Abstract
New indanones, designated celludinones A ((±)-1) and B (2), were isolated from the culture broth of the fungal strain Talaromyces cellulolyticus BF-0307. The structures of celludinones were elucidated by spectroscopic data, including 1D and 2D NMR. Celludinone A was found to be a mixture of racemic isomers ((±)-1), which were isolated by a chiral column. Compounds (+)-1 and (−)-1 inhibited the sterol O-acyltransferase (SOAT) 1 and 2 isozymes in a cell-based assay using SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells, while 2 selectively inhibited the SOAT2 isozyme.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alger HM, et al. Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization. J Biol Chem. 2010;285:14267–74.
Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL. Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes. J Biol Chem. 1998;273:26765–71.
Cases S, et al. ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem. 1998;273:26755–64.
Parini P, et al. ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. Circulation. 2004;110:2017–23.
Rudel LL, Lee RG, Cockman TL. Acyl coenzyme A:cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr Opin Lipidol. 2001;12:121–7.
Buhman KK, et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med. 2000;6:1341–7.
Willner EL, et al. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA. 2003;100:1262–7.
Yagyu H, et al. Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. J Biol Chem. 2000;275:21324–30.
Fazio S, et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest. 2001;107:163–71.
Ohshiro T, Tomoda H. Isoform-specific inhibitors of ACATs: recent advances and promising developments. Future Med Chem. 2011;3:2039–61.
Ohshiro T, Tomoda H. Acyltransferase inhibitors: a patent review (2010-present). Expert Opin Ther Pat. 2015;25:145–58.
Lada AT, et al. Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. J Lipid Res. 2004;45:378–86.
Ohshiro T, Rudel LL, Omura S, Tomoda H. Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes. J Antibiot. 2007;60:43–51.
Ohshiro T, et al. Pyripyropene A, an acyl-coenzyme A:cholesterol acyltransferase 2-selective inhibitor, attenuates hypercholesterolemia and atherosclerosis in murine models of hyperlipidemia. Arterioscler Thromb Vasc Biol. 2011;31:1108–15.
Ohshiro T, et al. New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models. J Pharmacol Exp Ther. 2015;355:299–307.
Kyo T, Kawamura Y, Okazaki T, Mizogami K, Morimoto S. A benzophenone compound FD-549. Japan: Taisho Pharma Co Ltd; 1996.
Fujii T, Hoshino T, Inoue H, Yano S. Taxonomic revision of the cellulose-degrading fungus Acremonium cellulolyticus nomen nudum to Talaromyces based on phylogenetic analysis. FEMS Microbiol Lett. 2014;351:32–41.
Fujii T, Koike H, Sawayama S, Yano S, Inoue H. Draft genome sequence of talaromyces cellulolyticus strain Y-94, a source of lignocellulosic biomass-degrading enzymes. Genome Announc. 2015;3:e00014–00015.
Casarini D, Mancinelli M, Mazzanti A, Boschi F. Stereodynamics and absolute configuration of stereolabile atropisomers in 2,2-dimethyl-1-aryl-1-indanols. Chirality. 2011;23:768–78.
Aoyama T, Shioiri T. New methods and reagents in organic synthesis. 8. Trimethylsilyldiazomethane. A new, stable, and safe reagent for the classical arndt-eistert synthesis. Tetrahedron Lett. 1980;21:4461–2.
Ohshiro T, et al. Selective inhibition of sterolO-acyltransferase 1 isozyme by beauveriolide III in intact cells. Sci Rep. 2017;7:4163.
Tomoda H, Omura S. Potential therapeutics for obesity and atherosclerosis: inhibitors of neutral lipid metabolism from microorganisms. Pharmacol Ther. 2007;115:375–89.
Acknowledgements
We wish to thank Ms. Noriko Sato and Dr. Kenichiro Nagai (Graduate School of Pharmaceutical Sciences, Kitasato University) for the measurements of NMR spectra and MS data, and Prof. L.L. Rudel (Wake Forest University, Winston-Salem, NC, USA) for kindly providing SOAT1-CHO and SOAT2-CHO cells. This work was supported by JSPS KAKENHI Grant numbers JP26253009 (HT) and JP16K18900 (TO), the Takeda Science Foundation (HT), and a Kitasato University Research Grant for Young Researchers (TO).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Ohshiro, T., Seki, R., Fukuda, T. et al. Celludinones, new inhibitors of sterol O-acyltransferase, produced by Talaromyces cellulolyticus BF-0307. J Antibiot 71, 1000–1007 (2018). https://doi.org/10.1038/s41429-018-0097-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41429-018-0097-0
This article is cited by
-
Celludinone C, a new dihydroisobenzofuran isolated from Talaromyces cellulolyticus BF-0307
The Journal of Antibiotics (2025)
-
New dihydronaphthothiophene derivatives by the biological transformation of seriniquinone using marine-derived actinomycete Streptomyces albogriseolus OM27-12
The Journal of Antibiotics (2022)
-
Voluhemins, new inhibitors of sterol O-acyltransferase, produced by Volutella citrinella BF-0440
The Journal of Antibiotics (2020)
