Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy.

The cellular defense system against exogenous substances makes therapeutics inefficient as intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS) or reactive nitrogen species (RNS) or other free radicals produced by the therapeutics. In the cancer cell microenvironment, the intracellular GSH level becomes exceptionally high to fight against oxidative stress created by the production of ROS/RNS or any free radicals, which are the byproducts of intracellular redox reactions or cellular respiration processes. Thus, in order to maintain redox homeostasis for survival of cancer cells and their rapid proliferation, the GSH level starts to escalate. In this circumstance, the administration of anticancer therapeutics is in vain, as the elevated GSH level reduces their potential by reduction or by scavenging the ROS/RNS they produce. Therefore, in order to augment the therapeutic potential of anticancer agents against elevated GSH condition, the GSH level must be depleted by hook or by crook. Hence, this Review aims to compile precisely the role of GSH in cancer cells, the importance of its depletion for cancer therapy and examples of anticancer activity of a few selected metal complexes which are able to trigger cancer cell death by depleting the GSH level.

2-Aryl-1H-imidazo[4,5-f][1,10]phenanthroline-Based Binuclear Ru(II)/Ir(III)/Re(I) Complexes as Mitochondria Targeting Cancer Stem Cell Therapeutic Agents.

A series of novel Ru(II)/Ir(III)/Re(I)-based organometallic complexes [Ru2L1, Ru2L2, Ir2L1, Ir2L2, Re2L1, and Re2L2] have been synthesized to assess their potency and selectivity against multiple cancer cells A549, HCT-116, and HCT-116 colon CSCs. The cytotoxic screening of the synthesized complexes has revealed that complex Ru2L1 and Ir2L2 are two proficient complexes among all, but Ru2L1 is the most potent complex. A significant binding constant value was observed for DNA and BSA in all complexes. Significant lipophilic properties allow them to penetrate cancer cell membranes, and substantial quantum yield (ϕf) values support bioimaging potential. Again, these complexes are particular for mitochondrial localization and produce a profuse amount of ROS to damage the mitochondrial DNA and then G1 phase cell-cycle arrest. Protein expression analysis unveiled that pro-apoptotic Bax protein overexpressed in Ru2L1-treated cells, whereas antiapoptotic Bcl-2 protein was expressed twofold in Ir2L2-treated cells, which correlated with autophagy reticence.

Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)quinoline-based Ir(III)-PTA complexes in MDA-MB-231 cancer cells.

Metal complexes play a crucial role in photo-activated chemotherapy (PACT), which has recently been used to treat specific disorders. Triple-negative breast cancer has an enormously high rate of relapse due to the existence and survival of cancer stem cells (CSCs) characterized by increased amounts of glutathione (GSH). Hence, designing a phototoxic molecule is an enticing area of research to combat triple-negative breast cancer (TNBC) via GSH depletion and DNA photocleavage. Herein, we focus on the application of PTA and non-PTA Ir(III) complexes for phototoxicity in the absence and presence of GSH against MDA-MB-231 TNBC cells. Between these two complexes, [Cp*IrIII(DD)PTA]·2Cl (DDIRP) exhibited better phototoxicity (IC50 ∼ 2.80 ± 0.52 µM) compared to the non-PTA complex [Cp*IrIII(DD)Cl]·Cl (DDIR) against TNBC cells because of the high GSH resistance power of the complex DDIRP. The significant potency of the complex DDIRP under photo irradiation in both normoxia and hypoxia conditions can be attributed to selective transportation, high cellular permeability and uptake towards the nucleus, GSH depletion by GSH-GSSG conversion, the ability of strong DNA binding including intercalation, and oxidative stress. The strong affinity to serum albumin, which serves as a carrier protein, aids in the transport of the complex to its target site while preventing glutathione (GSH) deactivation. Consequently, the complex DDIRP was developed as a suitable phototoxic complex in selective cancer therapy, ruling over the usual chemotherapeutic drug cisplatin and the PDT drug Photofrin. The ability of ROS generation under hypoxic conditions delivers this complex as a hypoxia-efficient selective metallodrug for the treatment of TNBC.

Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes for selective cancer therapy via a potential DNA damage mechanism.

Recently, achieving selective cancer therapy with trifling side effects has been a great challenge in the eradication of cancer. Thus, to amplify the cytoselective approach of complexes, herein, we developed a series of Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes and screened their potency against HeLa and MCF-7 cell lines together with the evaluation of their toxicity towards a normal kidney cell line (HEK-293). On meticulous investigation, complex [ReI(CO)3Cl(K2-N,N-(2c))] (3c) was found to be the most potent anticancer entity among other complexes. Complex 3c also showed competency to induce apoptosis in MCF-7 cells through G2/M phase cell-cycle arrest in association with the generation of ample reactive oxygen species (ROS), eventually leading to DNA intercalation and internucleosomal cleavage. The order of the cytotoxicity of these complexes depended on their lipophilic character and the electron-withdrawing halogen substitution at the para-position of the phenyl ring in the imidazophenanthroline ligand.

CuAAC "Click"-Derived Luminescent 2-(2-(4-(4-(Pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzo[d]thiazole-Based Ru(II)/Ir(III)/Re(I) Complexes as Anticancer Agents.

To enhance the cytoselective behavior of the complexes, we intended to develop a CuAAC "click"-derived synthetic protocol for the preparation of 2-(2-(4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzo[d]thiazole-based Ru(II)/Ir(III)/Re(I) complexes, and their cytotoxicity against three different cancer cell lines (MCF-7, HeLa, and U87MG) in consort with one normal cell line (HEK-293) was evaluated. In our detailed investigations, the significant cytotoxic nature of the Ru(II) complex 7a compared to Ir(III) and Re(I) complexes (7b and 7c, respectively) was observed. Complex 7a was capable of MCF-7 cell apoptosis via the inhibition of both S- and G2/M-phase cell cycle arrest in association with a substantial quantity of ROS production and DNA intercalation.

Different routes for the construction of biologically active diversely functionalized bicyclo[3.3.1]nonanes: an exploration of new perspectives for anticancer chemotherapeutics.

Cancer is the second most high-morbidity disease throughout the world. From ancient days, natural products have been known to possess several biological activities, and research on natural products is one of the most enticing areas where scientists are engrossed in the extraction of valuable compounds from various plants to isolate many life-saving medicines, along with their other applications. It has been noticed that the bicyclo[3.3.1]nonane moiety is predominant in most biologically active natural products owing to its exceptional characteristics compared to others. Many derivatives of bicyclo[3.3.1]nonane are attractive to researchers for use in asymmetric catalysis or as potent anticancer entities along with their successful applications as ion receptors, metallocycles, and molecular tweezers. Therefore, this review article discusses several miscellaneous synthetic routes for the construction of bicyclo[3.3.1]nonanes and their heteroanalogues in association with the delineation of their anticancer activities with few selective compounds.

GSH resistant, luminescent 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline-based Ru(II)/Ir(III)/Re(I) complexes for phototoxicity in triple-negative breast cancer cells.

Selective chemotherapeutic strategies necessitate the emergence of a photosensitive scaffold to abate the nuisance of cancer. In the current context, photo-activated chemotherapy (PACT) has, therefore, appeared to be very effective to vanquish the vehemence of triple-negative breast cancer (TNBC). Metal complexes have been identified to act well against cancer cell microenvironment (high GSH content, low pH, and hypoxia), and thus they have been employed in the treatment of various types of cancer. As TNBC is very challenging to treat owing to its poor prognosis, lack of a specific target, high chance of relapse, and strong metastatic ability, herein we have aspired to design GSH-resistant phototoxic Ru(II)/Ir(III)/Re(I) based pyrene imidazophenathroline complexes to selectively avert the triple-negative breast cancer. The application of complexes, [RuL], [IrL], and [ReL] in the absence and in the presence of GSH against MDA-MB-231TNBC cells, has revealed that they are very active upon irradiation of visible light compared to dark due to the creation of copious singlet oxygen (1O2) as reactive oxygen species (ROS). Among three synthesized complexes, [IrL] has shown outstanding potency (IC50 = 3.70 in the absence of GSH and IC50 = 3.90 in the presence of GSH). Also, the complex, [IrL] is capable of interacting with DNA with the highest binding constant (Kb = 0.023 × 106 M-1) along with higher protein binding affinity (KBSA = 0.0321 × 106 M-1). Here, it has been unveiled that all the complexes have been entitled to involve DNA covalent interaction through the available sites of both adenine and guanine bases.

Synthesis, characterization, photophysical and electrochemical properties, and biomolecular interaction of 2,2'-biquinoline based phototoxic Ru(II)/Ir(II) complexes.

The phototoxic nature of drugs has been seen to convey immense importance in photo activated chemotherapy (PACT) for the selective treatment of disease. Rationally, in order to eradicate the vehemence of cancer in a living body, the design of phototoxic molecules has been of growing interest in research to establish a selective strategy for cancer therapy. Therefore, the present work portrays the synthesis of a phototoxic anticancer agent by incorporating ruthenium(II) and iridium(III) metals into a biologically active 2,2'-biquinoline moiety, BQ. The complexes, RuBQ and IrBQ, have been revealed as effective anticancer agents with remarkable toxicity in the presence of light compared to the dark towards HeLa and MCF-7 cancer cell lines due to the production of a profuse amount of singlet oxygen (1O2) upon irradiation by visible light (400-700 nm). Complex IrBQ exhibited the best toxicity (IC50 = 8.75 µM in MCF-7 and 7.23 µM in HeLa) in comparison to the RuBQ complex under visible light. RuBQ and IrBQ displayed considerable quantum yields (Φf) along with a good lipophilic property, indicating the cellular imaging capability of both complexes upon significant accumulation in cancer cells. Also, the complexes have shown significant binding propensity with biomolecules, viz. deoxyribonucleic acid (DNA) as well as serum albumin (BSA, HSA).

G2/M-Phase-Inhibitory Mitochondrial-Depolarizing Re(I)/Ru(II)/Ir(III)-2,2'-Bipyrimidine-Based Heterobimetallic Luminescent Complexes: An Assessment of In Vitro Antiproliferative Activity and Bioimaging for Targeted Therapy toward Human TNBC Cells.

Triple-negative breast cancer (TNBC) is an extremely vicious subtype of human breast cancer having the worst prognosis along with strong invasive and metastatic competency. Hence, it can easily invade into blood vessels, and presently, no targeted therapeutic approach is available to annihilate this type of cancer. Metal complexes have successfully stepped into the anticancer research and are now being applauded due to their anticancer potency after the discovery of cisplatin. Many of these metal complexes are also well recognized for their activity toward breast cancer. As the TNBC is a very dangerous subtype and has long been a challenging ailment to treat, we have intended to develop a few brand new mixed metallic Ru(II)/Ir(III)/Re(I)-2,2'-bipyrimidine complexes [L'Re2], [L'RuRe], and [L'IrRe] to abate the unbridled proliferation of TNBC cells. The potency of the complexes against TNBC cells has been justified using MDA-MB-468 TNBC cell lines where complex [L'IrRe] has displayed significant potency among all the three complexes with an IC50 value of 24.12 µM. The complex [L'IrRe] has been competent to cause apoptosis of TNBC cells through inhibition of the G2/M phase in the cell cycle in association with a profuse amount of ROS generation and mitochondrial depolarization.

Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.

In vitro studies on the selective cytotoxic effect of luminescent Ru(II)-p-cymene complexes of imidazo-pyridine and imidazo quinoline ligands.

In recent years, Ru(II) complexes have gained high importance in medicinal chemistry due to their significant anti-cancer activities, which are directly related to their DNA binding ability. In this report, the chemistry and cytotoxicity of two new Ru(II) complexes containing imidazole pyridine (Ru-1) and imidazole quinoline (Ru-2) have been studied. The prepared compounds were characterized using infrared (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), isothermal titration calorimetry (ITC), UV-Vis, and fluorescence spectral techniques. The structural analyses show that the Ru(II) complexes exhibit a 'piano stool' coordination geometry and they are composed of one bound arene, two sigma bonded benzil nitrogen atoms, and labile chlorine linked to Ru(II). The photo-physical properties of these complexes were examined, and they exhibit absorption peaks at 260 nm and 380 nm, which are due to the involvement of intra-ligand charge transitions (ILCT) and metal-to-ligand charge transitions (MLCT), respectively. The binding process of the Ru(II) complexes with DNA and BSA is non-covalent in nature and the binding constants of Ru-1 and Ru-2 complexes with DNA and BSA were found to be 1 × 105 M-1 and 1 × 103 M-1, respectively. In the presence of the Ru(II) complexes, ethidium bromide (EtBr) is competitively displaced from DNA by intercalation of the Ru(II) complexes in DNA and it is well corroborated by viscosity and in silico studies. Both the ligands and Ru(II) complexes were carefully investigated in vitro for cytotoxicity against HeLa, MCF-7, and MDA-MB-231 cells. Surprisingly, both Ru(II) complexes exhibit superior cytotoxicity to cisplatin with a low LD50 value against the examined cancer cells. Besides, an insignificant effect on HEK normal cells (LD50 > 140 µM) was observed.

One pot three component synthesis of DNA targeting phototoxic Ru(II)-p-cymene dipyrido[3,2-a:2',3'-c]phenazine analogues.

We have developed a one pot three component synthetic protocol for half-sandwich Ru(II)-p-cymene dipyrido[3,2-a:2',3'-c]phenazine analogues for selective cancer therapy under light irradiation. On average, the cytotoxicity of all the complexes is indeed doubled upon light irradiation and also exhibited significant photo and dark selectivity against cancer cells with respect to normal cells. Out of five Ru(II) complexes (RuL1-RuL5), [(η6-p-cymene)RuIICl(K2-N,N-11-nitrodipyrido[3,2-a:2',3'-c]phenazine]PF6 (RuL4) exhibited the best phototoxicity (lowest IC50 under light irradiation). Intracellular ROS generation was studied by the 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. Moreover, these complexes exhibited a strong serum albumin and DNA binding capacity. These complexes also exhibited good stability in 10% DMSO-buffer and under 1 mM GSH conditions. Overall, the remarkable photocytotoxic efficacy of new Ru(II)-p-cymene dipyrido[3,2-a:2',3'-c]phenazine analogues (RuL1-RuL5) makes them potential photochemotherapeutics as an alternative of current PDT agents.

Target-specific mononuclear and binuclear rhenium(i) tricarbonyl complexes as upcoming anticancer drugs.

Metal complexes have gradually been attracting interest from researchers worldwide as potential cancer therapeutics. Driven by the many side effects of the popular platinum-based anticancer drug cisplatin, the tireless endeavours of researchers have afforded strategies for the design of appropriate metal complexes with minimal side effects compared to cisplatin and its congeners to limit the unrestricted propagation of cancer. In this regard, transition metal complexes, especially rhenium-based complexes are being identified and highlighted as promising cancer theranostics, which are endowed with the ability to detect and annihilate cancer cells in the body. This is attributed the amazing photophysical properties of rhenium complexes together with their ability to selectively attack different organelles in cancer cells. Therefore, this review presents the properties of different rhenium-based complexes to highlight their recent advances as anticancer agents based on their cytotoxicity results.

Ru(ii)arene(N

Herein, we have introduced a series of half-sandwich Ru(ii)arene(N^N bpy/phen)-based RAPTA complexes for brain cancer therapy. Among all the synthesized complexes, [(η6-p-cymene)RuII(κ2-N,N-4,7dimethyl phenanthroline)(PTA)]·2PF6 (4c) and [(η6-p-cymene)RuII(κ2-N,N-4,7diphenyl phenanthroline)(PTA)]·2PF6 (4d) showed outstanding potency against the T98G, LN229 and U87MG cancer cells. The antiproliferative activity of these complexes was reinforced by neurosphere, DNA intercalation, agarose gel electrophoresis, cell cycle analysis and time-dependent ROS detection assays. The real-time reverse transcription (RT)-polymerase chain reaction (PCR) study showed that complex 4c inhibited the TNF-α-induced NF-κB phosphorylation in glioma cells. Moreover, the in vivo biodistribution of complex 4c in different organs and the morphological patterns of widely used zebrafish embryos due to toxic effects have been evaluated.

[Ru(η6-p-cymene)(N

Herein, we have introduced a class of half-sandwich [Ru(η6-p-cymene)(N^O 8-hydroxyquinoline)(PTA)] complexes for brain cancer therapy. Among all the complexes, [RuL3PTA] and [RuL4PTA] exhibited excellent cytotoxicity profiles against T98G, LN229, and U87MG cancer cells. Notably, the antiproliferative activities of the relevant complexes were also supported by neurosphere, DNA intercalation, agarose gel electrophoresis, and time-dependent ROS detection assay studies. Detailed molecular assays were obtained via real-time reverse transcription (RT)-polymerase chain reaction (PCR) experiments. Moreover, the in vivo biodistribution of the [RuL4PTA] complex in different organs and the morphological patterns of zebrafish embryos due to toxic effects have been evaluated.

Mitochondria-targeted half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes as antiproliferative and bioimaging agents against triple negative breast cancer cells MDA-MB-468.

To reduce the side effects of marketed cancer drugs against triple negative breast cancer cells we have reported mitochondria targeting half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes for MDA-MB-468 cell therapy and diagnosis. Out of five Ir(iii) complexes (IrL1-IrL5), [iridium(iii)-Cp*-2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline]PF6 (IrL1) has exhibited the best cytoselectivity against MDA-MB-468 cells compared to normal HaCaT cells along with excellent binding efficacy with DNA as well as serum albumin. The subcellular localization study of the complex revealed the localization of the compound in cytoplasm thereby pointing to a possible mitochondrial localization and consequent mitochondrial dysfunction via MMP alteration and ROS generation. Moreover, the IrL1 complex facilitated a substantial G1 phase cell-cycle arrest of MDA-MB-468 cells at the highest tested concentration of 5 µM. The study verdicts support the prospective therapeutic potential of the IrL1 complex in the treatment and eradication of triple negative breast cancer cells. These results validate that these types of scaffolds will be fairly able to exert great potential for tumor diagnosis as well as therapy in the near future.

Iridium(III)-Cp*-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol analogues as hypoxia active, GSH-resistant cancer cytoselective and mitochondria-targeting cancer stem cell therapeutic agents.

Herein, we have introduced a series of iridium(III)-Cp*-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol complexes via a convenient synthetic methodology, which act as hypoxia active and glutathione-resistant anticancer metallotherapeutics. The [IrIII(Cp*)(L5)(Cl)](PF6) (IrL5) complex exhibited the best cytoselectivity, GSH resistance and hypoxia effectivity in HeLa and Caco-2 cells among the synthesized complexes. IrL5 also exhibited highly cytotoxic effects on the HCT-116 CSC cell line. This complex was localized in the mitochondria and subsequent mitochondrial dysfunction was observed via MMP alteration and ROS generation on colorectal cancer stem cells. Cell cycle analysis also established the potential of this complex in mediating G2/M phase cell cycle arrest.

2,2'-Bipyrimidine-based luminescent Ru(ii)/Ir(iii)-arene monometallic and homo- and hetero-bimetallic complexes for therapy against MDA-MB-468 and caco-2 cells.

To unearth suitable complexes that are capable of inhibiting the growth of MDA-MB-468 and Caco-2 cells, 2,2'-bipyrimidine-based luminescent Ru(ii)/Ir(iii)-arene monometallic and homo- and hetero-bimetallic complexes were synthesized. The complex [(η6-p-cymene)(η5-Cp*)RuIIIrIIICl2(K2-N,N-bipyrimidine)](PF6)2 [LRuIr] exhibited the best potency in both cells along with good GSH stability and strong binding efficacy with the biomolecules. The apoptotic event occurred in MDA-MB-468 cancer cells via cell cycle arrest.

Ru(ii), Ir(iii), Re(i) and Rh(iii) based complexes as next generation anticancer metallopharmaceuticals.

Several anticancer drugs such as cisplatin, and its analogues, epirubicin, and doxorubicin are well known for their anticancer activity but the therapeutic value of these drugs comes with certain side effects and they cannot distinguish between normal and cancer cells. Thus, a major challenge for researchers around the world is to develop an anticancer drug with the least toxicity and more target specificity. With the successful reporting of NAMI-A and KP1019, a new path has emerged in the anticancer field. Recently, several Ru(ii) complexes have been reported for their anticancer activity due to their enhanced cellular uptake and selectivity towards cancer cells. Apart from the Ru(ii) complexes, a large amount of research has been carried out with Ir(iii), Re(i), and Rh(iii) based complexes, which exhibited promising anticancer activity. The present review reports various Ru(ii), Ir(iii), Re(i), and Rh(iii) based complexes for their anticancer activity based on their cytotoxicity profiles, biological targets and mechanism of action.

GSH-resistant and highly cytoselective ruthenium(II)-p-cymene-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol complexes as potential anticancer agents.

To avoid the side effects of the current popular platinum-based anticancer drugs, researchers have made tireless attempts to design appropriate GSH-resistant Ru(ii)-arene complexes. In this regard, luminescent ruthenium(ii)-p-cymene-imidazophenanthroline complexes were developed as promising highly cytoselective cancer theraputic agents for HeLa and Caco-2 cells.