# Bifunctional Metformin–Phenolic Hybrids with Improved Anticancer and Antioxidant Properties: Evaluation on Glioma Cells

## TL;DR

Researchers developed new metformin-based compounds that show improved anticancer and antioxidant effects on glioma cells, potentially offering a better treatment for aggressive brain tumors.

## Contribution

The paper introduces novel metformin–phenolic hybrids with enhanced anticancer activity and a distinct mechanism of action compared to metformin.

## Key findings

- Two hybrids, 5a and 5h, showed increased cytotoxicity in glioblastoma cells while sparing healthy cells.
- The hybrids inhibit RTK–MAPK–PI3K signaling, causing cell cycle arrest and apoptosis.
- Unlike metformin, the hybrids do not primarily induce metabolic stress.

## Abstract

Glioblastoma is one of the most highly aggressive types of brain tumor in adults. With limited treatment options, current therapies remain insufficient due to its invasiveness and immune evasion, highlighting the urgent need for new treatments. Bifunctional molecules targeting multiple aspects of the disease could be promising to overcome drug resistance and tumor heterogeneity. Metformin has demonstrated protective effects against brain tumors but requires high doses for efficacy, making it of great interest for molecular optimization. In this context, we synthesized a series of nine metformin–phenolic molecules, combining the metformin guanidine framework with phenolic acids, which have well-established properties in inhibiting cancer cell migration and adhesion. Their impact on cytotoxicity, reactive oxygen species inhibition, and signaling pathways was investigated for glioma cell lines and stem cells. Two of these hybrids, 5a and 5h, particularly enhanced cytotoxicity in glioblastoma cells, selectively targeting cancer cells while sparing healthy ones. Their mechanism of action differed significantly from metformin. Unlike metformin, which mainly triggers metabolic stress, the hybrids broadly inhibit RTK–MAPK–PI3K signaling, leading to cell cycle arrest and apoptosis. The results suggest that these compounds could offer a more effective and synergistic approach for glioblastoma treatment.