Pyripyropene A
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| Category | Enzyme inhibitors |
| Catalog number | BBF-02592 |
| CAS | 147444-03-9 |
| Molecular Weight | 583.62 |
| Molecular Formula | C31H37NO10 |
| Purity | ≥95% |
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Description
Pyripyropene A is a powerful acyl-CoA: cholesterol acyltransferase 2 (ACAT2) inhibitor produced by the fungus Aspergillus fumigatus FO 1289. It inhibits acyl-CoA: cholesterol acyltransferase with an IC50 of 58 nmol/L.
Specification
| Synonyms | (3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-(acetoxymethyl)-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(pyridin-3-yl)-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H,11H-benzo[f]pyrano[4,3-b]chromene-3,6-diyl diacetate; (3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-(Acetoxymethyl)-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(pyridin-3-yl)-1,2,3,4,4a,5,6,6a,11,12,12a,12b-dodecahydrobenzo[f]pyrano[4,3-b]chromene-3,6-diyl diacetate |
| IUPAC Name | [(1S,2S,5S,6R,7R,9S,10S,18R)-5,9-diacetyloxy-18-hydroxy-2,6,10-trimethyl-16-oxo-14-pyridin-3-yl-11,15-dioxatetracyclo[8.8.0.02,7.012,17]octadeca-12(17),13-dien-6-yl]methyl acetate |
| Canonical SMILES | CC(=O)OCC1(C(CCC2(C1CC(C3(C2C(C4=C(O3)C=C(OC4=O)C5=CN=CC=C5)O)C)OC(=O)C)C)OC(=O)C)C |
| InChI | InChI=1S/C31H37NO10/c1-16(33)38-15-30(5)22-13-24(40-18(3)35)31(6)27(29(22,4)10-9-23(30)39-17(2)34)26(36)25-21(42-31)12-20(41-28(25)37)19-8-7-11-32-14-19/h7-8,11-12,14,22-24,26-27,36H,9-10,13,15H2,1-6H3/t22-,23+,24+,26+,27-,29+,30+,31-/m1/s1 |
| InChI Key | PMMQOFWSZRQWEV-RVTXXDJVSA-N |
Properties
| Appearance | Crystalline Solid |
Reference Reading
1.Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 3.
Ohtawa M1, Yamazaki H, Ohte S, Matsuda D, Ohshiro T, Rudel LL, Ōmura S, Tomoda H, Nagamitsu T. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3798-801. doi: 10.1016/j.bmcl.2013.04.075. Epub 2013 May 8.
In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). In particular, we investigated the possibility of introducing appropriate 1,11-O-benzylidene and 7-O-substituted benzoyl moieties into PPPA (1). The new o-substituted benzylidene derivatives showed higher selectivity for ACAT2 than PPPA (1). Among them, 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl PPPA derivative 7q and 1,11-O-o,o-dimethylbenzylidene-7-O-p-cyanobenzoyl PPPA derivative 7z proved to be potent ACAT2 inhibitors with unprecedented high isozyme selectivity.
2.Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 2.
Ohtawa M1, Yamazaki H, Matsuda D, Ohshiro T, Rudel LL, Ōmura S, Tomoda H, Nagamitsu T. Bioorg Med Chem Lett. 2013 May 1;23(9):2659-62. doi: 10.1016/j.bmcl.2013.02.088. Epub 2013 Mar 6.
Synthesis and structure-activity relationships of 7-O-p-cyanobenzoyl pyripyropene A derivatives with modification at C1 and 11 are described. Regioselective mono-deprotection of di-tert-butylsilylene acetal was critical in their synthesis.
3.New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models.
Ohshiro T1, Ohtawa M1, Nagamitsu T1, Matsuda D1, Yagyu H1, Davis MA1, Rudel LL1, Ishibashi S1, Tomoda H2. J Pharmacol Exp Ther. 2015 Nov;355(2):299-307. doi: 10.1124/jpet.115.227348. Epub 2015 Sep 3.
Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe(-/-)) mice or low-density lipoprotein receptor knockout (Ldlr(-/-)) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe(-/-) mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.
4.In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.
Matsuda D1, Ohshiro T2, Ohtawa M1, Yamazaki H1, Nagamitsu T1, Tomoda H1. J Antibiot (Tokyo). 2015 Jan;68(1):27-34. doi: 10.1038/ja.2014.91. Epub 2014 Jul 9.
Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis. Furthermore, dehydrogenation of the newly generated 11-alcoholic hydroxyl residue occurred in human and mouse-liver microsomes, while oxidation of the pyridine ring occurred in human and rabbit liver microsomes. On the other hand, hydrolysis of the 7-O-acetyl residue proceeded only in the mouse plasma. These data indicated that the in vitro metabolic profiles of 1 have subtle differences among animal species.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
