We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

Departamento de Farmacia Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile Santiago de Chile 702843 Chile

Departamento de Química Facultad de Ciencias Básicas Universidad de Antofagasta Av Angamos 601 Antofagasta 1240000 Chile

Departamento de Química Inorgánica Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile Santiago de Chile 702843 Chile

Departamento de Química Orgánica Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile Santiago de Chile 702843 Chile

Innopharma Screening Platform BioFarma Research Group Centre for Research in Molecular Medicine and Chronic Diseases University of Santiago de Compostela Santiago de Compostela 15706 Spain

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Hnevotinská 5 77900 Olomouc Czech Republic

Instituto de Química y Bioquímica Facultad de Ciencias Universidad de Valparaíso 2360102 Av Gran Bretaña 1111 Playa Ancha Valparaíso Casilla 5030 Chile

Laboratory of Growth Regulators Centre of the Region Haná for Biotechnological and Agricultural Research Palacký University and Institute of Experimental Botany AS CR Slechtitelu 27 783 71 Olomouc Czech Republic

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Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia