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The design of multi-targeted drugs has gained considerable interest in the last decade thanks to their advantages in the treatment of different diseases, including cancer. The simultaneous inhibition of selected targets from cancerous cells to induce their death represents an attractive objective for the medicinal chemist in order to enhance the efficiency of chemotherapy. In the present work, several alkynyl gold(I) phosphane complexes derived from 3-hydroxyflavones active against three human cancer cell lines, colorectal adenocarcinoma Caco-2/TC7, breast adenocarcinoma MCF-7 and hepatocellular carcinoma HepG2, have been synthesized and characterized. Moreover, these compounds display high selective index values towards differentiated Caco-2 cells, which are considered as a model of non-cancerous cells. The antiproliferative effect of the most active complexes [Au(L2b)PPh 3 (3b) and [Au(L2c)PTA] (4c) on Caco-2 cells, seems to be mediated by the inhibition of the enzyme cyclooxygenase-1/2 and alteration of the activities of the redox enzymes thioredoxin reductase and glutathione reductase. Both complexes triggered cell death by apoptosis, alterations in cell cycle progression and increased of ROS production. These results provide support for the suggestion that multi-targeting approach involving the interaction with cyclooxygenase-1/2 and the redox enzymes that increases ROS production, enhances cell death in vitro. All these results indicate that complexes [Au(L2b)PPh 3 and [Au(L2c)PTA] are promising antiproliferative agents for further anticancer drug development. Targeted therapies for cancer treatment have revolutionized the concept of oncological medicine. However, the single-target therapy is vanishing in favour of a multi-target approach, where new drugs are able to simultaneously target different molecules. Here we describe new alkynyl gold(I) phosphane complexes derived from 3-hydroxyflavones, whose mechanism of action involves cell death via two independent targets. Image 1 • Multi-targeted mechanism of action promoted by Alkynyl Gold(I) derivatives. • Interaction with COX-1/2 enzyme. • Interaction with the redox enzymes TrxR and GR leading to an increased ROS production. • Cell death via the intrinsic pathway and alteration of cell cycle progression. [ABSTRACT FROM AUTHOR]