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舍他康唑

舍他康唑用途

舍他康唑(FI7056游离碱)是一种广谱局部抗真菌剂,通过激活p38-COX-2-PGE2途径发挥抗炎活性。舍他康唑也是一种微管抑制剂,具有抗增殖作用,诱导细胞凋亡和自噬,还可以抑制细胞迁移[1][2][3][4]。

舍他康唑名称

[ CAS 号 ]:
99592-32-2

[ 中文名 ]:
舍他康唑

[ 英文名 ]:
sertaconazole

[中文别名 ]:

[英文别名 ]:

Sertaconazolum
Sertaconazol
T56 BSJ IG D1OYR BG DG&1- AT5N CNJ
Sertaconazole (INN)
MFCD00868881
Sertaconazolum [Latin]
sertaconazole
Ertaczo
Sertaconazol [Spanish]
FI-7045

舍他康唑生物活性

[ 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 >> 抗感染 >> 真菌

信号通路 >> 细胞周期/DNA损伤 >> 微管/微管蛋白

信号通路 >> 自噬 >> 自噬

信号通路 >> MAPK/ERK信号通路 >> p38 MAPK

研究领域 >> 炎症/免疫

信号通路 >> 细胞骨架 >> 微管/微管蛋白

[体外研究]

Sertaconazole(0.03-40µg/mL；24小时)抑制150株酵母菌,其中包括六种念珠菌,算术平均MIC为0.77µg/mL[1]。舍他康唑(1µg/mL；5、10、30、60分钟)以时间依赖性方式激活p38 MAP激酶[2]。Sertaconazole(1,2µg/mL；6,8或24小时)通过COX-2在角质形成细胞中增加PGE2的两倍释放,这依赖于p38激活[2]。西康唑(10、20、30、40µM；24小时)通过解聚间期微管和纺锤体微管,诱导强烈的有丝分裂阻滞,从而诱导染色体聚集缺陷并产生抗增殖作用[3]。Sertaconazole(20,40µM；24小时)通过p53途径诱导HeLa细胞凋亡[3]。Sertaconazole(20、30µM；24、48和72小时)以浓度依赖性方式抑制HeLa细胞的迁移[3]。舍他康唑(15,30µM；24小时)诱导A549、H460细胞自噬[4]。细胞存活率测定[1]细胞系：白念珠菌、吉列蒙念珠菌、克鲁西念珠菌、副硅氧烷、热带念珠菌、无毛念珠菌浓度：0.03-40µg/m孵育时间：24小时结果：对150株酵母菌(六种念珠菌),其中包括白念珠菌,吉列蒙弧菌、克鲁斯弧菌、副西罗弧菌、热带念珠杆菌、无毛弧菌,其算术平均MIC值分别为1.02、0.51、0.38,分别为0.31、1.67和0.78µg/mL。Western印迹分析[2]细胞系：HaCaT细胞浓度：1µg/mL孵育时间：5、10、30、60分钟结果：显示p38 MAP激酶和Hsp27的激活活性呈时间依赖性。Western印迹分析[2]细胞系：HaCaT细胞浓度：1,2µg/mL孵育时间：6或8小时结果：诱导COX-2表达50%,导致PGE2释放增加两倍。Western印迹分析[2]细胞系：siRNA转染的HaCaT细胞(无p38 MAP激酶表达)浓度：1µg/mL孵育时间：24小时结果：介导的PGE2诱导依赖于p38激活。细胞增殖试验[3]细胞系：HeLa、HEK-293、MCF-7、A549细胞浓度：0-100µM孵育时间：24小时结果：显示抗增殖活性,对HeLa,HEK-29 3、A549和MCF-9细胞的IC50分别为38、45.1、41.5和40.8µM。在浓度超过30μM时表现出有丝分裂阻滞活性和诱导细胞死亡,但有丝分裂细胞数量没有显著增加。解聚的间期微管和纺锤体微管导致染色体一致性缺陷。凋亡分析[3]细胞系：HeLa细胞浓度：10、20、40µM孵育时间：24小时结果：在浓度为10、20和40μM时,分别诱导约5%、10%和21%的细胞凋亡。Western Blot分析[3]细胞系：A549细胞浓度：20,40µM孵育时间：24小时结果：通过p53途径诱导凋亡,p53表达分别从30%到50%和95%,p21表达分别从11%到39%和40%。导致p53的两个直接转录靶标Noxa和Puma过度表达。细胞迁移试验[3]细胞系：HeLa细胞浓度：20、30µM孵育时间：24、48和72 h结果：在低于其IC50的浓度下抑制HeLa的迁移,其浓度依赖性。细胞自噬测定[4]细胞系：A549、H460细胞浓度：15、30µM孵育时间：24小时结果：内源性LC3点状细胞和LC3强度增加,这表明A549和H460中诱导了自噬。

[体内研究]

舍他康唑(1%(w/v)；应用于左耳一次)抑制TPA诱导的CD-1小鼠耳水肿[2]。动物模型：CD-1小鼠(TPA诱导的耳水肿模型)[2]。剂量：1%(w/v)给药：应用于左耳,一次。结果：通过介导PGE2的释放,小鼠的炎症反应明显减轻。

[参考文献]

[1]. Carrillo-Muñoz AJ, et al. In-vitro antifungal activity of sertaconazole, econazole, and bifonazole against Candida spp. J Antimicrob Chemother. 1995 Oct;36(4):713-6.

[2]. Sur R, et al. Anti-inflammatory activity of sertaconazole nitrate is mediated via activation of a p38-COX-2-PGE2 pathway. J Invest Dermatol. 2008 Feb;128(2):336-44.

[3]. Sebastian J, et al. Sertaconazole induced toxicity in HeLa cells through mitotic arrest and inhibition of microtubule assembly. Naunyn Schmiedebergs Arch Pharmacol. 2021 Jun;394(6):1231-1249.

[4]. Zhang W, et al. Sertaconazole provokes proapoptotic autophagy via stabilizing TRADD in nonsmall cell lung cancer cells. MedComm (2020). 2021 Dec 16;2(4):821-837.

舍他康唑物理化学性质

[ 密度 ]:
1.4±0.1 g/cm3

[ 沸点 ]:
614.1±55.0 °C at 760 mmHg

[ 分子式 ]:
C₂₀H₁₅Cl₃N₂OS

[ 分子量 ]:
437.770

[ 闪点 ]:
325.2±31.5 °C

[ 精确质量 ]:
435.997070

[ PSA ]:
55.29000

[ LogP ]:
7.49

[ 蒸汽压 ]:
0.0±1.7 mmHg at 25°C

[ 折射率 ]:
1.675

[ 储存条件 ]:
-20°C

舍他康唑毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: NI4376750

CHEMICAL NAME :: 1H-Imidazole, 1-(2-((7-chlorobenzo(b)thien-3-yl)methoxy)-2-(2,4-dic hlorophenyl)ethyl)-

CAS REGISTRY NUMBER :: 99592-32-2

LAST UPDATED :: 199707

DATA ITEMS CITED :: 11

MOLECULAR FORMULA :: C20-H15-Cl3-N2-O-S

MOLECULAR WEIGHT :: 437.78

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992

TYPE OF TEST :: LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >8 gm/kg

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

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,725,1992 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 54600 mg/kg/26W-C

TOXIC EFFECTS :: Blood - other changes Blood - changes in erythrocyte (RBC) count Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,732,1992

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 8400 mg/kg/28D-I

TOXIC EFFECTS :: Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases Biochemical - Metabolism (Intermediary) - xanthine, purine or nucleotides including urate

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,727,1992

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - species unspecified

DOSE/DURATION :: 32500 mg/kg/26W-I

TOXIC EFFECTS :: Blood - changes in leukocyte (WBC) count Nutritional and Gross Metabolic - weight loss or decreased weight gain Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42,732,1992 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 1950 mg/kg

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

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - cardiovascular (circulatory) system Reproductive - Specific Developmental Abnormalities - hepatobiliary system

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42(1),739,1992

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5550 mg/kg

SEX/DURATION :: female 16-31 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 42(1),739,1992

舍他康唑安全信息

[ 危害码 (欧洲) ]:
Xi

[ 安全声明 (欧洲) ]:
S22-S24/25

[ WGK德国 ]:
2

[ RTECS号 ]:
KM6557000

舍他康唑合成路线

详细合成路线

舍他康唑上下游产品

舍他康唑上游产品

舍他康唑下游产品

舍他康唑制备

在氮气保护下，将氢化钠(约50%) (1.60mmol)用六甲基磷酰胺(HMPT)(3×5m1)洗3次。在0℃和剧烈搅拌下，加入化合物(I)(0.372g，1.45mmo1)(其制备可参见Godefroi E F，et a1．J Med Chem，1969，12：784)在5ml六甲基磷酰胺的溶液，在0℃下搅拌至氢气放出停止，再在50℃下搅拌1h。冷至0℃，在搅拌下，缓慢加入溶于5ml六甲基磷酰胺的2-(溴甲基)苯并[b]噻吩(0.42g，1.60mmo1)(其制备参见Cuberes M．Et a1.Magn Reson Chem，1985，23：814)，在室温下搅拌5h。加入乙醚和水进行分配。分出有机层，水洗，干燥，浓缩。剩余物用硅胶层析提纯，得舍他康唑，收率62%，熔点146-147℃。