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

Names

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

[Synonym ]:
Disepron
APY-606
Clospirazine hydrochloride
Spiclomazine hydrochloride
Spiclomazine
Diceplon
1-Thia-4,8-diazaspiro(4.5)decan-3-one,8-(3-(2-chlorophenothiazin-10-yl)propyl)-,hydrochloride
8-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-thia-4,8-diazaspiro[4.5]decan-3-one hydrochloride

Biological Activity

[Description]:

Spiclomazine hydrochloride (APY-606) is an antipsychotic and antitumor agent. Spiclomazine hydrochloride inhibits KRas. Spiclomazine hydrochloride induces cancer cell apoptosis[1][2].

[Related Catalog]:

Research Areas >> Cancer

Signaling Pathways >> GPCR/G Protein >> Ras

Research Areas >> Neurological Disease

[Target]

K-RAS

[In Vitro]

Spiclomazine (0-100 μg/mL; 24 and 48 h) hydrochloride 以剂量依赖的方式抑制胰腺癌细胞的非接触集落形成[1]。 Spiclomazine (0.5x and 1x IC50; 48 h) hydrochloride 通过线粒体途径诱导 CFPAC-1 和 MIA PaCa-2 细胞凋亡，显著提高细胞内 ROS 水平[1]。 Spiclomazine (30 μg/mL; 24 h) hydrochloride 抑制 CFPAC-1 和 MIA PaCa-2 细胞的细胞运动性[1]。 Spiclomazine (10 and 20 μg/mL; 24 h) hydrochloride 在 G2 期时阻滞癌细胞周期进展[2]。 Cell Viability Assay[1] Cell Line: CFPAC-1, MIA PaCa-2, HEK-293 and HL-7702 cells Concentration: 0-100 μg/mL Incubation Time: 24 and 48 h Result: Resulted in a time and dose-dependent growth reduction of CFPAC-1 and MIA PaCa-2 cells. Exhibited less cytotoxicity to normal HEK-293 and HL-7702 cells. The IC50 for 48 h treatment was 15.2±2.0 μg/mL (31.5±2.0 μM) for CFPAC-1, 12.9±0.9 μg/mL (26.8±0.9 μM) for MIA PaCa-2, 41.9±1.4 μg/mL (86.9±1.4 μM) for HEK-293, and 71.2±3.3 μg/mL (147.7±3.3 μM) for HL-7702, respectively. Apoptosis Analysis[1] Cell Line: CFPAC-1 and MIA PaCa-2 cells Concentration: 7.6 and 15.2 μg/mL for CFPAC-1, 6.45 and 12.9 μg/mL for MIA PaCa-2 Incubation Time: 48 h Result: Increased early apoptotic cells. Western Blot Analysis[1] Cell Line: CFPAC-1 and MIA PaCa-2 cells Concentration: 10, 20 and 30 μg/mL Incubation Time: 24 h Result: The cleavages of caspase-3/9 were increased in a dose-dependent manner. The expression of Bax was up-regulated concomitant with the related attenuation of Bcl-2 protein expression. The level of cytochrome c in cytosol was increased accompanied by the decrease of the level of cytochrome c in mitochondria. Cell Migration Assay [1] Cell Line: CFPAC-1 and MIA PaCa-2 cells Concentration: 30 μg/mL Incubation Time: 24 h Result: Markedly suppressed the migration of both pancreatic carcinoma cells. Cell Invasion Assay[1] Cell Line: CFPAC-1 and MIA PaCa-2 cells Concentration: 30 μg/mL Incubation Time: 24 h Result: Suppressed the invasion by down-regulating the expression of MMP-2/9. Cell Cycle Analysis[2] Cell Line: MIA PaCa-2, CFPAC-1, BxPC-3, Capan-1 and SW1990 cells Concentration: 10 and 20 μg/mL Incubation Time: 24 h Result: Promoted cancer cell cycle arrest at either G2 phase in MIA PaCa-2, CFPAC-1, and BxPC-3 cell lines or S phase in Capan-1 and SW1990 cell lines.

[In Vivo]

Spiclomazine (68 mg/kg; i.p.; every other day for two weeks) hydrochloride 降低小鼠 MIA PaCa-2 异种移植肿瘤的生长[2]。 Animal Model: BALB/c mice, MIA PaCa-2 xenograft model[2] Dosage: 68 mg/kg Administration: Intraperitoneal injection, every other day for two weeks Result: Completely blocked the growth of tumors in three of the five mice.

[References]

[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.

Chemical & Physical Properties

[ Density]:
1.42g/cm3

[ Boiling Point ]:
695.3ºC at 760mmHg

[ Molecular Formula ]:
C₂₂H₂₅Cl₂N₃OS₂

[ Molecular Weight ]:
482.48900

[ Flash Point ]:
374.3ºC

[ Exact Mass ]:
481.08200

[ PSA ]:
86.18000

[ LogP ]:
6.12160

[ Vapour Pressure ]:
3.51E-19mmHg at 25°C

Toxicological Information

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