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 (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2(1) and [Cu(NO3)(L)]2(2). Both1and2exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL,1, and2are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5nmol/mL (2) for PLC/PRF/5. While the free ligand HLmay elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+and Cu2+),1and2are 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 HLhas a significantly longer half-lifet1/2of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HLas an effective chemotherapeutic drug via PO administration.