Ruboxistaurin(LY333531)mesylate

Molecular Weight (MW)	564.66
Formula	C29H32N4O6S
CAS No.	192050-59-2 (mesylate);
Storage	-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: N/A
Water: N/A
Ethanol: N/A
Other info	Chemical Name: (9S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione mesylate InChi Key: DUHQBKLTAVUXFF-FERBBOLQSA-N InChi Code: InChI=1S/C28H28N4O3.CH4O3S/c1-30(2)15-18-11-12-31-16-21(19-7-3-5-9-23(19)31)25-26(28(34)29-27(25)33)22-17-32(13-14-35-18)24-10-6-4-8-20(22)24;1-5(2,3)4/h3-10,16-18H,11-15H2,1-2H3,(H,29,33,34);1H3,(H,2,3,4)/t18-;/m0./s1 SMILES Code: O=C1NC(C(C2=CN(C3=CC=CC=C32)CCO[C@H](CN(C)C)CC4)=C1C5=CN4C6=CC=CC=C56)=O.OS(=O)(C)=O
Synonyms	LY-333531 Mesylate; LY333531;Ruboxistaurin mesylate; LY-333531; LY 333531; LY-333531 Mesylate

Molecular Weight (MW)

564.66

Formula

C29H32N4O6S

CAS No.

192050-59-2 (mesylate);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: N/A

Water: N/A

Ethanol: N/A

Other info

Chemical Name: (9S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione mesylate
InChi Key: DUHQBKLTAVUXFF-FERBBOLQSA-N
InChi Code: InChI=1S/C28H28N4O3.CH4O3S/c1-30(2)15-18-11-12-31-16-21(19-7-3-5-9-23(19)31)25-26(28(34)29-27(25)33)22-17-32(13-14-35-18)24-10-6-4-8-20(22)24;1-5(2,3)4/h3-10,16-18H,11-15H2,1-2H3,(H,29,33,34);1H3,(H,2,3,4)/t18-;/m0./s1
SMILES Code: O=C1NC(C(C2=CN(C3=CC=CC=C32)CCO[C@H](CN(C)C)CC4)=C1C5=CN4C6=CC=CC=C56)=O.OS(=O)(C)=O

Synonyms

LY-333531 Mesylate; LY333531;Ruboxistaurin mesylate; LY-333531; LY 333531; LY-333531 Mesylate

In Vitro	In vitro activity: LY333531 strikingly decreases the chance of HUVEC survival and the effect of LY333531 on apoptotic cell death in HUVEC significantly increases compared with the AGEs group. Blockade of PKC-beta up-regulates the expression of Bax and Bad proteins and down-regulates the expression of Bcl-2 protein. Moreover, LY333531 reduces the ratio of Bcl-2/Bax. LY333531 can further prompt AGEs-induced endothelial cells apoptosis. The increased expression of Bax, Bad and decreased expression of Bcl-2 and Bcl-2/Bax ratio are associated with the apoptotic process. Kinase Assay: Ruboxistaurin hydrochloride is a selective and ATP-competitive PKCβ inhibitor, with IC50s of 4.7 and 5.9 nM for PKCβI and PKCβII, shows less potent inhibition on PKCη (IC50, 52 nM), PKCα (IC50, 360 nM), PKCγ (IC50, 300 nM), PKCδ (IC50, 250 nM), and has no effect on PKCζ (IC50,>100 μM). Cell Assay: HUVECs are seeded into 96-well plates in low glucose DMEM with 10% FBS for 12 h. Afterwards, HUVECs are starved for 12 h and incubated with BSA (200 μg/ml), AGEs (200 μg/ml) and LY333531 (200 nM)+AGEs (200 μg/ml) for 48 h. Then, the medium is replaced with 0.5 mg/ml MTT and at 37 oC in a 95% air/5% CO2 incubator for 4 h. Finally, the medium containing MTT is aspirated and replaced by dimethyl sulphoxide (DMSO). OD is measured with a Microplate spectrophotometer. AGEs:advanced glycation end products.
In Vivo	LY333531 treatment (for a duration of 4 weeks) prevents excessive PKCb2 activation and attenuates cardiac diastolic dysfunction in rats with streptozotocin-induced diabetes. LY333531 suppresses the decreased expression of myocardial NO, Cav-3, phosphorylated (p)-Akt, and p-eNOS and also mitigates the augmentation of O2-, nitrotyrosine, Cav-1, and iNOS expression.
Animal model	Rats with streptozotocin-induced diabetes
Formulation & Dosage	Ruboxistaurin is administered orally at dosages of 0.1 (n = 8), 1.0 (n = 16), and 10.0 mg/kg/d (n = 8) for 4 weeks, from the time streptozotocin is injected in the rats. Immediately before acridine orange digital fluorography, rats are anesthetized with a mixture (1:1) of xylazine hydrochloride (4 mg/kg) and ketamine hydrochloride (10 mg/kg). The pupils are dilated with 0.5% tropicamide and 2.5% phenylephrine hydrochloride. A contact lens is placed on the cornea to maintain transparency throughout the experiments. Each rat has a catheter inserted into the tail vein and is placed on a movable platform. Body temperature is maintained between 37°C and 39°C throughout the experiment
References	J Med Chem. 1996 Jul 5;39(14):2664-71; Diabetes. 2013 Jul;62(7):2318-28; Pharmazie. 2011 Nov;66(11):881-7.

In Vitro

In vitro activity: LY333531 strikingly decreases the chance of HUVEC survival and the effect of LY333531 on apoptotic cell death in HUVEC significantly increases compared with the AGEs group. Blockade of PKC-beta up-regulates the expression of Bax and Bad proteins and down-regulates the expression of Bcl-2 protein. Moreover, LY333531 reduces the ratio of Bcl-2/Bax. LY333531 can further prompt AGEs-induced endothelial cells apoptosis. The increased expression of Bax, Bad and decreased expression of Bcl-2 and Bcl-2/Bax ratio are associated with the apoptotic process.

Kinase Assay: Ruboxistaurin hydrochloride is a selective and ATP-competitive PKCβ inhibitor, with IC50s of 4.7 and 5.9 nM for PKCβI and PKCβII, shows less potent inhibition on PKCη (IC50, 52 nM), PKCα (IC50, 360 nM), PKCγ (IC50, 300 nM), PKCδ (IC50, 250 nM), and has no effect on PKCζ (IC50,>100 μM).

Cell Assay: HUVECs are seeded into 96-well plates in low glucose DMEM with 10% FBS for 12 h. Afterwards, HUVECs are starved for 12 h and incubated with BSA (200 μg/ml), AGEs (200 μg/ml) and LY333531 (200 nM)+AGEs (200 μg/ml) for 48 h. Then, the medium is replaced with 0.5 mg/ml MTT and at 37 oC in a 95% air/5% CO2 incubator for 4 h. Finally, the medium containing MTT is aspirated and replaced by dimethyl sulphoxide (DMSO). OD is measured with a Microplate spectrophotometer. AGEs:advanced glycation end products.

In Vivo

LY333531 treatment (for a duration of 4 weeks) prevents excessive PKCb2 activation and attenuates cardiac diastolic dysfunction in rats with streptozotocin-induced diabetes. LY333531 suppresses the decreased expression of myocardial NO, Cav-3, phosphorylated (p)-Akt, and p-eNOS and also mitigates the augmentation of O2-, nitrotyrosine, Cav-1, and iNOS expression.

Animal model

Rats with streptozotocin-induced diabetes

Formulation & Dosage

Ruboxistaurin is administered orally at dosages of 0.1 (n = 8), 1.0 (n = 16), and 10.0 mg/kg/d (n = 8) for 4 weeks, from the time streptozotocin is injected in the rats. Immediately before acridine orange digital fluorography, rats are anesthetized with a mixture (1:1) of xylazine hydrochloride (4 mg/kg) and ketamine hydrochloride (10 mg/kg). The pupils are dilated with 0.5% tropicamide and 2.5% phenylephrine hydrochloride. A contact lens is placed on the cornea to maintain transparency throughout the experiments. Each rat has a catheter inserted into the tail vein and is placed on a movable platform. Body temperature is maintained between 37°C and 39°C throughout the experiment

References

J Med Chem. 1996 Jul 5;39(14):2664-71; Diabetes. 2013 Jul;62(7):2318-28; Pharmazie. 2011 Nov;66(11):881-7.

CAS NO:	192050-59-2
规格:	≥98%