排序方式: 共有14条查询结果,搜索用时 15 毫秒
1.
Janine N. Boodram Iain J. Mcgregor Peter M. Bruno Paul B. Cressey Dr. Michael T. Hemann Dr. Kogularamanan Suntharalingam 《Angewandte Chemie (International ed. in English)》2016,55(8):2845-2850
The breast cancer stem cell (CSC) potency of a series of copper(II)–phenanthroline complexes containing the nonsteroidal anti‐inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4 , selectivity kills breast CSC‐enriched HMLER‐shEcad cells over breast CSC‐depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC‐specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase‐2 (COX‐2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis. 相似文献
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Dr. Philipp von Grebe Dr. Kogularamanan Suntharalingam Prof. Dr. Ramon Vilar Dr. Pablo J. Sanz Miguel Prof. Dr. Sonja Herres‐Pawlis Prof. Dr. Bernhard Lippert 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(34):11429-11438
The reaction of tetrakis(pyridine‐2‐yl)pyrazine (tppz) with 2 equiv of (2,2′‐bpy)PtII in water yields two isomeric dinuclear cations, [{Pt(2,2′‐bpy)}2(tppz)]4+, in which Pt coordination exclusively takes place through the two pairs of pyridine‐2‐yl nitrogen atoms. The two conformational isomers differ in their overall shape, with the formation of “Z” and “U” shapes, which are formed at 40 °C (Z isomer, 1 ) and under reflux conditions (U isomer, 2 ), respectively. X‐ray crystal‐structure analyses of the Z isomer, [{Pt(2,2′‐bpy)}2(tppz)](PF6)4 ? 3 CHCl3 ? 4 H2O ( 1 a ), and of the U isomer, [{Pt(2,2′‐bpy)}2](PF6)4 ? 2 CH3CN ? 1.5 H2O ( 2 a ), were carried out. Co‐crystallization of compound 2 with PtCl2(2,2′‐bpy) yielded [{Pt(2,2′‐bpy)}2(tppz)](BF4)4?[PtCl2(2,2′‐bpy)] ? 4.5 H2O ( 3 ), in which the PtCl2(2,2′‐bpy) entity was sandwiched between the two 2,2′‐bpy faces of the U‐shaped cation ( 2 ). Quantum chemical calculations revealed that the U isomer was more stable than the Z isomer, both in the gas phase and in an aqueous environment. These two isomers display different affinities toward duplex DNA and human telomeric quadruplex DNA (Htelo), as concluded from CD spectroscopy and FID assays. Thus, the U isomer binds significantly more strongly to quadruplex DNA (DC50=0.38 μM ) than the Z isomer (DC50=8.50 μM ). 相似文献
3.
A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells 下载免费PDF全文
Dr. Malay Patra Dr. Timothy C. Johnstone Dr. Kogularamanan Suntharalingam Prof. Stephen J. Lippard 《Angewandte Chemie (International ed. in English)》2016,55(7):2550-2554
Three rationally designed glucose–platinum conjugates (Glc–Pts) were synthesized and their biological activities evaluated. The Glc–Pts, 1 – 3 , exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc–Pts were elucidated. For uptake into cells, Glc–Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro. 相似文献
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Dr. Zhiyin Xiao Ginevra Passeri Joshua Northcote-Smith Kuldip Singh Dr. Kogularamanan Suntharalingam 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(55):13846-13854
We report the anti-osteosarcoma stem cell (OSC) properties of a series of gallium(III)-polypyridyl complexes ( 5 - 7 ) containing diflunisal, a non-steroidal anti-inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8-tetramethyl-1,10-phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase-2 (COX-2) and kills osteosarcoma cells in a COX-2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase-dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX-2 and damaging nuclear DNA. 相似文献
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Savvas N. Georgiades Dr. Nurul H. Abd Karim Kogularamanan Suntharalingam Ramon Vilar Dr. 《Angewandte Chemie (International ed. in English)》2010,49(24):4020-4034
Guanine‐rich sequences of DNA can assemble into tetrastranded structures known as G‐quadruplexes. It has been suggested that these secondary DNA structures could be involved in the regulation of several key biological processes. In the human genome, guanine‐rich sequences with the potential to form G‐quadruplexes exist in the telomere as well as in promoter regions of certain oncogenes. The identification of these sequences as novel targets for the development of anticancer drugs has sparked great interest in the design of molecules that can interact with quadruplex DNA. While most reported quadruplex DNA binders are based on purely organic templates, numerous metal complexes have more recently been shown to interact effectively with this DNA secondary structure. This Review provides an overview of the important roles that metal complexes can play as quadruplex DNA binding molecules, highlighting the unique properties metals can confer to these molecules. 相似文献
7.
Yao-Rong Zheng Kogularamanan Suntharalingam Timothy C. Johnstone Stephen J. Lippard 《Chemical science》2015,6(2):1189-1193
This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(iv) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(ii) cage that can host four Pt(iv) prodrug guest molecules. Relying on host–guest interactions between adamantyl units tethered to the Pt(iv) molecules and the cage, four prodrugs could be encapsulated within one cage. This host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(iv) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules. 相似文献
8.
Ginevra Passeri Joshua Northcote-Smith Roshane Perera Nikola Gubic Kogularamanan Suntharalingam 《Molecules (Basel, Switzerland)》2022,27(10)
Apoptosis resistance is inherent to stem cell-like populations within tumours and is one of the major reasons for chemotherapy failures in the clinic. Necroptosis is a non-apoptotic mode of programmed cell death that could help bypass apoptosis resistance. Here we report the synthesis, characterisation, biophysical properties, and anti-osteosarcoma stem cell (OSC) properties of a new nickel(II) complex bearing 3,4,7,8-tetramethyl-1,10-phenanthroline and two flufenamic acid moieties, 1. The nickel(II) complex 1 is stable in both DMSO and cell media. The nickel(II) complex 1 kills bulk osteosarcoma cells and OSCs grown in monolayer cultures and osteospheres grown in three-dimensional cultures within the micromolar range. Remarkably, 1 exhibits higher potency towards osteospheres than the metal-based drugs used in current osteosarcoma treatment regimens, cisplatin and carboplatin, and an established anti-cancer stem cell agent, salinomycin (up to 7.7-fold). Cytotoxicity studies in the presence of prostaglandin E2 suggest that 1 kills OSCs in a cyclooxygenase-2 (COX-2) dependent manner. Furthermore, the potency of 1 towards OSCs decreased significantly upon co-treatment with necrostatin-1 or dabrafenib, well-known necroptosis inhibitors, implying that 1 induces necroptosis in OSCs. To the best of our knowledge, 1 is the first compound to implicate both COX-2 and necroptosis in its mechanism of action in OSCs. 相似文献
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Jiaxin Fang Owamagbe N. Orobator Chibuzor Olelewe Ginevra Passeri Kuldip Singh Prof. Samuel G. Awuah Dr. Kogularamanan Suntharalingam 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2024,136(6):e202317940
The cytotoxic and immunogenic-activating properties of a cobalt(III)-cyclam complex bearing the non-steroidal anti-inflammatory drug, flufenamic acid is reported within the context of anti-cancer stem cell (CSC) drug discovery. The cobalt(III)-cyclam complex 1 displays sub-micromolar potency towards breast CSCs grown in monolayers, 24-fold and 31-fold greater than salinomycin (an established anti-breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)-cyclam complex 1 is 69-fold and 50-fold more potent than salinomycin and cisplatin towards three-dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase-2 expression, and prompts caspase-dependent apoptosis. Breast CSCs treated with 1 exhibit damage-associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic-activating effects on breast CSCs. 相似文献