Chemistry – A European Journal

A Rationally Designed Bimetallic Platinum (II)‐Ferrocene Antitumor Agent Induces Non‐Apoptotic Cell Death and Exerts in Vivo Efficacy

AbstractDespite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)‐ferrocene hybrids that display multi‐pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi‐modal mechanism of action of these hybrid agents lead to non‐apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.

“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu2‐xSe−GOx for Cervical Cancer Therapy

AbstractCervical cancer, as a common malignant tumor of the reproductive system, seriously threatens women‘s life and health, and is difficult to be cured by traditional treatments, such as surgery, chemotherapy and radiotherapy. Fortunately, tumor microenvironment (TME)‐activated catalytic therapy with high efficiency and reduced off‐target toxicity has emerged as a novel treatment model. Herein, we designed a “four‐in‐one” nanozyme and natural enzyme symbiotic system of Cu2‐xSe−GOx for TME‐triggered cascaded catalytic enhanced cancer treatment. In response to unique TME, Cu2‐xSe with catalase activity could effectively catalyze over‐expressed H2O2 in cancer cells into O2. Subsequently, the glucose oxidase (GOx) could deplete intracellular glucose with the assistance of O2; this not only achieves starvation therapy, but also regenerates H2O2 to boost the generation of highly cytotoxic .OH due to the peroxidase activity of Cu2‐xSe. Moreover, although the free‐radical scavenger glutathione (GSH) is overexpressed in tumor cells, Cu2‐xSe with glutathione oxidase activity could effectively consume GSH for enhanced ROS production. Thus, the “four‐in‐one” nanozyme@natural enzyme symbiotic system of Cu2‐xSe−GOx could induce significant ROS accumulation at the tumor regions, thus providing a potential approach for the treatment of cervical cancer.

Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability

AbstractThe impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O β‐diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3)2Pt(L1‐H)]NO3 and [(DACH)Pt(L1‐H)]NO3 (L1=4,4,4‐trifluoro‐1‐ferrocenylbutane‐1,3‐dione, DACH=1R,2R‐cyclohexane‐1,2‐diamine) containing an electron deficient [L1‐H]– O˄O leaving ligand and [(NH3)2Pt(L2‐H)]NO3 and [(DACH)Pt(L2‐H)]NO3 (L2=1‐ferrocenylbutane‐1,3‐dione) containing an electron‐rich [L2‐H]– O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron‐withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Radiolabelled 177Lu‐Bispidine‐Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

AbstractRadioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid‐selective nonadentate bispidine ligand suitable for 177Lu3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN3) group as a bioconjugation handle for light‐induced labelling of proteins. Quantitative radiosynthesis of [177Lu]Lu‐1+ was accomplished in 10 minutes at 40 °C. Subsequent incubation of [177Lu]Lu‐1+ with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0–8.3, gave the radiolabelled mAb, [177Lu]Lu‐1‐azepin‐trastuzumab ([177Lu]Lu‐1‐mAb) in a decay‐corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK‐OV‐3 human ovarian cancer cells confirmed that [177Lu]Lu‐1‐mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK‐OV‐3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g−1 vs. 14.8±6.1 %ID g−1, respectively; P‐value=0.037). The data indicate that bispidine‐based ligand systems are suitable starting points for constructing novel, high‐denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides.

An Organometallic Gold(I) Bis‐N‐Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells

AbstractThe organometallic AuI bis‐N‐heterocyclic carbene complex [Au(9‐methylcaffeine‐8‐ylidene)2]+ (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G‐quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry‐based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal‐based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non‐covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress‐fibres and stress‐responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.

Influence of Ligand and Nuclearity on the Cytotoxicity of Cyclometallated C^N^C Platinum(II) Complexes

AbstractA series of cyclometallated mono‐ and di‐nuclear platinum(II) complexes and the parent organic ligand, 2,6‐diphenylpyridine 1 (HC^N^CH), have been synthesized and characterized. This library of compounds includes [(C^N^C)PtII(L)] (L=dimethylsulfoxide (DMSO) 2 and triphenylphosphine (PPh3) 3) and [((C^N^C)PtII)2(L‘)] (where L‘=N‐heterocycles (pyrazine (pyr) 4, 4,4‘‐bipyridine (4,4‘‐bipy) 5 or diphosphine (1,4‐bis(diphenylphosphino)butane (dppb) 6). Their cytotoxicity was assessed against four cancerous cell lines and one normal cell line, with results highlighting significantly increased antiproliferative activity for the dinuclear complexes (4–6), when compared to the mononucleated species (2 and 3). Complex 6 is the most promising candidate, displaying very high selectivity towards cancerous cells, with selectivity index (SI) values >29.5 (A2780) and >11.2 (A2780cisR), and outperforming cisplatin by >4‐fold and >18‐fold, respectively.

DNA‐Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light

AbstractPhotoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8‐Naphthalimides with their extended π system can behave as light‐harvesting groups, fluorescent probes and DNA intercalators. We conjugated N‐(carboxymethyl)‐1,8‐naphthalimide (gly‐R‐Nap) with an R substituent on the naphthyl group to photoactive diazido PtIV complexes to form t,t,t‐[Pt(py)2(N3)2(OH)(gly‐R‐Nap)], R=H (1), 3‐NO2 (2) or 4‐NMe2 (3). They show enhanced photo‐oxidation, cellular accumulation and promising photo‐cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre‐intercalation into DNA, resulting in enhanced photo‐induced DNA crosslinking. Complex 3 has a red‐shifted absorption band at 450 nm, allowing photoactivation and photo‐cytotoxicity with green light.

New Organometallic Ruthenium(II) Compounds Synergistically Show Cytotoxic, Antimetastatic and Antiangiogenic Activities for the Treatment of Metastatic Cancer

AbstractIn this study, we newly designed and synthesized a small library of ten structurally related C,N‐cyclometalated ruthenium(II) complexes containing various pyridine‐functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2′‐bipyridine, 5,5′‐dimethyl‐2,2′‐bipyridine, and 1,10‐phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization‐mass spectrometry, and single‐crystal X‐ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose‐ and cell line‐dependent IC50 values at the range of 3.3–15.0 μm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft‐bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI‐A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.

Palladium(II)‐η3‐Allyl Complexes Bearing N‐Trifluoromethyl N‐Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High‐Grade Serous Ovarian Cancer Tumoroids

AbstractThe first palladium organometallic compounds bearing N‐trifluoromethyl N‐heterocyclic carbenes have been synthesized. These η3‐allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02–0.5 μm). By choosing 1,3,5‐triaza‐7‐phosphaadamantane (PTA) as co‐ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2‐methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3‐allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids.

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

AbstractMany cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to further oxidative impairment triggered by agents generating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be a promising anticancer strategy. Herein, it is shown that a gold(I) complex containing an oleanolic acid derivative (4 b) induces apoptosis of ovarian cancer A2780 cells by activating endoplasmic reticulum stress (ERS). It can inhibit TrxR enzyme activity to elevate ROS, mediate ERS and mitochondrial dysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably, this complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.