Synthesis, characterization, and cancer cell-selective cytotoxicity of mixed-ligand cobalt(III) complexes of 8-hydroxyquinolines and phenanthroline bases.

Transition metal complexes exhibiting selective toxicity towards a broad range of cancer types are highly desirable as potential anticancer agents. Herein, we report the synthesis, characterization, and cytotoxicity studies of six new mixed-ligand cobalt(III) complexes of general formula [Co(B)2(L)](ClO4)2 (1-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 5, 6), and L is the monoanion of 8-hydroxyquinoline (HQ in 1, 3, 5) and 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 4, 6). The X-ray single crystal structures of complexes 1 and 2 as PF6- salts revealed a distorted octahedral CoN5O coordination environment. Complexes demonstrated good stability in an aqueous buffer medium and in the presence of ascorbic acid as a reductant. Cytotoxicity studies using a panel of nine cancer cell lines showed that complex 6, with the dppz and CQ ligands, was significantly toxic against most cancer cell types, yielding IC50 values in the range of 2 to 14 µM. Complexes 1, 3, and 5, containing the HQ ligand, displayed lower toxicity compared to their CQ counterparts. The phenanthroline complexes demonstrated marginal toxicity towards the tested cell lines, while the dpq complexes exhibited moderate toxicity. Interestingly, all complexes demonstrated negligible toxicity towards normal HEK-293 kidney cells (IC50 > 100 µM). The observed cytotoxicity of the complexes correlated well with their lipophilicities (dppz > dpq > phen). The cytotoxicity of complex 6 was comparable to that of the clinical drug cisplatin under similar conditions. Notably, neither the HQ nor the CQ ligands alone demonstrated noticeable toxicity against any of the tested cell lines. The Annexin-V-FITC and DCFDA assays revealed that the cell death mechanism induced by the complexes involved apoptosis, which could be attributed to the metal-assisted generation of reactive oxygen species. Overall, the dppz complex 6, with its remarkable cytotoxicity against a broad range of cancer cells and negligible toxicity toward normal cells, holds significant potential for cancer chemotherapeutic applications.

A dipyridophenazine Ni(II) dithiolene complex as a dual-acting cancer phototherapy agent activatable within the phototherapeutic window.

A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) within the phototherapeutic window (600-900 nm) can lead to significantly enhanced therapeutic outcomes, surpassing the efficacy observed with PDT or PTT alone in cancer phototherapy. Herein, we report a novel small-molecule mixed-ligand Ni(II)-dithiolene complex (Ni-TDD) with a dipyridophenazine ligand, demonstrating potent red-light PDT and significant near-infrared (NIR) light mild-temperature PTT activity against cancer cells and 3D multicellular tumour spheroids (MCTSs). The four-coordinate square planar complex exhibited a moderately intense absorption band (ε âˆ¼ 3700 M-1cm-1) centered around 900 nm and demonstrated excellent dark and photostability in an aqueous phase. Ni-TDD induced a potent red-light (600-720 nm) PDT effect on HeLa cancer cells (IC50 = 1.8 µM, photo irritation factor = 44), triggering apoptotic cell death through efficient singlet oxygen generation. Ni-TDD showed a significant intercalative binding affinity towards double-helical calf thymus DNA, resulting in a binding constant (Kb) âˆ¼ 106 M-1. The complex induced mild hyperthermia and exerted a significant mild-temperature PTT effect on MDA-MB-231 cancer cells upon irradiation with 808 nm NIR light. Simultaneous irradiation of Ni-TDD-treated HeLa MCTSs with red and NIR light led to a remarkable synergistic inhibition of growth, exceeding the effects of individual irradiation, through the generation of singlet oxygen and mild hyperthermia. Ni-TDD displayed minimal toxicity towards non-cancerous HPL1D and L929 cells, even at high micromolar concentrations. This is the first report of a Ni(II) complex demonstrating red-light PDT activity and the first example of a first-row transition metal complex exhibiting combined PDT and PTT effects within the clinically relevant phototherapeutic window. Our findings pave the way for designing and developing metal-dithiolene complexes as dual-acting cancer phototherapy agents using long wavelength light for treating solid tumors.

Mixed-Ligand Cobalt(III) Complexes of a Naturally Occurring Coumarin and Phenanthroline Bases as Mitochondria-Targeted Dual-Purpose Photochemotherapeutics.

The bioessential nature of cobalt and the rich photochemistry of its coordination complexes can be exploited to develop potential next-generation photochemotherapeutics. A series of six novel mixed-ligand cobalt(III) complexes of the formulation [Co(B)2(L)]ClO4 (1-6), where B is an N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1 and 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2 and 5), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3 and 6), and L is an O,O-donor dianionic ligand derived from catechol (1,2-dihydroxybenzene, cat2-, in 1-3) or esculetin (6,7-dihydoxycoumarin, esc2-, in 4-6), have been prepared and characterized, and their light-triggered cytotoxicity has been studied in cancer cells. The single-crystal X-ray diffraction structures of complexes 1 (as PF6- salt, 1a) and 2 show distorted octahedral geometries around the cobalt(III) center formed by the set of N4O2 donor atoms. The low-spin and 1:1 electrolytic complexes 1-6 display a d-d transition around 700 nm. Complexes 4-6 with a coordinated esc2- ligand additionally display a π → π* intraligand transition centered at 403 nm. Complexes 4-6 possessing a naturally occurring and photoactive esc2- ligand show high visible-light-triggered cytotoxicity against HeLa and MCF-7 cancer cells, yielding remarkably low micromolar IC50 values while being much less toxic under dark conditions. Control complexes 1-3 possessing the photoinactive cat2- ligand show significantly less cytotoxicity either in the presence of light or in the dark. The complex-induced cell death is apoptotic in nature caused by the formation of reactive oxygen species via a type 1 photoredox pathway. Fluorescence microscopy of HeLa cells treated with complex 6 reveals mitochondrial localization of the complex. A significant decrease in the dark toxicity of free esculetin and dppz base is observed upon coordination to cobalt(III). Complexes bind to calf-thymus DNA with significant affinity, but 6 binds with the greatest affinity. Complex 6 efficiently photocleaves supercoiled DNA to its nicked circular form when irradiated with visible light via a photoredox type 1 pathway involving hydroxyl radicals (HO•). Thus, complex 6 showing remarkable visible-light-triggered cytotoxicity but negligible toxicity in the dark is a good candidate for cancer photochemotherapy applications.

LMCT transition-based red-light photochemotherapy using a tumour-selective ferrocenyl iron(iii) coumarin conjugate.

A rationally designed iron(iii) complex (2a) with pendant ferrocene and naturally occurring coumarin (esculetin) shows LMCT transition-based mitochondria-targeted red-light (600-720 nm) induced apoptotic toxicity against cancer cells but remains innocuous in the dark and to normal cells.

Novel mitochondria targeted copper(ii) complexes of ferrocenyl terpyridine and anticancer active 8-hydroxyquinolines showing remarkable cytotoxicity, DNA and protein binding affinity.

Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. In this work, we report the synthesis, characterization and cytotoxicity of six novel copper(ii) complexes of the formula [Cu(R-tpy)(N-O)]NO3 (1-6), where R-tpy is 4'-phenyl-2,2':6',2''-terpyridine (Ph-tpy; 1-3) or 4'-ferrocenyl-2,2':6',2''-terpyridine (Fc-tpy; 4-6), N-O is the anion of 8-hydroxyquinoline (HQ in 1, 4), 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 5) or 5-nitro-8-hydroxyquinoline (NQ in 3, 6). The complex [Cu(Fc-tpy)2](ClO4)2 (7) has also been prepared as a control and structurally characterized. The optimized geometries and the frontier orbitals of the complexes have been obtained from DFT calculations. The ferrocenyl appended complexes having the anticancer active CQ (in 5) and NQ (in 6) ligands show remarkable cytotoxicity, giving the respective IC50 values of 0.75 µM and 0.52 µM in HeLa and 1.3 µM and 2.6 µM in MCF-7 cancer cells. The phenyl appended complexes 2 and 3 are less active than their ferrocenyl analogues in both the cells while the complexes of HQ (in 1, 4) are the least active. Interestingly, complexes 4-6 are significantly less toxic to MCF-10A normal cells. The DCFDA, annexin-V-FITC and propidium iodide nuclear staining assays reveal an apoptotic mechanism of cell death which is attributable to the metal-assisted generation of reactive oxygen species. Imaging experiments on HeLa cells reveals that complex 5 accumulates primarily inside the mitochondria. The complexes bind to calf thymus DNA with moderate affinity giving Kb values in the range of 6.3 × 104-7.4 × 104 M-1 and to HSA protein with significant affinity giving KHSA values in the range of 8.6 × 104-1.3 × 105 M-1. Their affinity for DNA suggests that mitochondrial DNA could be the target while their affinity for HSA suggests that they could be transported by HSA in the blood. This work is the first report to show that the ferrocenyl appended copper(ii) complexes of hydroxyquinoline ligands are remarkably cytotoxic to cancer cells but significantly less toxic to normal cells.

Mitochondrial selectivity and remarkable photocytotoxicity of a ferrocenyl neodymium(III) complex of terpyridine and curcumin in cancer cells.

A series of four novel neodymium(iii) complexes of the formulation [Nd(R-tpy)(O-O)(NO3)2] (), where R-tpy is 4'-phenyl-2,2':6',2''-terpyridine (Ph-tpy; , ) and 4'-ferrocenyl-2,2':6',2''-terpyridine (Fc-tpy; , ); O-O is the conjugate base of acetylacetone (Hacac; , ) or curcumin (Hcurc; , ), are synthesized and characterized. The single crystal structure of shows that the complex is a discrete mononuclear species with the Nd(iii) centre in a nine coordinate environment provided by a set of O6N3 donor atoms. Complexes and having the simple acac ligand are prepared as control compounds. Complex , possessing an appended ferrocenyl (Fc) and the curcumin moiety, is remarkably photocytotoxic to HeLa and MCF-7 cancer cells in visible light giving respective IC50 values of 0.7 µM and 2.1 µM while being significantly less toxic to MCF-10A normal cells (IC50 = 34 µM) and in the dark (IC50 > 50 µM). The phenyl appended complex , lacking a ferrocenyl moiety, is significantly less toxic to both the cell lines when compared with . Complexes and , lacking the photoactive curcumin moiety, do not show any apparent toxicity both in light and in the dark. The cell death is apoptotic in nature and is mediated by the light-induced formation of reactive oxygen species (ROS). Fluorescence imaging experiment with HeLa cells reveals mitochondrial accumulation of complex within 4 h of incubation. The complexes bind to calf thymus (ct) DNA with moderate affinity giving Kb values in the range of 10(4)-10(5) M(-1). The curcumin complexes and cleave plasmid supercoiled DNA to its nicked circular form in visible light via(1)O2 and ˙OH pathways. The presence of the ferrocenyl moiety is likely to be responsible for the enhanced cellular uptake and photocytotoxicity of complex . Thus, the mitochondria targeting complex , being remarkably cytotoxic in light but non-toxic in the dark and to normal cells, is a potential candidate for photochemotherapeutic applications.