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Promising 2,6,9-trisubstituted purine derivatives for anticancer compounds: Synthesis, 3D-QSAR, and preliminary biological assays
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SYSNO ASEP 0523953 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Promising 2,6,9-trisubstituted purine derivatives for anticancer compounds: Synthesis, 3D-QSAR, and preliminary biological assays Author(s) Salas, C. O. (CL)
Zarate, A. M. (CL)
Kryštof, Vladimír (UEB-Q) RID, ORCID
Mella, J. (CL)
Faundez, M. (CL)
Brea, J. (ES)
Loza, M. I. (ES)
Brito, I. (CL)
Hendrychová, Denisa (UEB-Q) ORCID
Jorda, Radek (UEB-Q) ORCID, RID
Cabrera, A. R. (CL)
Tapia, R. A. (CL)
Espinosa-Bustos, C. (CL)Number of authors 13 Article number 161 Source Title International Journal of Molecular Sciences. - : MDPI
Roč. 21, č. 1 (2020)Number of pages 28 s. Language eng - English Country CH - Switzerland Keywords 3d-qsar ; Apoptosis ; Cancer ; Cell cycle ; Cytotoxicity ; Purine derivatives Subject RIV FD - Oncology ; Hematology OECD category Oncology Method of publishing Open access Institutional support UEB-Q - RVO:61389030 UT WOS 000515378000161 EID SCOPUS 85077996434 DOI 10.3390/ijms21010161 Annotation 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2021 Electronic address http://doi.org/10.3390/ijms21010161
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