📚 BiometalDB

Light-activated compounds are powerful tools and potential agents for medical applications, as biological effects can be controlled in space and time. Ruthenium polypyridyl complexes can induce cytotoxic effects through multiple mechanisms, including acting as photosensitizers for singlet oxygen (¹O₂) production, generating other reactive oxygen species (ROS), releasing biologically active ligands, and creating reactive intermediates that form covalent bonds to biological molecules. A structure-activity relationship (SAR) study was performed on a series of Ru(II) complexes containing isomeric tetramethyl-substituted bipyridyl-type ligands. Three of the ligand systems studied contained strain-inducing methyl groups and created photolabile metal complexes, which can form covalent bonds to biomolecules upon light activation, while the fourth was unstrained and resulted in photostable complexes, which can generate ¹O₂. The compounds studied included both bis-heteroleptic complexes containing two bipyridine ligands and a third, substituted ligand and tris-homoleptic complexes containing only the substituted ligand. The photophysics, electrochemistry, photochemistry, and photobiology were assessed. Strained heteroleptic complexes were found to be more photoactive and cytotoxic then tris-homoleptic complexes, and bipyridine ligands were superior to bipyrimidine. However, the homoleptic complexes exhibited an enhanced ability to inhibit protein production in live cells. Specific methylation patterns were associated with improved activation with red light, and photolabile complexes were generally more potent cytotoxic agents than the photostable ¹O₂-generating compounds. Show less

Neutral half-sandwich organometallic ruthenium(II) complexes of the type [(η(6)-cymene)RuCl(2)(L)] (H1-H10), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single-crystal X-ray diffraction confirming a piano-stool geometry with η(6) coordination of the arene ligand. Hydrogen bonding between the N-H group of the heterocycle and a chlorine atom attached to Ru stabilizes the metal-ligand interaction. Complexes coordinated to a mercaptobenzothiazole framework (H1) or mercaptobenzoxazole (H6) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1-phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non-intercalative fashion and cause unwinding of plasmid DNA in a cell-free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIα activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen-bond donor on the heterocycle reduces the cytotoxicity. Show less

Ru(eta6-arene) complexes of epidermal growth factor receptor (EGFR) inhibiting tyrphostins 1a and 1b were prepared, characterized and tested for DNA interaction and bioactivity in four human tumor cell lines. The intrinsic cytotoxicity and cell line selectivity of o-hydroxyanisol 1a was greatly enhanced in its Ru(eta6-p-cymene) complex 2a and in its Ru(eta6-toluene) complex 3a. Complex 2a was particularly efficacious against multi-drug resistant EGFR(+) MCF-7/Topo breast carcinoma cells and also against mTOR-dependent EGFR(-) HL-60 leukemia cells. Complex 3a showed enhanced activity only against 518A2 melanoma cells and HL-60 cells, which are both known to express the mTOR protein. DNA was strongly metallated (ca. 1.7-2%) by all new Ru complexes without undergoing topological changes. Apparently, by complexation to Ru fragments tyrphostin derivatives can address additional biological targets in a manner instrumental to antitumoral strategies. Show less

Ruthenium(II) complexes developed for photodynamic therapy (PDT) are almost exclusively tris-bidentate systems with C₂ or D₃ symmetry. This is due to the fact that this structural framework commonly produces long-lived excited states, which, in turn, allow for the generation of large amounts of singlet oxygen (¹O₂) and other reactive oxygen species. Complexes containing tridentate ligands would be advantageous for biological applications as they are generally achiral (D_2d or C_2v symmetry), which eliminates the possibility of multiple isomers which could exhibit potentially different interactions with chiral biological entities. However, Ru(II) complexes containing tridentate ligands are rarely studied as candidates for photobiological applications, such as PDT, since they almost exclusively exhibit low quantum yields and very short excited-state lifetimes and, thus, are not capable of generating sufficient ¹O₂ or engaging in electron transfer reactions. Here, we report a proof-of-concept approach to make bis-tridentate Ru(II) complexes useful for PDT applications by altering their photophysical properties through the inclusion of N-heterocyclic carbene (NHC) ligands. Three NHC and two terpyridine ligands were studied to evaluate the effects of structural and photophysical modulations of bis-substituted Ru(II) complexes. The NHC complexes were found to have superior excited-state lifetimes, ¹O₂ production, and photocytotoxicity. To the best of our knowledge, these complexes are the most potent light-activated bis-tridentate complexes reported. Show less

As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which endow the organometallic complexes with potential for hypoxia targeting. In vitro tests showed the resulting complexes had higher anticancer activities in hypoxia than in normoxia against the tested cancer cell lines. Western blot analysis revealed that complexes 1-3 blocked HIF-1α protein accumulation under hypoxic conditions. Moreover, these complexes displayed much less cytotoxicity toward the normal human umbilical vein endothelial cell line (HUVEC), indicating that complexes 1-3 may be selectively cytotoxic for human cancer cell lines. These findings proved that ligation with YC-1 endowed these organometallic ruthenium(II) complexes with potential for hypoxia targeting in addition to enhancing their anticancer activities. Show less

The synthesis, spectroscopic characterisation and biological evaluation of mono- and bis-1,8-naphthalimide-conjugated ruthenium(ii)-polypyridyl complexes is presented. Spectroscopic DNA titrations, together with denaturation studies, show strong binding of both species to DNA through the naphthalimide arms. Linear and circular dichroism (LD and CD) spectroscopy reveal close association of the Ru(bpy)3(2+) core with DNA in the case of the mono-naphthalamide complex, [Ru(bpy)2(bpy-NAP)](2+). Significantly, binding by the second naphthalimide arm in the [Ru(bpy)2(bpy-NAP2)](2+) complex is found to displace the Ru(bpy)3(2+) centre from the DNA backbone. This 'negative allosteric effect' is found to have a dramatic influence on the photoinduced damage of plasmid DNA, and the viability of HeLa cancer cells upon photoactivation. Overall the study clearly maps and correlates the relationship between molecular structure, in vitro binding and activity, and in cellulo function. Show less

Two Ru(II) complexes [Ru(phen)2bppp](ClO4)2 (1) and [Ru(phen)27-Br-dppz](ClO4)2 (2) [phen=1,10 phenanthroline, 7-Br-dppz=7-fluorodipyrido[3,2-a:2',3'-c]phenazine, bppp=11-bromo-pyrido[2',3':5,6]pyrazino[2,3-f] [1,10]phenanthroline] have been synthesized and characterized by elemental analysis, ES-MS, (1)H-NMR, (13)C-NMR and IR. The in vitro cytotoxicity of the complexes examined against a panel of cancer cell lines (HeLa, Du145 and A549) by MTT method, both complexes show prominent anticancer activity against various cancer cells. Live cell imaging study and flow cytometric analysis demonstrate that both the complexes 1 and 2 could cross the cell membrane accumulating in the nucleus. Further, flow cytometry experiments showed that the cytotoxic Ru(II) complexes 1 and 2 induced apoptosis of HeLa tumor cell lines. Photo induced DNA cleavage studies have been performed and results indicate that both the complexes efficiently photo cleave pBR322 DNA. The binding properties of two complexes toward CT-DNA were investigated by various optical methods and viscosity measurements. The experimental results suggested that both Ru(II) complexes can intercalate into DNA base pairs. The complexes were docked into DNA-base pairs using the GOLD docking program. Show less

A new family of neutral ruthenium(II) arene complexes of the type [Ru(η⁶-arene)X(κ²- O, N-L)] (η⁶-arene = p-cym, bz; X = Cl^-, SCN^-; HL1 = 2-(2'-hydroxyphenyl)benzimidazole, HL2 = 2-(2'-hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η⁶- p-cym)(NCS)(κ²- O, N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ²- O, N-L2)(κ¹- S-DMSO)₂(μ-SCN)]₂ [3c] and [Ru(κ²- O, N-L2)(κ¹- S-DMSO)₃(SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT). Show less

Ruthenium complexes have been recently reported as potential chemotherapeutic agents that offer tumor selectivity and low tumor resistance. This study investigates the photochemistry and the effect of four strained photoactivatable polypyridyl ruthenium(II) complexes on non-small-cell lung cancer (A549) and triple negative breast cancer (MDA-MB-231) cells. All four ruthenium(II) complexes, [Ru(bpy)₂dmbpy]Cl₂ (C1) where (bpy = 2,2'-bipyridine and dmbpy = 6,6'-dimethyl-2,2'-bipyridine), [Ru(phen)₂dmbpy]Cl₂ (C2) where (phen = 1,10-phenanthroline), [Ru(dpphen)₂dmbpy]Cl₂ (C3) (where dpphen = 4,7-diphenyl-1,10-phenanthroline) and [Ru(BPS)₂dmbpy]Na₂ (C4) where (BPS = bathophenanthroline disulfonate) eject the dmbpy ligand upon activation by blue light. Determination of the octanol-water partition coefficient (log P) revealed that C3 was the only lipophilic complex (log P = 0.42). LC-MS/MS studies showed that C3 presented the highest cellular uptake. The cytotoxic effect of the complexes was evaluated with and without blue light activation using WST-1 kit. Data indicated that C3 exhibited the highest cytotoxicity after 72 h (MDA-MB-231, IC₅₀ = 0.73 µM; A549, IC₅₀ = 1.26 µM) of treatment. The phototoxicity indices of C3 were 6.56 and 4.64 for MDA-MB-230 and A549, respectively. Upon light activation, C3 caused significant ROS production and induced apoptosis in MDA-MB-231 cells as shown by flow cytometry. It also significantly increased Bax/Bcl2 ratio and PERK levels without affecting caspase-3 expression. C3 exhibited poor dark toxicity (IC₅₀ = 74 μM) on rat mesenchymal stem cells (MSCs). In conclusion, the physical property of the complexes dictated by the variable ancillary ligands influenced cellular uptake and cytotoxicity. C3 may be considered a promising selective photoactivatable chemotherapeutic agent that induces ROS production and apoptosis. Show less

We report [Ru^II(L)(η⁶-p-cym)Cl] (1 and 2) and [Pt^II(L)(DMSO)Cl] (3 and 4) complexes, where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL1) or o-vanillin (HL2). The complexes were characterized by single-crystal X-ray diffraction and other analytical techniques. The ¹H nuclear magnetic resonance data show that both the Ru(II) and Pt(II) complexes start forming the aquated complex within an hour. The aquated complexes are stable at least up to 24 h. The complexes bind to the N⁷ of the model nucleobase 9-ethylguanine (9-EtG). Interaction with calf thymus (CT) DNA shows moderate binding interactions with binding constants, K_b (3.7 ± 1.2) × 10³ M^-1 and (4.3 ± 1.9) × 10³ M^-1 for 1 and 3, respectively. The complexes exhibit significant antiproliferative activity against human pancreas ductal adenocarcinoma (Mia PaCa-2), triple negative metastatic breast adenocarcinoma (MDA-MB-231), hepatocellular carcinoma (Hep G2), and colorectal adenocarcinoma (HT-29) cell lines. The studies show that with the same ligand the Pt(II) complexes are more potent than the Ru(II) complexes. The in vitro potencies of all the complexes toward pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The Pt(II) and Ru(II) complexes show similar binding constants with CT-DNA, but the reactivity of the Pt(II) complex 3 with 9-EtG is faster and their overall cell killing pathways are different. This is evident from the arrest of the cell cycle by the Ru(II) complex 1 in the G2/M phase in contrast to the SubG1 phase arrest by the Pt(II) complex 3. The immunoblot study shows that 3 increases cyclin D and Bcl-2 expression in MDA-MB-231 due to the SubG1 phase arrest where these proteins express in greater quantities. However, both 1 and 3 kill in the apoptotic pathway via dose-dependent activation of caspase 3. Complex 3 depolarizes the mitochondria more efficiently than 1, suggesting its higher preference for the intrinsic pathway of apoptosis. Our work reveals that the same bidentate ligand with a change of the metal center, viz, Pt(II) or Ru(II), imparts significant variation in cytotoxic dosage and pathway of action due to specific intrinsic properties of a metal center (viz, coordination geometry, solution stability) manifested in a complex. Show less

Ru(ii) polypyridine complexes which can undergo photo-induced ligand dissociation and subsequent DNA covalent binding may potentially serve as photoactivated chemotherapeutic (PACT) agents. In this paper, three fluorinated dppz ligand coordinated Ru(ii) complexes (2-4) containing four monodentate pyridine ligands were studied. All complexes released one pyridine and covalently bound to DNA upon 470 nm irradiation. Compared with the parent complex [Ru(dppz)(py)₄]²⁺ (1), 2-4 displayed enhanced phototoxicity but diminished dark cytotoxicity, more favorable for PACT application. Complex 3 is the most efficient one with IC₅₀ values of about 8 μM toward HeLa and SKOV-3 cell lines, and also has a much higher IC₅₀ value toward normal L-02 cells. Our results indicate that fluorination on the retaining ligand may be an efficient way to improve the drug activity of Ru(ii) PACT agents. Show less

Two novel cyclometalated Ru(II) complexes containing isoquinoline ligand, [Ru(bpy)₂(1-Ph-IQ)](PF₆), (bpy = 2,2'-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and [Ru(phen)₂(1-Ph-IQ)](PF₆) (phen = 1,10-phenanthroline; RuIQ-2) were found to show high cytotoxic activity against NCI-H460, A549, HeLa and MCF-7 cell lines. Notably, both of them exhibited IC₅₀ values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes [Ru(bpy)₂(1-Py-IQ)](PF₆)₂ (Ru3) and [Ru(phen)₂(1-Py-IQ)](PF₆)₂ (Ru4) (1-Py-IQ = 1-pyridine-2-yl). The cellular uptake and intracellular localization displayed that the two cyclometalated Ru(II) complexes entered NCI-H460 cancer cells dominantly via endocytosis pathway, and preferentially distributed in the nucleus. Further investigations on the apoptosis-inducing mechanisms of RuIQ-1 and RuIQ-2 revealed that the two complexes could cause S, G2/M double-cycle arrest by regulating cell cycle related proteins. The two complexes also could reduce the mitochondrial membrane potential (MMP), promote the generation of intracellular ROS and trigger DNA damage, and then lead to apoptosis-mediated cell death. More importantly, RuIQ-2 exhibits low toxicity both towards normal HBE cells in vitro and zebrafish embryos in vivo. Accordingly, the developed complexes hold great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment. Show less

Photoactivated chemotherapy (PACT) is an emerging strategy for targeted cancer therapy. Strained Ru complexes with pseudo-octahedral geometry may undergo photo-induced ligand dissociation, forming aquated photoproducts that are significantly more cytotoxic compared to the precursor complex. The complexes investigated were the strained complex [Ru(bpy)₂BC]Cl₂ (where bpy = 2,2'-bipyridine and BC = bathocuproine) and its unstrained control [Ru(bpy)₂phen]Cl₂ (where phen = 1,10-phenanthroline). The uptake of [Ru(bpy)₂BC]Cl₂, assessed by ICP/MS, started immediately post-incubation and plateaued after 24 h. Active transport was found as the main mode of intracellular transport. Cell viability assays on A375 cells indicated a mean phototoxicity index of 340-fold, and the effect was shown to be primarily mediated by the aquated photoproducts rather than the dissociating ligands. A significant increase in ROS production and DNA damage was also observed. Flow cytometry confirmed the induction of early apoptosis at 48 h that proceeds to late apoptosis/necrosis by 72 h post-treatment. Western blot analysis of pro- and anti-apoptotic proteins revealed that apoptosis was mediated through an interplay between the intrinsic and extrinsic pathways, as well as autophagy and via inhibition of the MAPK and PI3K pathways. In conclusion, this study demonstrates that [Ru(bpy)₂BC]Cl₂ is a multi-mechanistic PACT drug which exhibits promising anticancer potential. Show less

A unique V-shaped "chiral" supramolecular scaffold, N-(4-pyridyl)-4-amino-1,8-naphthalimide Tröger's base (TBNap), was synthesized in good yield from a precursor N-(4-pyridyl)-4-amino-1,8-naphthalimide (Nap). TBNap was characterized using different spectroscopic methods and the molecular structure was elucidated by diffraction analysis. A new p-cymene-Ru(II)-curcumin conjugate (TB-Ru-Cur) was designed by reacting TBNap dipyridyl donor and ruthenium-curcuminato acceptor [RuCur = (p-cymene)Ru-(curcuminato)Cl] in the presence of silver triflate. TB-Ru-Cur was isolated in quantitative yield and characterized using Fourier transform infrared (FT-IR), NMR (¹H, ¹³C, and ¹⁹F), and electrospray ionization mass spectrometry (ESI-MS), and the molecular structure has been predicted using a computational study. Both TBNap and TB-Ru-Cur exhibited intramolecular charge transfer (ICT)-based fluorescence emission. Furthermore, the anticancer properties of TBNap, Ru-Cur, and TB-Ru-Cur were assessed in different cancer cell lines. Gratifyingly, the conjugate TB-Ru-Cur displayed fast-cellular internalization and good cytotoxicity against HeLa, HCT-116, and HepG2 cancer cells and the estimated IC₅₀ value was much lower than that of the precursors (TBNap and Ru-Cur) and the well-known chemotherapeutic drug cisplatin. Show less

A series of six Ru(arene) complexes, [(η(6)-p-cymene)Ru(dpb)(py-R)](2+) (1-6, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline, py-R = 4-substituted pyridine, R = N(CH3)2, NH2, OCH3, H, COOCH3 and NO2), were synthesized and their photochemical and photobiological properties were compared in detail. The electron push/pull character of the R groups has a significant impact on both ligand photodissociation and (1)O2 generation of the complexes. The photoinduced DNA covalent binding capabilities increase from 1 to 6 under both aerobic and anaerobic conditions, and DNA photocleavage occurs simultaneously in aerobic environments. 4 has the most potent phototoxicity against human lung carcinoma A549 cells among the examined complexes. The substituent effect may be ascribed to the influences of the R groups on the energy levels of (3)MC and (3)MLCT states as well as the energy gaps between (3)MC, (3)MLCT and dpb-based (3)IL states. Similar chemical modification on bidentate and arene ligands or other sites of the pyridine ligand may lead to more efficient agents with PDT and/or PACT activities. Show less

The four novel Ru(II) complexes [Ru(phen)2MAFIP](2+) (1) [MAFIP = 2-(5-(methylacetate)furan-2-yl)-1 H-imidazo[4,5-f] [1, 10]phenanthroline, phen = 1,10-Phenanthroline], [Ru(bpy)2MAFIP](2+) (2) (bpy = 2,2'-bipyridine) and [Ru(dmb)2MAFIP](2+) (3) (dmb = 4,4'-dimethyl-2,2'-bipyridine) and [Ru(hdpa)2MAFIP](2+) (4) (hdpa = 2,2-dipyridylamine) have been synthesized and fully characterized via elemental analysis, NMR spectroscopy, EI-MS and FT-IR spectroscopy. In addition, the DNA-binding behaviors of the complexes 1-4 with calf thymus DNA were investigated by UV-Vis absorption, fluorescence studies and viscosity measurement. The DNA-binding experiments showed that the complexes 1-4 interact with CT-DNA through an intercalative mode. BSA protein binding affinity of synthesized complexes was determined by UV/Vis absorption and fluorescence emission titrations. The binding affinity of ruthenium complexes was supported by molecular docking. The photoactivated cleavage of plasmid pBR322 DNA by ruthenium complexes 1-4 was investigated. All the synthesized compounds were tested for antimicrobial activity by using three Gram-negative (Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa) and three Gram-positive (Micrococcus luteus, Bacillus subtilis and Bacillus megaterium) organisms, these results indicated that complex 3 was more activity compared to other complexes against all tested microbial strains while moderate antimicrobial activity profile was noticed for complex 4. The antioxidant activity experiments show that the complexes exhibit moderate antioxidant activity. The cytotoxicity of synthesized complexes on HeLa cell lines has been examined by MTT assay. The apoptosis assay was carried out with Acridine Orange (AO) staining methods and the results indicate that complexes can induce the apoptosis of HeLa cells. The cell cycle arrest investigated by flow cytometry and these results indicate that complexes 1-4 induce the cell cycle arrest at G0/G1 phase. Show less

In the present work a novel C,N-cyclometalated benzimidazole Ru(ii) arene complex (GY34) was characterized by applying an alternative, diverse approach considering both chemical and biological aspects. RP-HPLC-ICP-MS and RP-HPLC-ESI-MS analysis proved that GY34 in both RPMI-1640 cell medium and ammonium acetate buffer was transformed into several subspecies and the importance of evaluating and controlling analyte stability throughout experiments was demonstrated. Applying a novel cell fractionation protocol GY34 was found to target cell nuclei and mitochondria in Ehrlich Lettré Ascites (ELA) cells, with the intracellular distribution depending on GY34 concentration in the cell medium during incubation. In ELA cells 96 ± 0.2% of cytosolic GY34 was bound to high-molecular species. Furthermore, using the tracer technique GY34 was found to reduce uptake and increase release of the organic osmolyte taurine in ELA cells, with innate resistance to Cisplatin and in A2780 human ovarian cancer cells, with acquired resistance to Cisplatin. Importantly, FACS analysis revealed that GY34 induced apoptosis in ELA cells. The present data suggest the potential of GY34 in overcoming Cisplatin resistance. The methodology applied can be used as a general protocol and an additional tool in the initial evaluation of novel metal-based drugs. Show less

The effect of polypyridyl Ru(II) complexes on the ability of cancer cells to migrate and invade, two features important in the formation of metastases, is evaluated. In vitro studies are carried out on breast cancer cell lines, MDA-MB-231 and MCF-7, as well as melanoma cell lines A2058 and A375. Three Ru(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and as a third ligand 2,2'-bipyridine (bpy), or its derivative with either 4-[3-(2-nitro-1H-imidazol-1-yl)propyl] (bpy-NitroIm), or 5-(4-{4'-methyl-[2,2'-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moiety attached are examined. The low sub-toxic doses of the studied compounds greatly affected the cancer cells by inhibiting cell detachment, migration, invasion, transmigration, and re-adhesion, as well as increasing cell elasticity. The molecular studies revealed that the Ru(II) polypyridyl complexes impact the activity of the selected integrins and upregulate the expression of focal adhesion components such as vinculin and paxillin, leading to an increased number of focal adhesion contacts. Show less

Two novel Ru(ii) polypyridyl complexes bearing imidazo-phenanthroline conjugated hydroxybenzoic acid groups were designed to enhance the tumor targeting ability as photosensitizers for photodynamic therapy. [Ru(bpy)2(phcpip)] (ClO4)2 (Ru-1) and [Ru(bpy)2(ohcpip)] (ClO4)2 (Ru-2) (bpy = 2,2'-bipyridine; phcpip = 2-(3-carboxyl-4-hydroxyphenyl) imidazo [4,5-f]phenanthroline; ohcpip = 2-(2-hydroxyl-3-carboxyphenyl) imidazo [4,5-f] [1,10] phenanthroline) were synthesized and their photodynamic antitumor activities were investigated. Both complexes displayed high photocytotoxicity toward cancerous cell lines HepG2, A549, MCF-7, and MDA-MB-231, but low photocytotoxicity toward normal cell lines GES-1 and Huvec. They were mainly localized at the nucleus of HepG2 cells after 24 h incubation, arrested the cell cycle at the G2/M phase and induced cancer cell apoptosis through reactive oxygen species (ROS) mediated pathways. Tumor targeting of the complexes is attributed to stronger molecular binding to DNA. Show less

Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF₆ (1), [Ru(HSpym)(bipy)(dppb)]PF₆ (2) and Ru[(SpymMe₂)(bipy)(dppb)]PF₆ (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120 min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 µM. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC. Show less