Photostimulated Anticancer Activity of Mitochondria Localized Rhenium(I) Tricarbonyl Complexes Bearing 1H-imidazo[4,5-f][1,10]phenanthroline Ligands Against MDA-MB-231 Cancer Cells.

We have introduced Re(I) tricarbonyl complexes (ReL1 - ReL6) [Re(CO)3(N^N)Cl] where N^N=extensive π conjugated imidazo-[4,5-f][1,10]-phenanthroline derivatives that helps in strong DNA intercalation, enhanced photophysical behavior, increase the 3π-π* character of T1 state for PDT and high value of lipophilicity for cell membrane penetration. These complexes exhibited prominent intraligand/ligand-centered (π-π*/1LC) absorption bands at λ 260-350 nm and relatively weak metal-to-ligand charge-transfer (1MLCT) bands within the λ 350-550 nm range. Among the six synthesized complexes, [(CO)3ReICl(K2-N,N-2-(4-(1-benzyl-1H-tetrazol-5-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline] (ReL6) exhibited outstanding potency (IC50~6 µM, PI>9) under yellow light irradiation compared to dark conditions. Importantly, extremely lipophilic complex ReL6 showed effective penetration through the cell membrane and localized primarily in mitochondria (Pearson's correlation coefficient, PCC=0.918) of MDA-MB-231 cells. Complex ReL6 exhibited more than 9 times higher photo-toxicity in normoxic and hypoxic environment of tumor by inducing 1O2 generation (type II PDT), radical generation triggered by NADH oxidation (type I PDT). This complex is a promising candidate for TNBC treatment in hypoxic tumors, with efficacy comparable to photofrin and have demonstrated CO release ability under UV light irradiation.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.