGE凝胶上分离。使用所示的适当抗体检测人或小鼠穿孔素。抗肌动蛋白抗体用作上样对照[2]。

[细胞实验]

按照上述极性标记物的方案，通过染色增殖标记物Ki67或凋亡标记物切割的半胱天冬酶3来评估细胞增殖和凋亡。将MCF10变体在3D rBM覆盖培养物中生长4天，并用0.1％DMSO，5μMCO74MeMe或5μM盐酸曲霉毒素处理。通过用Zeiss Axiophot落射荧光显微镜在两个单独的盖玻片上计数总共100个结构来确定Ki67或切割的半胱天冬酶3阳性结构的百分比。如果结构含有至少一个Ki67细胞染色，则认为结构为Ki67阳性。如果结构含有至少一个对切割的半胱天冬酶3呈阳性的细胞并且阳性细胞不定位于发育中腔的中心，则认为结构为半胱天冬酶3阳性[3]。

[动物实验]

小鼠和猪[4]使用豚鼠（雄性，Hartley品系，平均体重400g，对应于约6周龄的动物）。使用表达含有wtβ-分泌酶位点和伦敦突变β-分泌酶位点序列的人AβPP的雄性转基因小鼠。通过强饲法递送药物提供了精确给药的优点但是具有创伤性，因此仅适合于相对短的给药期（长达约一周）。通过管饲递送用于豚鼠研究。将氧化苦参素以指定浓度（0.1,1.0,5和10mg / kg）悬浮于Me 2 SO中，并使用饲管每日通过管饲法施用。通过管饲单独的Me 2 SO处理载体对照动物。大鼠[5]使用雄性近交DS大鼠。断奶的大鼠喂食含有0.3％NaCl的实验室饲料直至7周龄。 7周后喂食8％NaCl饮食的DS大鼠在第12周表现为继发于高血压的补偿性同心左心室（LV）肥大，并且在19周时出现肺部充血的致命性LV失败的明显阶段。因此，DS大鼠从7周龄开始喂食8％NaCl饮食，随机分为HF组，Aloxistatin组（每天每公斤体重10 mg，每隔一天腹腔注射）或奥美沙坦组（3）在12至19周龄期间每天的mg / kg（每组n = 10）。奥美沙坦（一种ARB）和Aloxistatin的剂量在初步实验和之前的研究中确定。保持在0.3％NaCl饮食上的DS大鼠用作年龄匹配的对照（对照组，n = 10）。在19周龄时，通过腹膜内过量戊巴比妥钠（50mg / kg）使所有大鼠安乐死，取出心脏用于生物学和组织学分析。从腹主动脉收集动脉血以测量肾素活性。使用非侵入性尾套法在7周龄，每周的清醒大鼠中测量收缩压和心率。在单独的实验中，以与上述实验相同的方式给予来自7周龄的低盐饮食的12周龄DS大鼠，载体，奥美沙坦或盐酸曲霉素（每组n = 5），用于测量靶向mRNA和蛋白质水平的LV组织立即置于液氮中并储存在-80℃。

[参考文献]

[1]. Doh-Ura K, et al. Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol. 2000 May;74(10):4894-7.

[2]. Konjar S, et al. Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L. Immunology. 2010 Oct;131(2):257-67.

[3]. Mullins SR, et al. Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins. Biol Chem. 2012 Dec;393(12):1405-16.

[4]. Hook G, et al. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity. J Alzheimers Dis. 2011;26(2):387-408.

[5]. Cheng XW, et al. Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment. Am J Pathol. 2008 Aug;173(2):358-69.

[相关活性小分子]

阿洛司他丁物理化学性质

[ 密度 ]:
1.2±0.1 g/cm3

[ 沸点 ]:
470.5±55.0 °C at 760 mmHg

[ 熔点 ]:
126.2°C

[ 分子式 ]:
C₁₇H₃₀N₂O₅

[ 分子量 ]:
342.431

[ 闪点 ]:
238.4±31.5 °C

[ 精确质量 ]:
342.215485

[ PSA ]:
97.03000

[ LogP ]:
3.64

[ 外观性状 ]:
固体;White to Almost white powder to crystal

[ 蒸汽压 ]:
0.0±2.6 mmHg at 25°C

[ 折射率 ]:
1.530

[ 储存条件 ]:
−20°C

[ 水溶解性 ]:
Soluble in DMSO, DMF or ethanol

阿洛司他丁MSDS

详细MSDS(安全技术说明书)

阿洛司他丁毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: RR0404300

CHEMICAL NAME :: Oxiranecarboxylic acid, 3-(((3-methyl-1-(((3-methylbutyl)amino)carbonyl)butyl )amino) carbonyl)-, ethyl ester, (2S-(2-alpha,3-beta(R*)))-

CAS REGISTRY NUMBER :: 88321-09-9

LAST UPDATED :: 199612

DATA ITEMS CITED :: 16

MOLECULAR FORMULA :: C17-H30-N2-O5

MOLECULAR WEIGHT :: 342.49

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >10 gm/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Olfaction) - effect, not otherwise specified Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2050 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >5 gm/kg

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

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >10 gm/kg

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

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 3270 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >7 gm/kg

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

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 600 mg/kg/30D-C

TOXIC EFFECTS :: Liver - other changes Kidney, Ureter, Bladder - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - hamster

DOSE/DURATION :: 14 gm/kg/14D-C

TOXIC EFFECTS :: Liver - other changes Kidney, Ureter, Bladder - other changes Blood - other changes

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 60 gm/kg

SEX/DURATION :: male 30 day(s) pre-mating

TOXIC EFFECTS :: Reproductive - Paternal Effects - testes, epididymis, sperm duct Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 60 gm/kg

SEX/DURATION :: female 30 day(s) pre-mating

TOXIC EFFECTS :: Reproductive - Maternal Effects - ovaries, fallopian tubes Reproductive - Maternal Effects - uterus, cervix, vagina

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2750 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - physical

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 2750 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - eye/ear Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 6500 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 1300 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 6500 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Embryo or Fetus - fetal death

MUTATION DATA

TYPE OF TEST :: Cytogenetic analysis

TEST SYSTEM :: Rodent - hamster Lung

DOSE/DURATION :: 200 mg/L

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,815,1986

阿洛司他丁安全信息

[ 个人防护装备 ]:
dust mask type N95 (US);Eyeshields;Gloves

[ 危害码 (欧洲) ]:
Xi: Irritant;

[ 风险声明 (欧洲) ]:
R36/37/38

[ 安全声明 (欧洲) ]:
S26;S36

[ 危险品运输编码 ]:
3077

[ WGK德国 ]:
2

[ RTECS号 ]:
RR0404300

阿洛司他丁合成路线

详细合成路线

阿洛司他丁文献

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Preferential expression of a bromoperoxidase in sporophytes of a red alga, Pyropia yezoensis.

Mar. Biotechnol. 17(2) , 199-210, (2015)

A 2,158 bp cDNA (PyBPO1) encoding a bromoperoxidase (BPO) of 625 amino acids was isolated from Pyropia yezoensis. Phylogenetic analysis using amino acid sequences of BPOs suggested that P. yezoensis a...

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