Thiazole Functionalization of Thiosemicarbazone for Cu(II) Complexation: Moving toward Highly Efficient Anticancer Drugs with Promising Oral Bioavailability.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (H) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl()] () and [Cu(NO)()] (). Both and exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. H, , and are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC) values as low as 3.26 nmol/mL (H), 2.18 nmol/mL (), and 2.54 × 10 nmol/mL () for PLC/PRF/5. While the free ligand H may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe and Cu), and are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of H has a significantly longer half-life of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying H as an effective chemotherapeutic drug via PO administration.