👤 Lai YW

In this article, we report a novel targeting strategy involving the combination of an enzyme-instructed self-assembly (EISA) moiety and a strained cycloalkyne to generate large accumulation of bioorthogonal sites in cancer cells. These bioorthogonal sites can serve as activation triggers in different regions for transition metal-based probes, which are new ruthenium(II) complexes carrying a tetrazine unit for controllable phosphorescence and singlet oxygen generation. Importantly, the environment-sensitive emission of the complexes can be further enhanced in the hydrophobic regions offered by the large supramolecular assemblies, which is highly advantageous to biological imaging. Additionally, the (photo)cytotoxicity of the large supramolecular assemblies containing the complexes was investigated, and the results illustrate that cellular localization (extracellular and intracellular) imposes a profound impact on the efficiencies of photosensitizers. Show less

Title: Photofunctional cyclometallated iridium(III) polypyridine methylsulfone complexes as sulfhydryl-specific reagents for bioconjugation, bioimaging and photocytotoxic applications. Abstract: We report herein near-infrared (NIR)-emitting cyclometallated iridium(III) complexes bearing a heteroaromatic methylsulfone moiety as sulfhydryl-specific reagents; one of the complexes was conjugated to cysteine and cysteine-containing peptides and proteins for bioimaging and photocytotoxic applications. Show less

A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate β-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that β-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation. Show less

Two ruthenium(II) polypyridyl complexes, [Ru(bpy)(2)(ptpn)](2+) (1) (bpy = 2,2'-bipyridine, ptpn = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]1,10-phenanthroline) and [Ru(phen)(2)(ptpn)](2+) (2) (phen = 1,10-phenanthroline), were synthesized and characterized. Crystal structure analysis shows that complex 1 has a large planar aromatic area and possesses the potential to fit the geometric structure of G-quadruplex. The interaction of the G-quadruplex DNA with Ru(ii) complexes was explored by means of circular dichroism (CD), fluorescence resonance energy transfer (FRET) melting assay, competitive FRET assay and polymerase chain reaction (PCR) stop assay. The results indicated that complexes 1 and 2 both have the ability to promote the formation and stabilization of the human telomeric d[(TTAGGG)(n)] (HTG22) quadruplex and exhibit high G-quadruplex DNA selectivity over duplex DNA. The telomere repeat amplification protocol (TRAP) assay and long-term proliferation experiments further demonstrate that the Ru(II) complexes are potent telomerase inhibitors and HeLa cell proliferation inhibitors. Show less

We present a new class of phosphorescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N(⁾C)2(bpy-CONH-PEG)](PF6) (bpy-CONH-PEG = 4-(N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine, number average molecular weight (Mn) = 5272.23, weight average molecular weight (Mw) = 5317.38, polydispersity index (PDI) = 1.009; HN(⁾C = 2-phenylpyridine, Hppy (1a), 2-((1,1'-biphenyl)-4-yl)pyridine, Hpppy (2a), 2-phenylquinoline, Hpq (3a), 2-phenylbenzothiazole, Hbt (4a), 2-(1-naphthyl)benzothiazole, Hbsn (5a)). The photophysical, photochemical, and biological properties of these complexes have been compared with those of their PEG-free counterparts [Ir(N(⁾C)2(bpy-CONH-Et)](PF6) (bpy-CONH-Et = 4-(N-ethylaminocarbonyl)-4'-methyl-2,2'-bipyridine; HN(⁾C = Hppy (1b), Hpppy (2b), Hpq (3b), Hbt (4b), Hbsn (5b)). Upon irradiation, all the complexes exhibited intense and long-lived green to orange-red emission under ambient conditions. The emission was phosphorescence in nature and can be quenched by O2 with the generation of singlet oxygen ((1)O2). The quantum yields for (1)O2 production of the complexes in aerated DMSO (0.24-0.83) were found to be dependent on the excited-state lifetimes of the complexes, which can be altered using different cyclometalating ligands (N(⁾C). Cell-based assays indicated that the PEG complexes were noncytotoxic in the dark (IC50 > 300 μM); however, most of them became significantly cytotoxic upon irradiation (IC50 = 3.4 - 23.2 μM). Laser-scanning confocal microscopy images revealed localization of complex 3a in the mitochondrial region of HeLa cells and the induction of rapid necrotic cell death upon light activation. Additionally, the lack of dark toxicity and potential application of the PEG complexes as a visualizing reagent have been demonstrated using zebrafish (Danio rerio) as an animal model. Show less

A series of luminescent cyclometalated iridium(III) dipyridoquinoxaline complexes [Ir(N--C)(2)(N--N)](PF(6)) (HN--C = 1-phenylpyrazole, Hppz, N--N = dipyrido[3,2-f:2',3'-h]quinoxaline, dpq (1a), 2-(n-butylamido)dipyrido[3,2-f:2',3'-h]quinoxaline, dpqa (1b); HN--C = 7,8-benzoquinoline, Hbzq, N--N = dpq (2a), dpqa (2b); HN--C = 2-phenylquinoline, Hpq, N--N = dpq (3a), dpqa (3b)) has been synthesized and characterized. Cyclic voltammetric studies revealed a reversible or quasi-reversible iridium(IV/III) oxidation couple at about +1.13 to +1.32 V and a reversible diimine reduction couple at about -1.10 to -1.29 V versus SCE. Upon photoexcitation, all the complexes displayed intense and long-lived green to orange triplet metal-to-ligand charge-transfer ((3)MLCT) (dpi(Ir) --> pi*(dpq or dpqa)) emission in aprotic organic solvents at room temperature and in low-temperature glass. In aqueous solution, these complexes were only weakly emissive or even non-emissive. The lipophilicity of all the complexes has been determined by reversed-phase HPLC. The cytotoxicity of these iridium(III) complexes toward the human cervix epithelioid carcinoma (HeLa) and Madin-Darby canine kidney (MDCK) cell lines has been evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cellular uptake of the complexes by MDCK cells has been examined by laser-scanning confocal microscopy. Most importantly, apparent nucleolar staining was observed after the cells were treated by the complexes. The interactions of these complexes with proteins, DNA, and RNA have also been studied by emission titrations and SDS-PAGE gel staining. The results revealed that the complexes bound to the hydrophobic pockets of proteins, intercalated into the base-pairs of double-stranded DNA, but did not appear to interact with RNA. Show less

A series of luminescent cyclometalated iridium(III) polypyridine indole complexes, [Ir(N--C)(2)(N--N)](PF(6)) (HN--C = 2-phenylpyridine (Hppy), N--N = 4-((2-(indol-3-yl)ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine (bpy-ind) (1a), N--N = 4-((5-((2-(indol-3-yl)ethyl)aminocarbonyl)pentyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine (bpy-C6-ind) (1b); HN--C = 7,8-benzoquinoline (Hbzq), N--N = bpy-ind (2a), N--N = bpy-C6-ind (2b); and HN--C = 2-phenylquinoline (Hpq), N--N = bpy-ind (3a), N--N = bpy-C6-ind (3b)), have been synthesized, characterized, and their photophysical and electrochemical properties and lipophilicity investigated. Photoexcitation of the complexes in fluid solutions at 298 K and in alcohol glass at 77 K resulted in intense and long-lived luminescence (lambda(em) = 540-616 nm, tau(o) = 0.13-5.15 mus). The emission of the complexes has been assigned to a triplet metal-to-ligand charge-transfer ((3)MLCT) (dpi(Ir) --> pi*(N--N)) excited state, probably with some mixing of triplet intraligand ((3)IL) (pi --> pi*) (pq) character for complexes 3a,b. Electrochemical measurements revealed that all the complexes showed an irreversible indole oxidation wave at ca. +1.1 V versus SCE, a quasi-reversible iridium(IV/III) couple at ca. +1.3 V, and a reversible diimine reduction couple at ca. -1.3 V. The interactions of these complexes with an indole-binding protein, bovine serum albumin (BSA), have been studied by emission titrations, and the K(a) values are on the order of 10(4) M(-1). Additionally, the cytotoxicity of the complexes toward human cervix epithelioid carcinoma (HeLa) cells has been examined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC(50) values of the complexes ranged from 1.1 to 6.3 microM, which are significantly smaller than that of cisplatin (30.7 microM) under the same experimental conditions. Furthermore, the cellular uptake of the complexes has been investigated by flow cytometry and laser-scanning confocal microscopy. The microscopy images indicated that complex 3a was localized in the perinuclear region upon interiorization. Temperature-dependence experiments suggested that the internalization of the complex was an energy-requiring process such as endocytosis. This has been confirmed by cellular-uptake experiments involving the luminescent conjugates Ir-BSA and Ir-TF (TF = holo-transferrin), which were prepared by conjugation of the proteins with the complex [Ir(pq)(2)(phen-NCS)](PF(6)) (phen-NCS = 5-isothiocyanato-1,10-phenanthroline). Show less