Espinosa-Bustos, ChristianChristianEspinosa-BustosZárate, Ana MariaAna MariaZárateCastro-Alvarez, AlejandroAlejandroCastro-AlvarezGuerrero, SimonSimonGuerreroKogan, Marcelo JavierMarcelo JavierKoganSalas, Cristian O.Cristian O.Salas2025-10-102025-10-102025222860https://hdl.handle.net/20.500.12740/23417In this work, a series of 30 new 2,6,9-trisubstituted purine derivatives were synthesised and evaluated in silico as potential ligands of the Smoothened (SMO) receptor, as well as their ability to inhibit growth in Hedgehog (Hh)-dependent and Hh-independent cancer cell lines. The synthesis involved a convergent strategy, conventional methods and microwave irradiation. Initial antitumour evaluation was performed by testing cell growth inhibition in seven cancer cell lines and one non-neoplastic cell line (HEK-293) at 50 μM. IC<inf>50</inf> values were determined for compounds showing < 50 % cell viability. Compounds 7l and 9j showed promising results with high cytotoxicity in three Hh-dependent cell lines and low cytotoxicity in HEK-293 cells. Compound 7l was more potent and selective than gemcitabine in BxPC-3, AsPc-1 and MIA-PaCa-2 cells and more than 5-fluorouracil in HT-29 cells, while 9j was more potent and selective than 5-fluorouracil in HCT116 and HT-29 cells. Molecular docking studies in SMO allowed the recognition of two binding sites related to ligand size and purine substitution patterns, while 7l bound to the top pocket (TMD-1), 9j bound to a deeper pocket (TMD-2). This study provides new evidence supporting the purine ring as a privileged scaffold for the development of new antitumour drugs targeting the SMO receptor. © 2025 Elsevier B.V., All rights reserved.restrictedAccessCANCERCYTOTOXICITYDOCKING STUDYMICROWAVE-ASSISTED SYNTHESISPURINE DERIVATIVESSMOOTHENED RECEPTORCELL CULTURE5-FLUOROURACILCANCER CELL LINESCELL LINESDOCKING STUDIESHEK-293IN-SILICOMICROWAVE ASSISTED SYNTHESISMOLECULAR DOCKINGArtículo https://doi.org/10.1016/j.molstruc.2024.141228