 Chemical Structure.png)
Ruboxistaurin HCl, the hydrochloride salt of Ruboxistaurin (LY-333531; LY333531), is a novel, potent and specific inhibitor of PKCβ (protein kinase C) with diabetic effects. It competitively and reversibly inhibits PKCβ1 and PKCβ2 with IC50 values of 4.7 and 5.9 nM respectively. Ruboxistaurin has usefulness to treat diabetic nephropathy and diabetic macular edem. 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.
Physicochemical Properties
| Molecular Formula | C28H28N4O3.HCL | |
| Molecular Weight | 505.01 | |
| Exact Mass | 504.192 | |
| CAS # | 169939-93-9 | |
| Related CAS # | Ruboxistaurin;169939-94-0;Ruboxistaurin mesylate;192050-59-2;Ruboxistaurin-d6 hydrochloride;1794767-04-6 | |
| PubChem CID | 9870785 | |
| Appearance | Orange to red solid powder | |
| LogP | 4.644 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 36 | |
| Complexity | 872 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | CN(C)C[C@@H]1CCN2C=C(C3=CC=CC=C32)C4=C(C5=CN(CCO1)C6=CC=CC=C65)C(=O)NC4=O.Cl |
|
| InChi Key | NYQIEYDJYFVLPO-FERBBOLQSA-N | |
| InChi Code | InChI=1S/C28H28N4O3.ClH/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;/h3-10,16-18H,11-15H2,1-2H3,(H,29,33,34);1H/t18-;/m0./s1 | |
| Chemical Name | (12E,32E,7S)-7-((dimethylamino)methyl)-22,25-dihydro-11H,21H,31H-6-oxa-1,3(3,1)-diindola-2(3,4)-pyrrolacyclononaphane-22,25-dione hydrochloride | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | With IC50s of 4.7 and 5.9 nM for PKCβI and PKCβII, rutosiden hydrochloride is an ATP-competitive, selective inhibitor of PKCβ. It has less effective inhibition on PKCη (IC50, 52 nM), PKCα (IC50, 360 nM), PKCγ (IC50, 300 nM), and PKCδ (IC50, 250 nM), and has no impact on PKCζ (IC50, >100 μM)[1]. Under normal growth settings, rutosidestatin (10 and 400 nM) significantly reduces glucose-induced monocyte adhesion to levels that are equivalent to the monocytes' baseline adhesion to endothelial cells. Ruboxistaurin (10 and 400 nM) doses do not change endothelial cell proliferation or the expression of adhesion molecules on the endothelium[2]. Ruboxistaurin (LY333531; 10 nM) suppresses the increases in swiprosin-1 in human renal glomerular endothelial cells (HRGECs) treated with high glucose (HG) and decreases the viability of HRGECs induced by HG[3]. | ||
| ln Vivo | In diabetic mice, rutinistaurin (1 mg/kg; 8 weeks) significantly reduces swiprosin-1 overexpression and GEC apoptosis while also improving renal glomerular damage. In diabetic mice, rutoxistaurin also significantly reduces the expression of PARP, cleaved-caspase9, cleaved-caspase3, and the Bax/Bcl-2 ratio[3]. Ruboxistaurin (0.1, 1.0, or 10.0 mg/kg; po) significantly lowers the quantity of leukocytes stuck in the diabetic rats' retinal microcirculation[4]. | ||
| Animal Protocol |
|
||
| References |
[1]. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinas. [2]. Ruboxistaurin: LY 333531. Drugs R D. 2007;8(3):193-199. [3]. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J Diabetes Sci Technol. 2007 Nov;1(6):929-35. [4]. PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2702-6. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.67 mg/mL (1.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.67 mg/mL (1.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9802 mL | 9.9008 mL | 19.8016 mL | |
| 5 mM | 0.3960 mL | 1.9802 mL | 3.9603 mL | |
| 10 mM | 0.1980 mL | 0.9901 mL | 1.9802 mL |