Polypyridyl Ruthenium(II) Complexes with Red-Shifted Absorption: New Promises in Photodynamic Therapy

In the field of cancer photodynamic therapy (PDT) research, development of metal-based PDT drugs that can be used under red light exposure is the “holy grail” to achieve. This highlight highlighted few current literatures on polypyridyl-based Ru(II) complexes with significantly red-shifted absorption to achieve in-vitro and in-vivo PDT effect in 540–600 nm light. The enormous potential of judicial ligand choice and in-silico optimization to achieve the red light, metal-based PDT drugs are discussed.     

Bis(dipyridophenazine)(2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Hexafluorophosphate: A Lesson in Stubbornness

Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor‐targeting peptide bioconjugates of a cytotoxic bis(dppz)‐Ru^II complex [Ru(dppz)₂(CppH)](PF₆)₂ ( 1 ) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size‐based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1 , the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.     

Rational Design of Ruthenium Complexes Containing 2,6‐Bis(benzimidazolyl)pyridine Derivatives with Radiosensitization Activity by Enhancing p53 Activation

The rational design of metal‐based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis‐benzimidazole derivatives: Ru(bbp)Cl₃ ( 1 ), [Ru(bbp)₂]Cl₂ ( 2 a ) (in which bbp=2,6‐bis(benzimidazol‐1‐yl)pyridine), and [Ru(bnbp)₂]Cl₂ ( 2 b ) (where bnbp=2,6‐bis‐(6‐nitrobenzimidazol‐2‐yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b promotes radiation‐induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p‐p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin‐B, leading to G2M arrest. Moreover, p‐p53 activates caspases‐3 and ‐8, triggers cleavage of poly(ADP‐ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium‐based radiosensitizers for use in cancer therapy.     

Highly Charged Ru(II) Polypyridyl Complexes as Photosensitizer Agents in Photodynamic Therapy of Epithelial Ovarian Cancer Cells

Ovarian cancer recurrence is frequent and associated with chemoresistance, leading to extremely poor prognosis. Herein, we explored the potential anti-cancer effect of a series of highly charged Ru(II)-polypyridyl complexes as photosensitizers in photodynamic therapy (PDT), which were able to efficiently sensitize the formation of singlet oxygen upon irradiation (Ru1²⁺ and Ru2²⁺) and to produce reactive oxygen species (ROS) in their corresponding dinuclear metal complexes with the Fenton active Cu(II) ion/s ([CuRu1]⁴⁺ and [Cu₂Ru2]⁶⁺). Their cytotoxic and anti-tumor effects were evaluated on human ovarian cancer A2780 cells both in the absence or presence of photoirradiation, respectively. All the compounds tested were well tolerated under dark conditions, whereas they switched to exert anti-tumor activity following photoirradiation. The specific effect was mediated by the onset of programed cell death, but only in the case of Ru1²⁺ and Ru2²⁺ was preceded by the loss of mitochondrial membrane potential soon after photoactivation and ROS production, thus supporting the occurrence of apoptosis via type II photochemical reactions. Thus, Ru(II)-polypyridyl-based photosensitizers represent challenging tools to be further investigated in the identification of new therapeutic approaches to overcome the innate chemoresistance to platinum derivatives of some ovarian epithelial cancers and to find innovative drugs for recurrent ovarian cancer.     

Cyt-C Mediated Mitochondrial Pathway Plays an Important Role in Oocyte Apoptosis in Ricefield Eel (Monopterus albus)

Apoptosis plays a key role in the effective removal of excessive and defective germ cells, which is essential for sequential hermaphroditism and sex change in vertebrates. The ricefield eel, Monopterus albus is a protogynous hermaphroditic fish that undergoes a sequential sex change from female to male. Previous studies have demonstrated that apoptosis is involved in sex change in M. albus. However, the apoptotic signaling pathway is unclear. In the current study, we explored the underlying mechanism of apoptosis during gonadal development and focused on the role of the mitochondrial apoptosis signaling pathway in sex change in M. albus. Flow cytometry was performed to detect apoptosis in gonads at five sexual stages and ovary tissues exposed to hydrogen peroxide (H₂O₂) in vitro. Then the expression patterns of key genes and proteins in the mitochondrial pathway, death receptor pathway and endoplasmic reticulum (ER) pathway were examined. The results showed that the apoptosis rate was significantly increased in the early intersexual stage and then decreased with the natural sex change from female to male. Quantitative real-time PCR revealed that bax, tnfr1, and calpain were mainly expressed in the five stages. ELISA demonstrated that the relative content of cytochrome-c (cyt-c) in the mitochondrial pathway was significantly higher than that of caspase8 and caspase12, with a peak in the early intersexual stage, while the levels of caspase8 and caspase12 peaked in the late intersexual stage. Interestingly, the Pearson’s coefficient between cyt-c and the apoptosis rate was 0.705, which suggests that these factors are closely related during the gonadal development of M. albus. Furthermore, the cyt-c signal was found to be increased in the intersexual stage by immunohistochemistry. After incubation with H₂O₂, the mRNA expression of mitochondrial pathway molecules such as bax, apaf-1, and caspase3 increased in ovary tissues. In conclusion, the present results suggest that the mitochondrial apoptotic pathway may play a more important role than the other apoptotic pathways in sex change in M. albus.     

Hexakis(PCP‐Platinum and ‐Ruthenium) Complexes by the Transcyclometalation Reaction and Their Use in Catalysis

Hexakis(PCP‐pincer) complexes [C₆{PtBr(PCP)}₆] ( 5d ) and [C₆{RuCl(PCP)(PPh₃)}₆] ( 5e ) were synthesized via the transcyclometalation (TCM) procedure. Mixing the hexakis(PCHP‐arene) ligand 7 with six equivalents of [PtBr(NCN)] ( 1a ) or [RuCl(NCN)(PPh₃)] ( 1b ), respectively, resulted in the selective metalation of all PCP‐ligand sites and the concomitant formation of six equivalents of the NCHN‐arene ligand. This procedure was found to be superior over existing metalation procedures. In addition, hexakisruthenium complex 5e was applied as homogeneous catalyst in the hydrogen transfer reactions of cyclohexanone, acetophenone and benzophenone to the corresponding alcohols. In these reactions, the activity per ruthenium center of 5e was found to be of the same order of magnitude as that of the mononuclear analogue [RuCl(PCP)(PPh₃)] 3b , indicating that all ruthenium centers act as independent catalytic sites.     

Hyperpolarization Induced by Lipopolysaccharides but Not by Chloroform Is Inhibited by Doxapram,an Inhibitor of Two-P-Domain K+ Channel (K2P)

Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The Drosophila larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the Drosophila larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on Drosophila muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval Drosophila body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS.