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.

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.

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.

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.

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.

Mitochondria specific highly cytoselective iridium(iii)-Cp* dipyridophenazine (dppz) complexes as cancer cell imaging agents.

Cancer is the most incurable pernicious disease to date after cardiovascular disease with an immeasurable rate of mortality. However, effective cancer medication and therapy are still castles in the sky to researchers. Therefore, in search of an appropriate strategy to annihilate cancer, we have designed a set of Ir(iii)-Cp* dipyridophenazine complexes as luminescent anticancer agents combining the cancer inhibiting potency of the planar dipyridophenazine (dppz) moiety through DNA interaction and mitochondrial dysfunction with the wonderful photoluminescence ability and target specificity of iridium metal. Hence, with the synergy of these dual aspects in the same system, we have aspired to emphasize the theranostic approach of cancer treatment in the present study by preparing effective, aqueous-soluble, mitochondria-targeting, highly cytoselective, luminescent, cancer cell-permeable scaffolds, enabling diagnosis as well as the healing of cancer cells in the body. Here, the presence of the cyclopentadienyl (Cp*) moiety in association with the fluorine group has boosted the lipophilic character of the complexes. Also, the cytotoxicity screening of the prepared Cp*Ir(iii)-dipyridophenazine complexes (IrL1-IrL7) against colorectal adenocarcinoma cells (Caco-2) and human epitheloid cervix carcinoma cells (HeLa) clearly identified them as potential anticancer agents and imaging studies unveiled their superb cellular imaging properties. Among them, the complex [(η5-Cp*)IrCl(11-fluorodipyrido[3,2-a:2',3'-c]phenazine)] (IrL6) achieved the best cytoselectivity. However, the superiority of the anticancer potency of [(η5-Cp*)IrCl(benzo[i]dipyrido[3,2-a:2',3'-c]phenazine)] (IrL3) was also corroborated by its activity against the most aggressive colorectal carcinoma cell line (HT-29), whereas (η5-Cp*)IrCl(11-(trifluoromethyl)dipyrido[3,2-a:2',3'-c]phenazine (IrL5) came into the limelight as the best theranostic agent as it showed remarkable cytoselectivity as well as significant cellular imaging properties, endowing it with the highest quantum yield value among all the complexes.

DNA targeting half sandwich Ru(II)-p-cymene-N

For diagnosing and annihilating cancer in the human body, herein, we have adopted a one pot convenient synthetic protocol to synthesize a library of half sandwich Ru(ii)-p-cymene-N^N complexes under continuous sonication and isolated their regioisomers by preparative thin layer chromatography followed by justification of stability using DFT. The present work has resulted in a library of ruthenium arene complexes and their isolated regioisomers following environmentally benign green processes and their screening of anticancer activity in terms of cytotoxicity and selectivity against cancer cell lines where [(η6-p-cymene)RuCl{2-(5,6-dichloro-1H-benzo[d]imidazole-2-yl)quinolone}] (11j) has been elicited to be significantly more potent as well as selective in Caco-2 and HeLa cell lines than the normal HEK-293 cell line compared to cisplatin and it has even shown marked cytotoxicity against the more aggressive HT-29 colorectal cancer cell line being capable of producing oxidative stress or arresting the cell cycle. Moreover, these types of Ru(ii)-arene complexes exhibited excellent binding efficacy with DNA and the compounds [(η6-p-cymene)RuCl{5-chloro-2-(6-(4-chlorophenyl)pyridin-2-yl)benzo[d]thiazole}]PF6 (8l4), [(η6-p-cymene)Ru-2-(6-(benzofuran-2-yl)pyridin-2-yl)-5-chlorobenzo[d]thiazole (8l9) and [(η6-p-cymene)RuCl{2-(6-nitro-1H-benzo[d]imidazol-2-yl)quinolone}]Cl (11f') and might be applied for cancer theranostic treatment due to their good fluorescence properties and remarkable potency.

Mitochondria-Targeting Click-Derived Pyridinyltriazolylmethylquinoxaline-Based Y-Shaped Binuclear Luminescent Ruthenium(II) and Iridium(III) Complexes as Cancer Theranostic Agents.

Due to several negative issues, market available drugs have been gradually losing their importance in the treatment of cancer. With a view to discover suitable drugs capable of diagnosing as well as inhibiting the growth of cancer cells, we have aspired to develop a group of theranostic metal complexes which will be (i) target specific, (ii) cytoselective, thus rendering the normal cell unaffected, (iii) water-soluble, (iv) cancer cell permeable, and (v) luminescent, being beneficial for healing the cancer eternally. Therefore, to reach our goal, we have prepared novel Ru(II)- and Ir(III)-based bimetallic and hetero bimetallic scaffolds using click-derived pyridinyltriazolylmethylquinoxaline ligands followed by metal coordination. Most of the compounds have displayed significant cytoselectivity against colorectal adenocarcinoma (Caco-2) and epithiloid cervical carcinoma (HeLa) cells with respect to normal human embryonic kidney cells (HEK-293) compared to cisplatin [cis-diamminedichloroplatinum(II)] along with excellent binding efficacy with DNA as well as serum albumin. Complex [(η6-p-cymene)(η5-Cp*)RuIIIrIIICl2(K2-N,N-L)](PF6)2 [RuIrL] exhibited the best cytoselectivity against all the human cancer cells and was identified as the most significant cancer theranostic agent in terms of potency, selectivity, and fluorescence quantum yield. Investigation of the localization of complex [Ir2L] and [RuIrL] in the more aggressive colorectal adenocarcinoma cell HT-29 indicates that mitochondria are the key cellular target for destroying cancer cells. Mitochondrial dysfunction and G2/M phase cell cycle arrest in HT-29 cell were found to be involved in the apoptotic cell death pathway induced by the test complexes [Ir2L] and [RuIrL]. These results validate the concept that these types of complexes will be reasonably able to exert great potential for tumor diagnosis as well as therapy in the near future.

Luminescent anticancer ruthenium(ii)-p-cymene complexes of extended imidazophenanthroline ligands: synthesis, structure, reactivity, biomolecular interactions and live cell imaging.

Of late, cancer has become a terrible disease affecting people throughout the world. Keeping this in mind, we tried to design drugs that are more lipophilic, target-specific, water-soluble, cytoselective and fluorescent. In this regard, we reported novel ruthenium(ii)-p-cymene imidazophenanthroline scaffolds as effective DNA targeting agents. The planarity of imidazophenanthroline ligands caused the Ru(ii) complex to be a good intercalator. An extended π-electronic conjugation was introduced in the imidazophenanthroline moieties through the Suzuki and Sonogashira coupling reactions. Here, we synthesized nine Ru(ii) complexes (16a-b, 17a-d, and 19a-c). Among these, [(η6-p-cymene)RuCl(K2-N,N-2-(4'-methyl-[1,1'-BIphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (16b) exhibited the best potency and selectivity with excellent cellular uptake; [(η6-p-cymene)RuCl(K2-N,N-2-(4-(phenylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (17a) acted as a cytoselective probe for live cell imaging.