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 the efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1 and 2 are 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 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via sequestration of bio-relevant metal ions (i.e. Fe3+ and Cu2+), 1 and 2 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 HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared to that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

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). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are 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 × 10⁻⁵ nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe³⁺ and Cu²⁺), 1 and 2 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 HL has a significantly longer half-life t_1/2 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 HL as an effective chemotherapeutic drug via PO administration.

Reactive oxygen species (ROS)-mediated cancer therapy has attracted extensive attention due to its high spatiotemporal selectivity and minimal side effects. Herein, we report a nonanuclear Pd-based coordination cage of Pd₆-TMPP(Ni), constructed from Ni-chelated TMPP(Ni) as the metalloligand and Pd²⁺ ions (H₂TMPP = meso-tetrakis (6-methylpyridin-3-yl) porphyrin). Pd₆-TMPP(Ni) integrates dual ROS-generation for cancer therapy, viz., hydroxyl radical (•OH) production and photoinduced singlet oxygen (¹O₂) generation. In vitro cytotoxicity assays against cancer cell lines NCI-H82 (lung cancer), A549 (lung cancer), KYSE-510 (esophageal cancer), and Te-1 (esophageal cancer) reveal its potent dark toxicity (IC₅₀: 1.9–2.1 μmol L⁻¹) and phototoxicity (IC₅₀: 0.8–1.5 μmol L⁻¹), which is attributed to enhanced intracellular ROS accumulation. This work develops a versatile therapeutic platform that harnesses Ni-induced •OH for chemodynamic therapy (CDT) and porphyrin-generated ¹O₂ for photodynamic therapy (PDT), thereby mitigating the oxygen dependence of conventional PDT.

We herein demonstrate that the thiosemicarbazone (TSC) ligand N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) can coordinate with Ga3+ to give the cationic complex of [Ga(L)2]NO3 featuring an the octahedral Ga(III) center. [Ga(L)2]NO3 may undergo metathesis with both Fe2+ and Fe3+ and result in the formation of respective Fe2+- and Fe3+ complex. Meanwhile, [Ga(L)2]NO3 is also susceptible to anion exchange with solidum hyaluronate (NaA) to produce the nanoformulation of [Ga(L)2]A with boosted aqueous solubility and cell targetability. [Ga(L)2]A demonstrated remarkable in vitro cytotoxicity against NCI-H82 and A549 (lung cancer), as well as KYSE-510 and Te-1 (esophageal cancer) cell lines, featuring half maximal inhibitory concentration (IC50) values in the range of 0.102 − 2.616 μmol L−1. This work highlights the potential of using non-toxic and biocompatible Ga3+ as the central ion to prepare TSC-based nanomedicines for combating cancer.

Reactive oxygen species (ROS)-mediated cancer therapy has attracted extensive attention due to its high spatiotemporal selectivity and minimum side-effects. Herein, we report a nonanuclear Pd-based coordination cage of Pd6-TMPP(Ni), constructed from Ni-chelated TMPP(Ni) as the metalloligand and Pd2+ ions (H2TMPP = meso-tetrakis (6-methylpyridin-3-yl) porphyrin). Pd6-TMPP(Ni) integrates dual ROS-generation for cancer therapy, viz., hydroxyl radical (•OH) production and photoinduced singlet oxygen (1O2) generation. In vitro cytotoxicity assays against cancer cell lines NCI-H82 (lung cancer), A549 (lung cancer), KYSE-510 (esophageal cancer), and Te-1 (esophageal cancer), reveal its potent dark toxicity (IC₅₀: 1.867–2.107 μmol L−1) and phototoxicity (IC₅₀: 0.835–1.528 μmol L−1), which is attributed to enhanced intracellular ROS accumulation. This work develops a versatile therapeutic platform that harnesses Ni-induced •OH for chemodynamic therapy (CDT) and porphyrin-generated ¹O₂ for photodynamic therapy (PDT), thereby mitigating the oxygen dependence of conventional PDT.

We herein demonstrate that the thiosemicarbazone (TSC) ligand N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) can coordinate with Ga³⁺ to give cationic complex [Ga(L)₂]NO₃ featuring an octahedral Ga(III) center. [Ga(L)₂]NO₃ undergoes metathesis with both Fe²⁺ and Fe³⁺, resulting in the formation of respective Fe²⁺- and Fe³⁺ complexes. [Ga(L)₂]NO₃ is also susceptible to anion exchange with sodium hyaluronate (NaA) to produce the nanoformulation [Ga(L)₂]A with boosted aqueous solubility and cell targeting. [Ga(L)₂]A demonstrated remarkable in vitro cytotoxicity against NCI-H82 and A549 (lung cancer), as well as KYSE-510 and Te-1 (esophageal cancer) cell lines, featuring half maximal inhibitory concentration (IC₅₀) values in the range 0.102–2.616 μmol L⁻¹. This work highlights the potential of using non-toxic and biocompatible Ga³⁺ as the central ion to prepare TSC-based nanomedicines for combating cancer.