TY  - JOUR
N2  - The combination of compounds with complementary bioactivities into hybrid molecules is an emerging concept in drug discovery. In this study, we aimed to synthesize new hybrid compounds based on p53-MDM2/X protein-protein interaction spiropyrazoline oxindole-based inhibitors and ataxia telangiectasia and Rad3-related (ATR) protoflavone-based inhibitors through copper(i) catalysed azide-alkyne cycloaddition. Five new hybrids were prepared along with three representative reference fragments. The compounds were tested against human breast cancer cell lines MCF-7 (hormone-dependent, wild-type p53) and MDA-MB-231 (triple-negative, mutant p53). Most of the new hybrids were more cytotoxic than their reference fragments and several showed 2-4 times selective toxicity against MDA-MB-231 cells. Relevant pharmacological benefit gained from the hybrid coupling was further confirmed by virtual combination index calculations using the Chou method. Compound 13 modulated doxorubicin-induced DNA damage response through inhibiting the ATR-dependent activation of Chk-1, while increasing the activation of Chk-2. Our results suggest that the new hybrids may serve as new leads against triple negative breast cancer.
AV  - public
VL  - 14
UR  - https://doi.org/10.1039/d3md00251a
Y1  - 2023///
IS  - 9
A1  -  Girst Gábor
A1  -  Lopes Elizabeth A.
A1  -  Goncalves Lidia M.
A1  -  Espadinha Margarida
A1  -  Kúsz Norbert
A1  -  Wang Hui-Chun
A1  -  Santos Maria M. M.
A1  -  Hunyadi Attila
ID  - publicatio29306
TI  - Hybrid molecules of protoflavones and spirooxindole derivatives with selective cytotoxicity against triple-negative breast cancer cells
EP  - 1786
JF  - RSC MEDICINAL CHEMISTRY
SN  - 2632-8682
SP  - 1778
ER  -