Synthetic Chalcone Derivatives as Inhibitors of Cathepsins K and B, and Their Cytotoxic Evaluation by Suelem Demuner Ramalho a ) b ), Aline Bernades c ), Giulio Demetrius a ), Caridad Noda-Perez* c ), Paulo Cezar Vieira b ), Caio Yu dos Santos b ), James Almada da Silva b ), Manoel Odorico de Moraes d ), and Kristiana Cerqueira Mousinho d ) a ) Department of Chemistry, State University of Goia ´s, 495, Ana ´polis, GO, Brazil b ) Department of Chemistry, Federal University of Sa ˜o Carlos, 13565-905, Sa ˜o Carlos, SP, Brazil c ) Chemical Institute, Federal University of Goia ´s, 74001-970, Goia ˆnia, GO, Brazil (phone: þ 55- 6235211094; fax: þ 55-6235211167; e-mail: carynoda@yahoo.com.br) d ) Department of Physiology and Pharmacology, Federal University of Ceara ´, 3157, Fortaleza, CE, Brazil A series of chalcone derivatives, 1 – 15, were prepared by Claisen Schmidt condensation and evaluated for their cytotoxicities on tumor cell lines and also against proteolytic enzymes such as cathepsins B and K. Of the compounds synthesized, ( E)-3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1- one (12), ( E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (13), ( E)-3-(4-methoxyphenyl)-1-phenyl- prop-2-en-1-one (14), and ( E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (15) showed significant cytotoxicities. The most effective compound was 15, which showed high cytotoxic activity with an IC 50 value lower than 1 mg/ml, and no selectivity on the tumor cells evaluated. Substituents at C(4) of ring B were found to be essential for cytotoxicity. In addition, it was also demonstrated that some of these chalcones are moderate inhibitors of cathepsin K and have no activity against cathepsin B. Introduction. – Cancer is a leading cause of death worldwide. According to the World Health Organization (WHO), deaths from cancer are projected to continue rising to over 11 million in 2030. Cancer arises from a change in one single cell, and this change may be started by either external agents or inherited genetic factors [1] . Among the methods used to control the cancer are chemotherapeutic agents, which unfortunately possess high toxicity, multidrug resistance (MDR), and limited effectiveness [2 – 4]. So, the development of new drugs plays an important role in cancer control [5]. Most of the successful anticancer drugs acting as antimitotics originate in natural compounds [6] . Flavonoids are an extensive and diversified group of compounds found in edible plants with high abundance [7 – 9]. Among flavonoids, chalcones have been identified as interesting compounds, which are associated with a wide range of biological properties such as antimalarial [10], antileishmanial [11], antioxidative activities [12], antiviral [13], analgesic [14], anti-inflammatory activities [12], and cytotoxicity towards cancer cell lines [8] [15]. They consist of open-chain flavonoids, and one of the most widely cited mechanism is that chalcones exert their cytotoxic activity by interfering with mitotic phase in the cell cycle [3] [7] [15] [16]. In fact, it has been reported that chalcones act as tubulin-polymerization inhibitors. Tubulin occurs as a heterodimer of a- and b-subunits, and plays a vital role in various biochemical processes of cell survival and growth [17] [18]. CHEMISTRY & BIODIVERSITY – Vol. 10 (2013) 1999 # 2013 Verlag Helvetica Chimica Acta AG, Zürich