Original article Synthesis and cytotoxic activity of a-santonin derivatives Francisco F.P. Arantes a , Luiz C.A. Barbosa a, * , Elson S. Alvarenga a , Anto ˆnio J. Demuner a , Daniel P. Bezerra b , Jose ´ R.O. Ferreira b , Letı ´cia V. Costa-Lotufo b , Cla ´ udia Pessoa b , Manoel O. Moraes b a Department of Chemistry, Federal University of Viçosa, Av. P.H. Rolfs, S/N, CEP 36570-000 Viçosa, MG, Brazil b Department of Physiology and Pharmacology, Federal University of Ceara ´, Rua Coronel Nunes de Melo 1127, CEP 60431-970 Fortaleza, CE, Brazil article info Article history: Received 31 July 2008 Received in revised form 2 March 2009 Accepted 26 March 2009 Available online xxx Keywords: a-Santonin derivatives Photochemistry Sesquiterpene lactones Cytotoxicity abstract Ten a-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10a- acetoxy-3-oxo-1,7aH,6,11bH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10a-hydroxy-3-oxo- 1,7aH,6,11bH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using a-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of a-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7aH,6bH,11- (phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7aH,6bH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10a-acetoxy-3-oxo-1,7aH,6bH-guai-4, 11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10a-acetoxy-3b-hydroxy-1,7aH,6,11bH-guai-4-en-6,12-olide (10) and 3b,10a-hydroxy-1,7aH,6,11bH- guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC 50 values in the range of 0.36–14.5 mM, showed as common structural feature the presence of an a-methylidene-g-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction According to the World Health Organization (WHO), cancer is an important health problem that claims the lives of more than seven million people worldwide on an annual basis [1]. As a consequence, search for new anticancer drugs is highly demanding nowadays. However, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable side effects. There- fore, the development of innovative and efficacious tumor-specific drug delivery protocols or systems is urgently needed [2,3]. Within this framework, the natural products continue to be a rich source of new promising substances [4]. Sesquiterpene lactones (SQLs) are a class of naturally occurring plant terpenoids of Asteraceae family, known for their various biological activities such as anti-inflam- matory, phytotoxic, antimicrobial, antiprotozoal, and, cytotoxicity against different tumor cell lines [5–9]. These different activities have been linked mainly to the a-methylene-g-lactone functionality, which is prone to react with suitable nucleophiles, e.g., sulfhydryl groups of cysteine, in a Michael addition fashion. These reactions are nonspecific, leading to the inhibition of a large number of enzymes or factors involved in key biological processes [10–15]. It is well known, however, that the a-methylene-g-lactone moiety is not an absolute requirement for cytotoxicity. It has been demonstrated that thiols do undergo ‘‘Michael-type’’ additions not only to the exocyclic methylene of sesquiterpene lactones but also to the a,b-unsaturated cyclo- pentenone moiety [12]. The precise mechanism by which SQLs inhibit the cell growth remains unclear. Several experimental data indicate that cytotoxic activity of these compounds is strongly related to their inhibitory * Corresponding author. Tel.: þ55 31 3899 3068; fax: þ55 31 3899 3065. E-mail address: lcab@ufv.br (L.C.A. Barbosa). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech ARTICLE IN PRESS 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.03.036 European Journal of Medicinal Chemistry xxx (2009) 1–7 Please cite this article inpress as: F.F.P. Arantes, et al., Synthesis and cytotoxic activity of a-santonin derivatives, European Journal of Medicinal Chemistry (2009), doi:10.1016/j.ejmech.2009.03.036