Novel potent organoselenium compounds as cytotoxic agents in prostate cancer cells Daniel Plano, a Carmen Sanmartı ´n, a Esther Moreno, a Celia Prior, b Alfonso Calvo b and Juan Antonio Palop a, * a Seccio ´n de Sı ´ntesis, Departamento de Quı ´mica Orga ´nica y Farmace ´utica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain b Oncology Division, Center for Applied Medical Research, CIMA, University of Navarra, Pı´o XII, 53, E-31008 Pamplona, Spain Received 31 August 2007; revised 4 October 2007; accepted 5 October 2007 Available online 17 October 2007 Abstract—A series of 17 symmetrical substituted imidothiocarbamate and imidoselenocarbamate derivatives has been syn by reacting appropriately substituted acyl chlorides with alkyl imidothiocarbamates and alkyl imidoselenocarbamates. The moral activities of the compounds were evaluated in vitro by examining their cytotoxic effects against human prostate can (PC-3). Five compounds showed interesting activity levels and 3p (IC 50 = 1.85 lM) was 7.3 times more active than the standard eto- poside used in the treatment of prostate cancer and emerges as the most interesting compound. 2007 Elsevier Ltd. All rights reserved. Numerous observations in the epidemiological literature have linked various dietary, lifestyle, genetic, and non- traditionalfactors with the risk of developing prostate cancer. 1 Prostate cancer is the most common cancer in men and the second highest cause of male cancer deaths in the United States and the United Kingdom. In recent years,many epidemiological studies 2–5 have suggested that an essential trace element, such as selenium (Se), acts to protect against cancer, particularly prostate can- cer. 6 There is a marked geographic variability of Se in food and this is related to local soil content. Se is also widely available in over-the-counter supplements and multivitamins. There is increasing evidence to suggest that Se works by inhibiting important molecular path- ways of the early carcinogenesis in a variety of experi- mental modelsand that the anticanceractivity is dependent on its chemical form. Se occurs in both or- ganic and inorganic forms. The organic form is found predominantly in grains, fish,meat,poultry,eggs,and dairy products and enters the food chain through plant consumption. 7,8 A number of potentialmechanisms have been proposed for its antitumorigenic effects and these include antiandrogen activity. 9,10 It has also been suggested that selenium may exert growth inhibitory ef- fects by regulation of p53, 11,12 by antioxidant function, 13 DNA damage, 14 and numerous pathways involve apop- tosis 15–19 as a critical event. The regulatory mechanisms of apoptosis are extremely complex and for selenium compoundsthey mainly involvemitochondrialpath- way, 15,16 protein kinases, 17 tumor necrosisfactor, 18 and reactive oxygen species. 19 A survey of the diverse lit- erature in this field shows that very few organoselenium compounds have been described, but those that have do show promising activities. Among them are the seleno- proteins, 20 such as selenomethionine and methylseleno- cysteine, and a number of synthetic derivatives such as p-xylylbismethylselenide, sodium selenite, 21 and methyl- seleninic acid. 22 In addition, the combination of some of these derivatives with chemotherapeutic agents shows synergisticactivity in prostatecancer.For instance, methylselenocysteine enhances the effect of docetaxel, 23 whereasmethylseleninic acid improvessubstantially the therapeutic effect of etoposide in vivo. 24 In recent reports, we have described 25–28 the synthesis, cytotoxicity, and apoptotic evaluation of a series of sym- metrical diaryl derivatives. We observed that symmetry is a structuralproperty thatis frequently present in cytotoxic and proapoptotic drugs. 29 In addition,some 0960-894X/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.10.022 Keywords: Organoselenium; Cytotoxics; Prostate. * Corresponding author. Tel.: +34 948 425 600; fax: +34 948 425 649; e-mail: jpalop@unav.es Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 6853–6859