Inhibitors DOI: 10.1002/anie.200605207 Phloroglucinol Derivatives Guttiferone G, Aristoforin, and Hyperforin: Inhibitors of Human Sirtuins SIRT1 and SIRT2** Claudia Gey, Sergiy Kyrylenko, Lothar Hennig, Lien-HoaD. Nguyen, Anita Büttner, Hung D. Pham, and Athanassios Giannis* Dedicated to Professor Peter Welzel on the occasion of his 70th birthday SirtuinsareclassIIIhistonedeacetylasesandarehomologous tosilentinformationregulator2(Sir2)ofyeast. [1] Deacetyla- tionbysirtuinswasshowntobeNAD + dependent, with the acetyl group being transferred to the ADP-ribose portion of NAD + toyield2’-O-acetyl-ADP-ribose(OAADPR)andfree nicotinamide. [2] Seven enzymes of this class have been identified in humans so far (SIRT1–7), but the function of mostofthemremainselusive. [3] However,SIRT1andSIRT2 have been intensively investigated. [4,5] SIRT1wasshowntoinactivatetumorsuppressorprotein p53 by deacetylating Lys382. [4] In this way, SIRT1 prevents cells from apoptosis induced by DNA damage and stress. Other transcription factors deacetylated by SIRT1 are the Forkhead transcription factors FOXO1, FOXO3, and FOXO4aswellasKu70,NFk-B,andMyoD. [5] Furthermore, SIRT1regulatesHIVreplicationbydeacetylationoftheviral transcriptionfactorTat. [6] SIRT2togetherwithHDAC6were showntodeacetylate a-tubulin, [7] thusrenderingthemcontrol elementsintheformationofmicrotubules.Inaccordancewith that finding, SIRT2 was shown to control mitosis within the cellcycle. [8] After the identification of the yeast Sir2 protein as a regulator of gene expression, sirtuins have now been pro- posedtoinfluenceavarietyofcellularprocesses,amongthem energy metabolism, cell-cycle progression, muscle differen- tiation, fat mobilization, and aging. [5] Therefore, the use of small molecules as regulators of sirtuin activity is of high pharmacological interest. However, only a few inhibitors of sirtuins have been reported so far. With the exception of nicotinamide, which is released during the reaction with the deacetylase and which serves as an internal inhibitor by blocking NAD + hydrolysis, [9] most of the inhibitors are syntheticallyderivedandwereidentifiedinlibraryscreening studies. Sirtuin inhibitors can roughly be grouped into NAD + derivatives (nicotinamide, carba-NAD + , NADH), coumarin derivatives(dihydrocoumarin,A3,splitomicin,HR73),and2- hydroxynaphthaldehyde derivatives (2-OH-naphthaldehyde, sirtinol, para-sirtinol, M15, cambinol). [6,10] Other inhibitors are CD04097 (which consists of three highly substituted benzenerings),thetricyclicderivativeJFD00244,andindole derivativeEX527. [11] Themostpotentinhibitoramongthemis EX527, which inhibits SIRT1 at a nanomolar concentration andSIRT2atalowmicromolarconcentration; [11b] sirtinolwas shown to inhibit only SIRT2 (IC 50 = 38 mm). [12a] Recently, several adenosine mimetics were identified as inhibitors of sirtuins. [12b] Herein we present a new class of compounds originating fromnaturalsourcesthatinhibitbothSIRT1andSIRT2ata low micromolar concentration: guttiferoneG, which was extracted from Garcinia cochinchinensis , a tree growing in Vietnam; hyperforin, a well known pharmacological agent initially extracted from Hypericum perforatum (St.John)s wort), and its synthetic derivative aristoforin. Furthermore, we propose that the pharmacological effects of the phloro- glucinol derivative hyperforin and of the guttiferones are associatedwithsirtuinactivity. Fractionationofthepetroleumetherextractofthebarkof Garcinia cochinchinensis afforded compound 1. The molec- ular formula was established as C 43 H 58 O 6 from high-resolu- tion mass spectrometry ([M+H] + : m/z 671.4318). Detailed examination by 1D and 2D NMR methods and comparison with the literature data resulted in the identification of 1 as guttiferoneG(Scheme1).The 1 Hand 13 CNMRdata(seethe Supporting Information) are in good agreement with the literaturedataofguttiferoneG. [13] The compound isolated from Garcinia cochinchinensis , however, showed positive specific rotation ([a] D = + 27.1degcm 3 g À1 dm À1 , c = 1.7gcm À3 , CHCl 3 ), while the specific rotation of guttiferoneG isolated from Garcinia macrophylla was negative ([a] D = À25degcm 3 g À1 dm À1 , c = 0.04gcm À3 ,CHCl 3 ). [13a] Thusitispresumedthatourisolated guttiferoneGisthe(+)enantiomer(Scheme1). [*] C. Gey, Dr. L. Hennig, A. Büttner, Prof.Dr. A. Giannis Institut für Organische Chemie Universität Leipzig Johannisallee 29, 04103 Leipzig (Germany) Fax: (+ 49)341-973-6599 E-mail: giannis@uni-leipzig.de Dr. S. Kyrylenko Department of Biochemistry University of Kuopio Yliopiostonranta 1E, 70210 Kuopio (Finland) E-mail: kyrylenk@messi.uku.fi Dr. L.-H. Nguyen, Prof. Dr. H. D. Pham Department of Organic Chemistry University of Natural Sciences Ho Chi Minh City, 227 Nguyen Van Cu, District 5, HCMC (Vietnam) E-mail: lienhoa@saigonnet.vn [**] We thank Prof. Peter Welzel for helpful discussions and the Bundesministerium für Forschung und Technologie (BioChance- PLUS) for financial support. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 5219 Angew. Chem. Int. Ed. 2007, 46, 5219 –5222 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim