Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Easy but Efficient: Facile Approach to Molecule with Theoretically Justified Donor-Acceptor Structure for Effective Photothermal Conversion and Intravenous Photothermal Therapy.

To accelerate the pace in the field of photothermal therapy (PTT), it is urged to develop easily accessible photothermal agents (PTAs) showing high photothermal conversion efficiency (PCE). As a proof-of-concept, hereby a conventional strategy is presented to prepare donor-acceptor (D-A) structured PTAs through cycloaddition-retroelectrocyclization (CA-RE) reaction, and the resultant PTAs give high PCE upon near-infrared (NIR) irradiation. By joint experimental-theoretical study, these PTAs exhibit prominent D-A structure with strong intramolecular charge transfer (ICT) characteristics and significantly twisting between D and A units which account for the high PCEs. Among them, the DMA-TCNQ exhibits the strongest absorption in NIR range as well as the highest PCE of 91.3% upon irradiation by 760-nm LED lamp (1.2 W cm-2). In vitro and in vivo experimental results revealed that DMA-TCNQ exhibits low dark toxicity and high phototoxicity after IR irradiation along with nude mice tumor inhibition up to 81.0% through intravenous therapy. The findings demonstrate CA-RE reaction as a convenient approach to obtain twisted D-A structured PTAs for effective PTT and probably promote the progress of cancer therapies.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

Cytotoxic cis-ruthenium(III) bis(amidine) complexes.

In chemotherapy, the search for ruthenium compounds as alternatives to platinum compounds is proposed because of their unique properties. However, the geometry effect of ruthenium complexes is sparely investigated. In this paper, we report the synthesis of a series of bis(acetylacetonato)ruthenium(III) complexes bearing two amidines (1-) in a cis configuration. These complexes are highly cytotoxic against various cancer cell lines, including a cisplatin-resistant cell line. In vitro studies suggested that the representative complex can induce cell cycle G0/G1 phase arrest, decrease the mitochondrial membrane potential, elevate the intracellular reactive oxygen species level, and cause DNA damage and caspase-mediated mitochondrial pathway apoptosis in NCI-H460 cells. In vivo, it can effectively inhibit tumor xenograft growth in nude mouse models with no body weight loss. In combination with the reported trans-bis(amidine)ruthenium(III) complexes, we found that ruthenium(III) bis(amidine) complexes could be cytotoxic in both trans and cis geometries, which is in contrast to platinum-based compounds.

Osmium(VI) nitride triggers mitochondria-induced oncosis and apoptosis.

We report a new osmium(VI) nitrido complex bearing a nonplanar tetradentate ligand with potent anticancer activity. This complex causes mitochondrial damage, which induces liver cancer cell death via oncosis and apoptosis. This is the first osmium-based anticancer candidate that induces oncosis.

A cytotoxic nitrido-osmium(VI) complex induces caspase-mediated apoptosis in HepG2 cancer cells.

The osmium(vi) nitrido complex [OsVI(N)(sap)(py)Cl] is a potential anti-cancer drug with promising in vitro antiproliferative activities toward a panel of cancer cell lines, including cisplatin-resistant cells (IC50 values of 2.8-13.8 µM). This drug targets DNA and changes its conformation via covalent binding and insertion. In vitro studies indicate that the drug induces HepG2 cells G2/M phase arrest, disrupts the mitochondrial membrane potential and causes caspase-mediated apoptosis. Further in vivo studies using HepG2-bearing nude mice reveal that this drug not only shows good antitumor efficacy of inhibiting tumor growth, but also does not show the side effect of weight loss.

Surface optimization of gold nanoparticle mass tags for the sensitive detection of protein biomarkers via immuno-capture LI-MS.

HPV-induced cervical cancer is one of the most lethal cancers. Therefore, the development of a reliable and accurate method for the early diagnosis of HPV infections is highly important. Here, gold nanoparticles (AuNPs) were utilized as mass tags in an immuno-capture LI-MS assay for the detection of HPV marker proteins. Through the optimization of the amount of antibodies and surface charges on AuNPs, high antigen detection efficiency with minimal non-specific binding was achieved. With optimized antibody-conjugated AuNPs, low attomole amount of HPV proteins in HeLa cell lysate was quantified.

Synthesis and antitumor activity of a series of osmium(VI) nitrido complexes bearing quinolinolato ligands.

A series of osmium(VI) nitrido complexes supported by quinolinolato ligands have been prepared and they exhibit promising in vitro anti-cancer activities. These results establish that Os(VI)≡N is a potentially versatile and promising platform for the design of a variety of high-valent anti-cancer drugs.

Osmium(VI) complexes as a new class of potential anti-cancer agents.

A nitridoosmium(VI) complex [Os(VI)(N)(sap)(OH(2))Cl] (H(2)sap = N-salicylidene-2-aminophenol) displays prominent in vitro and in vivo anti-cancer properties, induces S- and G2/M-phase arrest and forms a stable adduct with dianionic 5'-guanosine monophosphate.

From encapsulation to polypseudorotaxane: unusual anion networks driven by predesigned metal bis(terpyridine) complex cations.

Solvothermal reactions of CuSCN, metal (Mn2+, Fe2+, Co2+, Ni2+, Cu2+) sulfate, and terpyridine (2,2':6',2' '-terpyridine or 4'-p-tolyl-2,2':6',2' '-terpyridine) in the presence of triphenylphosphine yielded a series of hybrid coordination compounds, in which in situ formed metal bis(terpyridine) complex cations are encapsulated by a 3D anionic network or entangled by 2D heartlike networks, forming encapsulation or polypseudorotaxane supramolecules. The complex cations play a role as template to direct the fabrication of the structures.