螺氯马嗪

螺氯马嗪用途

盐酸斯皮洛马嗪(APY-606)是一种抗精神病药和抗肿瘤药。盐酸斯皮洛马嗪抑制KRas。盐酸史匹克霉嗪诱导癌症细胞凋亡[1][2]。
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螺氯马嗪名称

[ CAS 号 ]:
27007-85-8

[ 中文名 ]:
螺氯马嗪

[ 英文名 ]:
1-Thia-4,8-diazaspiro[4.5]decan-3-one,8-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-, hydrochloride (1:1)

[英文别名 ]:

螺氯马嗪生物活性

[ 描述 ]:

盐酸斯皮洛马嗪(APY-606)是一种抗精神病药和抗肿瘤药。盐酸斯皮洛马嗪抑制KRas。盐酸史匹克霉嗪诱导癌症细胞凋亡[1][2]。

[ 相关类别 ]:

研究领域 >> 癌症
信号通路 >> G 蛋白偶联受体/G 蛋白 >> 拉斯
研究领域 >> 神经疾病

[ 靶点 ]

K-RAS


[体外研究]

盐酸斯皮洛马嗪(0-100μg/mL；24和48小时)以剂量依赖的方式抑制胰腺癌细胞的非接触集落形成[1]。 盐酸斯皮洛嗪(0.5x和1x IC50；48小时)通过线粒体途径诱导 CFPAC-1型和 迈阿密PaCa-2细胞凋亡,显著提高细胞内 放射性同位素水平[1]。 盐酸斯皮洛马嗪(30μg/mL；24小时)抑制 CFPAC-1型和 迈阿密PaCa-2细胞的细胞运动性[1]。 盐酸斯皮洛马嗪(10和20μg/mL；24小时)在 第2组期时阻滞癌细胞周期进展[2]。 细胞活力测定[1]细胞系：CFPAC-1、MIA PaCa-2、HEK-293和HL-7702细胞浓度：0-100μg/mL培养时间：24和48小时结果：导致CFPAC-1和MIA PaCa-2细胞的生长时间和剂量依赖性减少。对正常HEK-293和HL-7702细胞的细胞毒性较小。CFPAC-1治疗48小时的IC50为15.2±2.0μg/mL(31.5±2.0μM),MIA PaCa-2为12.9±0.9μg/mL,HEK-293为41.9±1.4μg/mL和HL-7702为71.2±3.3μg/mL。细胞凋亡分析[1]细胞系：CFPAC-1和MIA PaCa-2细胞浓度：CFPAC1为7.6和15.2μg/mL,MIA PaCa-2为6.45和12.9μg/mL培养时间：48小时结果：早期凋亡细胞增加。Western Blot分析[1]细胞系：CFPAC-1和MIA PaCa-2细胞浓度：10、20和30μg/mL培养时间：24小时结果：caspase-3/9的裂解以剂量依赖的方式增加。Bax表达上调,Bcl-2蛋白表达减弱。胞浆中细胞色素c水平升高,线粒体中细胞色素c水平降低。细胞迁移试验[1]细胞系：CFPAC-1和MIA PaCa-2细胞浓度：30μg/mL培养时间：24小时结果：显著抑制两种胰腺癌细胞的迁移。细胞侵袭试验[1]细胞系：CFPAC-1和MIA PaCa-2细胞浓度：30μg/mL培养时间：24小时结果：通过下调MMP-2/9的表达抑制侵袭。细胞周期分析[2]细胞株：MIA-PaCa-2、CFPAC-1、BxPC-3、Capan-1和SW1990细胞浓度：10和20μg/mL培养时间：24小时结果：促进了MIA-PaCa-2、CFPAC-1和BxPC-2细胞株G2期或Capan-1与SW1990细胞系S期的癌症细胞周期阻滞。

[体内研究]

盐酸斯皮洛马嗪(68 mg/kg；静脉注射；两周内每隔一天)降低小鼠 迈阿密PaCa-2异种移植肿瘤的生长[2]。 动物模型：BALB/c小鼠,MIA PaCa-2异种移植模型[2]剂量：68 mg/kg给药：腹膜内注射,每隔一天,持续两周结果：完全阻断了五只小鼠中的三只的肿瘤生长。

[参考文献]

[1]. Zhao W, et al. Spiclomazine induces apoptosis associated with the suppression of cell viability, migration and invasion in pancreatic carcinoma cells. PLoS One. 2013 Jun 20;8(6):e66362.  

[2]. Guo X, et al. Spiclomazine displays a preferential anti-tumor activity in mutant KRas-driven pancreatic cancer. Oncotarget. 2018 Jan 8;9(6):6938-6951.  

螺氯马嗪物理化学性质

[ 密度 ]:
1.42g/cm3

[ 沸点 ]:
695.3ºC at 760mmHg

[ 分子式 ]:
C22H25Cl2N3OS2

[ 分子量 ]:
482.48900

[ 闪点 ]:
374.3ºC

[ 精确质量 ]:
481.08200

[ PSA ]:
86.18000

[ LogP ]:
6.12160

[ 蒸汽压 ]:
3.51E-19mmHg at 25°C

螺氯马嗪毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :
XI2277500
CHEMICAL NAME :
1-Thia-4,8-diazaspiro(4.5)decan-3-one, 8-(3-(2-chlorophenothiazin-10-yl)propyl)-, hydrochloride
CAS REGISTRY NUMBER :
27007-85-8
LAST UPDATED :
199203
DATA ITEMS CITED :
11
MOLECULAR FORMULA :
C22-H24-Cl-N3-O-S2.Cl-H
MOLECULAR WEIGHT :
482.52
WISWESSER LINE NOTATION :
T C666 BN ISJ EG B3- AT6N DXTJ D-& BT5SXMV EHJ &GH

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 :
3800 mg/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Behavioral - changes in REM sleep (human) Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
2950 mg/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Behavioral - changes in REM sleep (human) Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - rat
DOSE/DURATION :
>5490 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Oral
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
3800 mg/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Behavioral - changes in REM sleep (human) Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
3200 mg/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity) Behavioral - changes in REM sleep (human) Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970
TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Subcutaneous
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
>5490 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,487,1970 ** REPRODUCTIVE DATA **
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
60 mg/kg
SEX/DURATION :
female 9-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Effects on Newborn - live birth index (measured after birth)
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,497,1970
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
300 mg/kg
SEX/DURATION :
female 9-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetal death
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,497,1970
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
60 mg/kg
SEX/DURATION :
female 7-12 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4)
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,497,1970
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
240 mg/kg
SEX/DURATION :
female 7-12 day(s) after conception
TOXIC EFFECTS :
Reproductive - Specific Developmental Abnormalities - musculoskeletal system
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,497,1970
TYPE OF TEST :
TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE :
Oral
DOSE :
600 mg/kg
SEX/DURATION :
female 7-12 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetal death
REFERENCE :
OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 4,497,1970
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