{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:11:15Z","timestamp":1790856675722,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2018,8,10]],"date-time":"2018-08-10T00:00:00Z","timestamp":1533859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1\u20133 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2\/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2\/M phase in all the cell lines used, similar concentrations of 1\u20133 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.<\/jats:p>","DOI":"10.3390\/molecules23081996","type":"journal-article","created":{"date-parts":[[2018,8,10]],"date-time":"2018-08-10T10:52:01Z","timestamp":1533898321000},"page":"1996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Bartolomeo","family":"Bosco","sequence":"first","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Defant","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Messina","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5573-1914","authenticated-orcid":false,"given":"Tania","family":"Incitti","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Sighel","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"},{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Bozza","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yari","family":"Ciribilli","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8767-1637","authenticated-orcid":false,"given":"Alberto","family":"Inga","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Casarosa","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0297-3685","authenticated-orcid":false,"given":"Ines","family":"Mancini","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1038\/cdd.2010.14","article-title":"Cell reprogramming: Expectations and challenges for chemistry in stem cell biology and regenerative medicine","volume":"17","author":"Anastasia","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1021\/ja037390k","article-title":"Dedifferentiation of lineage committed cells by a small molecule","volume":"126","author":"Chen","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1038\/sj.cdd.4401958","article-title":"Reversine-treated fibroblasts acquire myogenic competence in vitro and in regenerating skeletal muscle","volume":"13","author":"Anastasia","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1074\/jbc.M804055200","article-title":"Reversine increases the plasticity of lineage-committed cells toward neuroectodermal lineage","volume":"284","author":"Lee","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_5","first-page":"23","article-title":"Reversine increase the plasticity of bone marrow-derived mesenchymal stem cell for generation of cardiomyocyte in vitro","volume":"44","author":"Pikir","year":"2012","journal-title":"Acta Med. Indones."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrc1526","article-title":"Aurora-A\u2014A guardian of poles","volume":"5","author":"Marumoto","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1083\/jcb.200208092","article-title":"The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore\u2013microtubule attachment and in maintaining the spindle assembly checkpoint","volume":"161","author":"Hauf","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nrm3888","article-title":"Signalling dynamics in the spindle checkpoint response","volume":"15","author":"London","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1002\/prot.25174","article-title":"Structural basis of reversine selectivity in inhibiting Mps1 more potently than Aurora B kinase","volume":"84","author":"Hiruma","year":"2016","journal-title":"Proteins Struct. Funct. Bioinf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1002\/jcb.24197","article-title":"The synthetic purine reversine selectively induces cell death of cancer cells","volume":"113","author":"Piccoli","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.4161\/cc.20621","article-title":"Preferential killing of p53-deficient cancer cells by reversine","volume":"11","author":"Galluzzi","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1158\/1535-7163.MCT-07-2051","article-title":"Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells","volume":"7","author":"Amabile","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_13","first-page":"1293","article-title":"The 2,6-disubstituted purine reversine induces growth arrest and polyploidy in human cancer cells","volume":"31","author":"Hsieh","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1083\/jcb.201001036","article-title":"Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine","volume":"190","author":"Santaguida","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s12282-012-0400-z","article-title":"Reversine induces cell cycle arrest, polyploidy, and apoptosis in human breast cancer cells","volume":"21","author":"Kuo","year":"2012","journal-title":"Breast Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1007\/s11095-012-0727-3","article-title":"Reversine, a 2,6-disubstituted purine, as an anti-cancer agent in differentiated and undifferentiated thyroid cancer cells","volume":"29","author":"Hua","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.biopha.2012.08.001","article-title":"Autophagy induction of reversine on human follicular thyroid cancer cells","volume":"66","author":"Lu","year":"2012","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1097\/CAD.0000000000000563","article-title":"Reversine induces autophagic cell death through the AMP-activated protein kinase pathway in urothelial carcinoma cells","volume":"29","author":"Fang","year":"2018","journal-title":"Anti-Cancer Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/bcr426","article-title":"The p53 pathway in breast cancer","volume":"4","author":"Gasco","year":"2002","journal-title":"Breast Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1016\/j.bmcl.2012.04.131","article-title":"Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors","volume":"22","author":"Kumar","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.1021\/jm050221l","article-title":"Reversine and its 2-substituted adenine derivatives as potent and selective adenosine receptor antagonists","volume":"48","author":"Perreira","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1002\/poc.1668","article-title":"Prototropy and p-electron delocalization for purine and its radical ions\u2013DFT studies","volume":"23","author":"Raczynska","year":"2010","journal-title":"J. Phys. Org. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1007\/s00894-013-1926-5","article-title":"Variations of the tautomeric preferences and \u03c0-electron delocalization for the neutral and redox forms of purine when proceeding from the gas phase (DFT) to water (PCM)","volume":"19","year":"2013","journal-title":"J. Mol. Model."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1126\/science.1068999","article-title":"A system for stable expression of short interfering RNAS in mammalian cells","volume":"296","author":"Brummelkamp","year":"2002","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.1073\/pnas.0813333106","article-title":"A Panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53","volume":"106","author":"Sur","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1038\/cdd.2014.79","article-title":"p53-Directed translational control can shape and expand the universe of p53 target genes","volume":"21","author":"Zaccara","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/ncb0510-424","article-title":"A mitotic role for the DNA damage responsive CHK2 kinase","volume":"12","author":"Sato","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1158\/1541-7786.MCR-14-0177","article-title":"p53 Promotes cell survival due to the reversibility of its cell cycle checkpoints","volume":"13","author":"Lukin","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_29","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Vreven, T., Kudin, K.N., and Burant, J.C. (2004). Gaussian, Gaussian, Inc.. Revision E.01."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional thermochemistry. III. The role of exact exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comp. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nchembio.345","article-title":"Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function","volume":"6","author":"Filippakopoulos","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/8\/1996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:17:56Z","timestamp":1760195876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/8\/1996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,10]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,8]]}},"alternative-id":["molecules23081996"],"URL":"https:\/\/doi.org\/10.3390\/molecules23081996","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,10]]}}}