Enantioselective Synthesis, DFT Calculations, and Preliminary Antineoplastic Activity of Dibenzo 1-Azaspiro[4.5]decanes on Drug-Resistant Leukemias

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Title: Enantioselective Synthesis, DFT Calculations, and Preliminary Antineoplastic Activity of Dibenzo 1-Azaspiro[4.5]decanes on Drug-Resistant Leukemias
Authors: Mendes, Joseane A. | Merino, Pedro | Soler, Tatiana | Salustiano, Eduardo J. | Costa, Paulo R.R. | Yus, Miguel | Foubelo, Francisco | Buarque, Camilla D.
Research Group/s: Síntesis Asimétrica (SINTAS)
Center, Department or Service: Universidad de Alicante. Departamento de Química Orgánica | Universidad de Alicante. Instituto Universitario de Síntesis Orgánica
Keywords: Chiral sulfinyl imines | Tetralones | Chromanone | Thiochromanone | Diastereoselective addition | N-arylation | 1-azaspiro[4.5]decanes | DFT calculations | Multifactorial drug resistance | Collateral sensitivity
Knowledge Area: Química Orgánica
Issue Date: 17-Jan-2019
Publisher: American Chemical Society
Citation: The Journal of Organic Chemistry. 2019, 84(4): 2219-2233. doi:10.1021/acs.joc.8b03203
Abstract: The addition of 2-bromobenzylmagnesium bromide to chiral N-tert-butanesulfinyl imines derived from tetralone-type ketones proceeds with high levels of diastereocontrol. The resulting sulfinamide derivatives were transformed into dibenzoazaspiro compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. Similar results have been obtained considering either diethyl ether or toluene as a solvent, in both cases in an excellent agreement with experimental findings. NCI topological calculations have also been used to evidence crucial noncovalent interactions. In addition, the azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar range. Notably, both the halogen-substituted (R)- and (S)-8g and -8h as well as (R)-8j were at least two times more effective on a multidrug-resistant derivative than on the parental cell line, exerting a collateral sensitivity effect.
Sponsor: We acknowledge the continued financial support from the Spanish Ministerio de Economía y Competitividad (MINECO; project CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2016-76155-R, CTQ2017-85093-P), FEDER, the Generalitat Valenciana (PROMETEOII/2014/017), and the University of Alicante. We thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo” and technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain). We also thank Prof. Vivian M. Rumjanek for providing FEPS cells and Prof. Adriano D. Andricopulo for the preliminary cytotoxicity screening. This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
URI: http://hdl.handle.net/10045/88431
ISSN: 0022-3263 (Print) | 1520-6904 (Online)
DOI: 10.1021/acs.joc.8b03203
Language: eng
Type: info:eu-repo/semantics/article
Rights: © 2019 American Chemical Society
Peer Review: si
Publisher version: https://doi.org/10.1021/acs.joc.8b03203
Appears in Collections:INV - SINTAS - Artículos de Revistas

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