Abstract

The Hedgehog (Hh) signaling pathway plays varied and critical roles in animal development, homeostasis and diseases. This essential signaling pathway is involved in the modulation of the fate and behavior of cancer stem cells, as well as tumor growth and survival in many human cancer types. Hh ligands activate the pathway through binding Patched (Ptc), leading to the depression of Smoothened (SMO). SMO signals through a complex transduction machinery that includes the Gli family of transcription factors, resulting in the expression of Hh target genes, including Gli1 and Ptc.1,2 The SMO can be modulated by small molecules agonists or antagonists, such as LY2940680 a potent antitumor agent or purine derivatives as purmorphamine. Due to the relevance in Hh signaling pathway for the activation of a wide variety of cancers, our group is interested in the development of new ligands of SMO endowed with higher ability to inhibit the tumor growth. Therefore, using a 3D-molecular model of SMO made by us, we design and synthesized a library of tri-substituted purine derivatives andi investigated for their potential role as anti-tumor agents. Nineteen compounds were evaluated in vitro in lung (H1975) and colon cancer (HCT116) cell lines to determine their potential effect on cell toxicity by the MTT method and potential antiproliferative effects. Cytotoxicity assays showed that for H1975 cell line, IC50 values ranged from 38 to 83 nM; whereas, HT116 cell line, IC50 values were from 26 to 73 nM. In both cases resulting values were compared to as well-known and effective anti-cancer drug, etoposide. Currently, we are studying these compounds as potential antagonist agents