Synthesis, antitumoral activity, and in silico studies on Smoothened receptor of new 2,6,9-trisubstituted purine derivatives

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dc.article.number141228
dc.catalogadorvzp
dc.contributor.authorEspinosa Bustos, Christian Marcelo
dc.contributor.authorZarate Méndez, Ana María
dc.contributor.authorCastro Álvarez, Alejandro
dc.contributor.authorGuerrero, Simón
dc.contributor.authorKogan, Marcelo J.
dc.contributor.authorSalas Sánchez, Cristian Osvaldo
dc.date.accessioned2025-03-14T16:33:44Z
dc.date.available2025-03-14T16:33:44Z
dc.date.issued2025
dc.description.abstract© 2024 Elsevier B.V.In 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. IC50 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.
dc.fuente.origenSCOPUS
dc.identifier.doi10.1016/j.molstruc.2024.141228
dc.identifier.issn0022-2860
dc.identifier.scopusidSCOPUS_ID:85213967725
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/102636
dc.identifier.urihttps://doi.org/10.1016/j.molstruc.2024.141228
dc.information.autorucEscuela de Química; Espinosa Bustos, Christian Marcelo; 0000-0001-6038-8439; 142011
dc.information.autorucEscuela de Química; Zarate Méndez, María; S/I; 169850
dc.information.autorucEscuela de Química; Salas Sánchez, Cristian Osvaldo; 0000-0001-7620-2459; 101425
dc.language.isoen
dc.publisherElsevier B.V.
dc.revistaJournal of Molecular Structure
dc.rightsacceso restringido
dc.subjectCancer
dc.subjectCytotoxicity
dc.subjectDocking study
dc.subjectMicrowave-assisted synthesis
dc.subjectPurine derivatives
dc.subjectSmoothened receptor
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSynthesis, antitumoral activity, and in silico studies on Smoothened receptor of new 2,6,9-trisubstituted purine derivatives
dc.typeartículo
dc.volumen1328
sipa.codpersvinculados142011
sipa.codpersvinculados169850
sipa.codpersvinculados101425
sipa.trazabilidadSCOPUS;2025-01-19
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