<p>Metformin is a widely prescribed antidiabetic drug that has attracted sustained interest for cancer repurposing; however, its translation to oncology has been constrained by intrinsic physicochemical limitations. We employed rational lipid-modification as a medicinal chemistry strategy to re-engineer metformin for anticancer applications. A series of lipid-modified metformin analogues were synthesized via N,N-dialkylation, while preserving the pharmacophoric biguanide core. Compared to native metformin, which displayed negligible cytotoxicity across tested cell lines, lipid-modified derivatives exhibited pronounced, concentration-dependent cytotoxic effects in multiple cancer cells with comparatively attenuated activity in non-cancerous cells. The most promising analogue, M12, demonstrated robust apoptosis induction and inhibition of wound-healing behaviour in oral cancer cells, whereas parent metformin remained inactive under identical conditions. These findings establish lipid-conjugation as a chemistry-driven strategy to overcome intrinsic barriers to cellular access and unlock latent anticancer activity in metformin, providing proof-of-concept for structural re-engineering of structurally constrained, clinically established drugs towards oncology applications.</p> Graphical Abstract <p></p>