Multifunctional SAHA-Derived 8-Hydroxyquinoline Metallopharmacophores: HDAC Inhibition and Antiproliferative Activity

Abstract

SAHA (vorinostat) is a clinically used pan-HDAC inhibitor, making SAHA-derived scaffolds attractive for multifunctional designs that combine HDAC modulation with additional cytotoxic mechanisms. Here, we replaced the SAHA cap group with an 8-hydroxyquinoline (8-HQ) chelator to generate a hydroxamate ligand (L1) and a series of Ru(II), Os(II), Ir(III), and Rh(III) half-sandwich complexes. L1 potently inhibited HDACs in vitro, while metal coordination generally attenuated HDAC inhibitory activity. In cells, L1 and selected complexes increased α-tubulin acetylation and elevated histone H3 acetylation at higher concentrations, consistent with broader HDAC engagement. The compounds showed moderate to high antiproliferative activity across multiple human cancer cell lines and low resistance factors in cisplatin-resistant models.Notably, the ester analogue L2 was inactive against HDACs in vitro yet retained antiproliferative activity, suggesting an HDACindependent contribution consistent with the 8-HQ pharmacophore and its metal-tunable reactivity. Among the complexes, the Rh(Cp*) derivative retained strong antiproliferative potency, highlighting the multifunctional nature of this platform.