Design and synthesis of naphthylchalcones as novel anti-leukaemia agents.

Autor: Leitão EPT; Process Chemistry Development, HovioneFarmaCiencia S.A., Estrada do Passo do Lumiar, Campus do Lumiar, Edificio S, 1649-038 Lisboa, Portugal. Electronic address: eleitao@hovione.com., Ascenso OS; Instituto de Tecnologia Química e Biológica, António Xavier, Universidade Nova de Lisboa, Apartado 127, 2780-901 Oeiras, Portugal., Santos de Almeida T; CBIOS - Universidade Lusófona's Research Center for Biosciences and Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal., González I; Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), University of Las Palmas de Gran Canaria, Spain., Hernández I; Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), University of Las Palmas de Gran Canaria, Spain., Quintana J; Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), University of Las Palmas de Gran Canaria, Spain., Estévez F; Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), University of Las Palmas de Gran Canaria, Spain., Rijo P; CBIOS - Universidade Lusófona's Research Center for Biosciences and Health Technologies, Campo Grande 376, 1749-024 Lisboa, Portugal; Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon (ULisboa), Lisbon, Portugal. Electronic address: patricia.rijo@ulusofona.pt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Dec; Vol. 117, pp. 105348. Date of Electronic Publication: 2021 Sep 21.
DOI: 10.1016/j.bioorg.2021.105348
Abstrakt: A series of new hydroxylated chalcone derivatives with different substitution patterns on a phenyl ring A and B, were prepared by Claisen-Schmidt condensation in an aqueous alkaline base. The antiproliferative activity of the studied compounds was evaluated against the human leukaemia cell line U-937. The structure-activity relationship of these naphthylchalcones was investigated by the introduction of one methoxy or two methyl groups on the A ring, the introduction of a methoxy group on the naphthyl ring or by varying the position of the methoxy group on the A ring. The results revealed that the naphthylchalcone containing a methoxy group in position 6́ of the A ring was the most cytotoxic compound, with an IC 50 value of 4.7 ± 0.5 μM against U-937 cells. This synthetic chalcone induced S and G 2 -M cell cycle arrest, a time-dependent increase in sub-G 1 ratio and annexin-V positive cells, caspase activation and poly(ADP-ribose) polymerase cleavage. Apoptosis induction was blocked by a pan-caspase inhibitor and by the selective caspase-3/7 inhibitor and attenuated by the inhibition of c-jun N-terminal kinases / stress-activated protein kinases (JNK/SAPK) and phosphoinositide 3-kinase. The structure-activity relationship of naphthylchalcones against human leukaemia cells reveals that the major determining in cytotoxicity is the presence of a methoxy group in position 6́ of the A ring that suggest the potential of this compound or derivatives in the development of new anti-leukaemia drugs.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: