75225-51-3

Usage

Definition

ChEBI: A polyketide obtained by hydrolysis of the pyranone ring of lovastatin.

InChI:InChI=1/C24H38O6/c1-5-15(3)24(29)30-21-11-14(2)10-17-7-6-16(4)20(23(17)21)9-8-18(25)12-19(26)13-22(27)28/h6-7,10,14-16,18-21,23,25-26H,5,8-9,11-13H2,1-4H3,(H,27,28)/t14-,15-,16-,18+,19+,20-,21-,23-/m0/s1

Upstream product

• 75330-75-5 lovastatin 
• 132748-10-8 (3R,5R)-3,5-dihydroxy-7-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoic acid 
• 1730-91-2 (S)-2-Methylbutyric acid 
• 945630-22-8 α-S-methylbutyryl-S-N-acetylcysteamine 
• 87069-91-8 α-S-methylbutyryl-CoA 

Downstream Products

• 75330-75-5 lovastatin 
• 151006-15-4 (4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one 
• 132748-10-8 (3R,5R)-3,5-dihydroxy-7-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoic acid 
• 1431473-49-2 (1S,3R,7S,8S,8αR)-8-(2-((2R,4R)-4-((tert-butyldimethylchlorosilane)oxy)-6-oxohexahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8α-hexahydronaphthalene-1-yl(4-nitrophenyl)carbonate 
• 1431473-50-5 (4R,6R)-6-[2-((1S,2S,6R,8S,8aR)-8-[((4-ethynylphenyl)carbamoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-3,4,5,6-tetrahydro-2H-pyran-2-one 
• 1431473-51-6 (4R,6R)-6-[2-((1S,2S,6R,8S,8aR)-8-[((4-ethynylbenzyl)carbamoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-3,4,5,6-tetrahydro-2H-pyran-2-one 
• 79902-31-1 (4R,6R)-6-[2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-3,4,5,6-tetrahydro-2H-pyran-2-one 
• 1431473-54-9 (4R,6R)-6-[2-((1S,2S,6R,8S,8aR)-8-[((4-{1-[7-(hydroxyamino)-7-oxoheptyl]-1H-1,2,3-triazol-4-yl}phenyl)carbamoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthyl)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-3,4,5,6-tetrahydro-2H-pyran-2-one 
• 1431473-52-7 C₄₁H₆₀N₄O₇Si 

Relevant academic research and scientific papers

Lipophilic statins inhibit growth and reduce invasiveness of human endometrial stromal cells

Purpose: To compare effects of lipid-soluble statins (simvastatin, lovastatin, atorvastatin) and water-soluble statin (pravastatin) on growth and invasiveness of human endometrial stromal (HES) cells. Methods: Endometrial biopsies were collected during the proliferative phase from five volunteers. HES cells were isolated and cultured in the absence or in the presence of simvastatin, lovastatin, atorvastatin, and pravastatin. Effects of statins on DNA synthesis, cell viability, activity of caspases 3/7 and invasiveness were evaluated. Results: The proliferation of HES cells was significantly decreased by simvastatin (by 47–89%), lovastatin (by 46–78%), and atorvastatin (by 21–48%) in a concentration-dependent manner. Activity of executioner caspases 3/7 was significantly increased by simvastatin (by 10–25%), lovastatin (by 19%) and atorvastatin (by 7–10%) in a concentration-dependent manner. The greatest effects were observed in response to simvastatin. Accounting for the effects of statins on cell number, the invasiveness of HES cells was significantly decreased in cells treated with simvastatin (by 49%), lovastatin (by 54%), and atorvastatin (by 53%). Pravastatin had little or no effects on any of the tested endpoints. Conclusions: Present findings demonstrate that only lipid-soluble among tested statins were effective in inhibition of growth and invasiveness of HES cells. These findings may have clinical relevance in treatment of endometriosis.

The evaluation of statins as potential inhibitors of the LEDGF/p75-HIV-1 integrase interaction

Lovastatin was identified through virtual screening as a potential inhibitor of the LEDGF/p75-HIV-1 integrase interaction. In an AlphaScreen assay, lovastatin inhibited the purified recombinant protein-protein interaction (IC50 = 1.97 ± 0.45 μM) more effectively than seven other tested statins. None of the eight statins, however, yielded antiviral activity in vitro, while only pravastatin lactone yielded detectable inhibition of HIV-1 integrase strand transfer activity (31.65% at 100 μM). A correlation between lipophilicity and increased cellular toxicity of the statins was observed.

DUAL ACTION INHIBITORS AGAINST HISTONE DEACETYLASES AND 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE

Disclosed herein are novel compounds of formula (I), and uses thereof. The compounds of Formula (I) are inhibitors of histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR). Also provided are methods of using the

Acyltransferase mediated polyketide release from a fungal megasynthase

(Chemical Equation Presented) LovF is a highly reducing polyketide synthase (HR-PKS) from the filamentous fungus Aspergillus terreus. LovF synthesizes the α-S-methylbutyrate side chain that is subsequently transferred to monacolin J to yield the cholesterol-lowering natural productlovastatin. In the report, we expressed the full length LovF and recons tituted the megasynthase activities in vitro. We confirmed the diketide product of LovF is offloaded from the LovF ACP domain by the dissociatedacyltransferase LovD. This represents the first example of acyltransfer ase-mediated release of polyketide products from fungal PKSs. We determined LovD primarily interacts with the ACP domain of LovF and the protein-protein interactions lead to highly efficient transfer of the diketide product. The catalytic efficiency is enhanced nearly 1 × 106-fold when LovF was used as the acyl carrier instead of N-acetylcysteamine. Reconstitution and characterization of the LovF offloading mechanism provide new insights into the functions of fungal HR-PKS.

Association between risk of myopathy and cholesterol-lowering effect: A comparison of all statins

In the present study, we examined the mechanisms underlying the cytotoxicity of pitavastatin, a new statin, and we compared the in vitro potencies of muscle cytotoxicity using a prototypic embryonal rhabdomyosarcoma cell line (RD cells), a typical side effect of statins and compared the cholesterol-lowering effects of statins using Hep G2 hepatoma cells. Pitavastatin reduced the number of viable cells and caused caspase-9 and -3/7 activation in a time- and concentration-dependent manner. The comparison of cytotoxities of statins showed that statins significantly reduced cell viability and markedly enhanced activity of caspase-3/7 in concentration-dependent manner. On the other hand, the effects of hydrophilic statins, pravastatin, rosuvastatin were very weak. The rank order of cytotoxicity was cerivastatin > simvastatin acid> fluvastatin > atorvastatin > lovastatin acid > pitavastatin ? rosuvastatin, pravastatin. Statin-induced cytotoxicity is associated with these partition coefficients. On the other hand, the cholesterol-lowering effect of statins did not correlate with these partition coefficients and cytotoxicity. Thus, it is necessary to consider the association between risk of myopathy and cholesterol-lowering effect of a statin for precise use of statins.

METHODS FOR MAKING SIMVASTATIN AND INTERMEDIATES

The invention provides synthetic chemical and chemoenzymatic methods of producing simvastatin and various intermediates. In one aspect, enzymes such as hydrolases, e.g., esterases, are used in the methods of the invention.

Monocarboxylate transporter mediates uptake of lovastatin acid in rat cultured mesangial cells.

To clarify the uptake mechanism(s) for statins, we examined whether monocarboxylate transporter (MCT) contributed to the uptake of lovastatin acid by rat cultured mesangial cells. Expression of mRNAs for MCT1, 2, and 4 was confirmed in mesangial cells. Th

Inhibitory effect of statins on fetal bovine serum-induced proliferation of rat cultured mesangial cells and correlation between their inhibitory effect and transport characteristics

Mesangial cells play an important role in physiologic functions, including the regulation of glomerular filtration, and as a pathogenic factor for proliferative glomerulonephritis. We compared the potencies of the inhibitory effects of simvastatin acid, lovastatin acid, and pravastatin on fetal bovine serum (FBS)-induced proliferation of rat cultured mesangial cells, and examined the correlation between their inhibitory effects and intracellular concentrations. We also investigated the transport of the statins in the cells, and whether or not their intracellular concentrations were determined by their transport characteristics. It appeared that the growth inhibitory effects on FBS-induced proliferation of mesangial cells of simvastatin acid and lovastatin acid were approximately the same, but that of pravastatin was extremely weak compared with the others. The growth inhibitory effects of these agents were suggested to depend, at least in part, on the amount incorporated intracellularly. Simvastatin acid, lovastatin acid, and pravastatin appeared to be taken up by mesangial cells via a common carrier, the uptake capacity being determined by their lipophilicity. Therefore, it was thought that the growth inhibitory effects of the statins partially depended on their carrier-mediated uptake by mesangial cells. (C) 2000 Wiley-Liss, Inc.