ORCID Profile
0000-0001-9806-0893
Current Organisations
The University of Auckland
,
Université du Québec à Montréal
,
Treasury Board of Canada Secretariat
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Publications
Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells
Publisher: MDPI AG
Date: 29-01-2021
DOI: 10.3390/PH14020103
Abstract: Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.
Physicochemical studies on the copper(ii ) binding by glycated collagen telopeptides
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4OB02536A
Abstract: The strong interaction between advanced glycation end-products and Cu( ii ) ions has been revealed using site-specifically glycated collagenous peptides.
Influence of Structural Variation on the Anticancer Activity of RAPTA-Type Complexes: ptn versus pta
Publisher: American Chemical Society (ACS)
Date: 27-01-2009
DOI: 10.1021/OM800899E
Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand
Publisher: Springer Science and Business Media LLC
Date: 06-04-2010
DOI: 10.1007/S00775-010-0654-X
Abstract: The anticancer ruthenium-arene compound [Ru(eta(6)-C(6)H(5)CF(3))(pta)Cl(2)] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing alpha,alpha,alpha-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compounds known. To rationalize the high observed cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5'-GTATTGGCACGTA-3') were studied using NMR spectroscopy, high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium-chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concentration, which is a special property of the compound not observed for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomolecule reaction mixtures contained mostly [Ru(pta)]-biomolecule adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compounds were not observed in the protein or DNA binding studies. Gel electrophoresis experiments revealed a significant degree of decomposition of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3.
Incorporation of β‐Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels, DNA Cleavage and Antiproliferative Activity**
Publisher: Wiley
Date: 04-12-2021
Abstract: Redox‐active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α‐amino acid Gly with the β‐amino acid β‐Ala at position 2 (Gly2→β‐Ala2) of the ATCUN motif reinstates ROS production ( • OH and H 2 O 2 ). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β‐Ala2‐containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β‐Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β‐Ala2 peptide complexes had lower IC 50 values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP‐MS measurements.
Managerial leadership behaviors: A longitudinal investigation of the role of job demands and resources, and implications for managers' own well‐being
Publisher: Wiley
Date: 27-03-2023
DOI: 10.1111/APPS.12468
Abstract: Although le research has documented the implications, and organizational drivers, of leadership behaviors, very little research has considered these associations, and their consequences, from the perspective of managers. The present four‐wave longitudinal study addresses this limitation by focusing, using the Job Demands‐Resources model, on the work‐related drivers (job control, recognition, and workload) of transformational, transactional and laissez‐faire leadership behaviors, and the associations between these behaviors and manifestations of managers' psychological well‐being at work (job satisfaction, burnout, and turnover intentions). Analyzing data from 691 high‐level managers (i.e. school principals) using novel random intercept cross‐lagged panel model analyses, our results revealed that higher levels of job control and recognition, and lower levels of workload, predicted higher levels of transformational and transactional leadership behaviors. In contrast, laissez‐faire leadership behaviors were only negatively predicted by recognition. Transformational leadership was associated with the most desirable outcome levels (higher levels of job satisfaction, lower levels of turnover intentions and burnout), followed by transactional and laissez‐faire leadership. Most of these associations were limited to the between‐person‐level, reflecting stable mechanisms of influence, rather than at the within‐person level, suggesting the presence of homeostatic mechanism helping high levels managers to maintain a stable level of functioning over time.
On-Resin Conjugation of the Ruthenium Anticancer Agent Plecstatin-1 to Peptide Vectors
Publisher: American Chemical Society (ACS)
Date: 23-08-2023
A Solid Support‐Based Synthetic Strategy for the Site‐Selective Functionalization of Peptides with Organometallic Half‐Sandwich Moieties
Publisher: Wiley
Date: 02-02-2022
Abstract: The number of donor atoms available on peptides that can competitively coordinate to metal centers renders the site‐selective generation of advanced metal‐peptide conjugates in high purity a challenging venture. Herein, we present a transmetalation‐based synthetic approach on solid support in which an imidazolium pro‐ligand can be used to selectively anchor a range of transition metal half‐sandwich complexes onto peptides in the presence of multiple coordinative motifs. Amenable to solid support, a range of N ‐terminus and/or lysine conjugated metal‐peptide conjugates were obtained in high purity after cleavage from the resin. The metalated peptides were evaluated for their anticancer properties against human cancer cell lines. While no cytotoxic activity was observed, this platform has the potential to i) provide a pathway to site‐selective peptide labelling, ii) be explored as a biorthogonal handle and/or iii) generate a new strategy for ligand design in transition metal catalysts.
Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding
Publisher: Wiley
Date: 04-03-2022
Abstract: A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pd n Pt m L 4 ] 6+ ( DC1 : n =1, m =2 and DC2 : n =2, m =1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and Pd II ions. 1 H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1 , which features two identical cavities, binding two 2,6‐diaminoanthraquinone ( DAQ ) guest molecules was determined by single‐crystal X‐ray crystallography. In addition, DC1 was shown to bind two molecules of 5‐fluorouracil ( 5‐FU ) in a statistical (non‐cooperative) manner. In contrast, DC2 , which features two different cage cavities, was found to interact with two different guests, 5‐FU and cisplatin , selectively.
A Reduced‐Symmetry Heterobimetallic [PdPtL4]4+ Cage: Assembly, Guest Binding, and Stimulus‐Induced Switching
Publisher: Wiley
Date: 30-04-2020
A Reduced‐Symmetry Heterobimetallic [PdPtL4]4+ Cage: Assembly, Guest Binding, and Stimulus‐Induced Switching
Publisher: Wiley
Date: 30-04-2020
Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2Complexes
Publisher: American Chemical Society (ACS)
Date: 19-02-2020
Carbon Monoxide is an Inhibitor of HIF Prolyl Hydroxylase Domain 2
Publisher: Wiley
Date: 29-06-2021
Abstract: Hypoxia‐inducible factor prolyl hydroxylase domain 2 (PHD2) is an important oxygen sensor in animals. By using the CO‐releasing molecule‐2 (CORM‐2) as an in situ CO donor, we demonstrate that CO is an inhibitor of PHD2. This report provides further evidence about the emerging role of CO in oxygen sensing and homeostasis.
Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism
Publisher: Oxford University Press (OUP)
Date: 24-06-2021
Abstract: Increasingly explored over the last decade, gold complexes have shown great promise in the field of cancer therapeutics. A major obstacle to their clinical progression has been their lack of in vivo stability, particularly for gold(III) complexes, which often undergo a facile reduction in the presence of biomolecules such as glutathione. Herein, we report a new class of promising anticancer gold(I)–gold(III) complexes with the general formula [XAuI(μ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuIIIX] [X = Cl (1), Br (2), NO3 (3)] which feature two gold atoms in different oxidation states (I and III) in a single molecule. Interestingly, gold(I)–gold(III) complexes (1–3) are stable against glutathione reduction under physiological-like conditions. In addition, complexes 1–3 exhibit significant cytotoxicity (276-fold greater than cisplatin) toward the tested cancer cells compared to the noncancerous cells. Moreover, the gold(I)–gold(III) complexes do not interact with DNA-like cisplatin but target cellular thioredoxin reductase, an enzyme linked to the development of cisplatin drug resistance. Complexes 1–3 also showed potential to inhibit cancer and endothelial cell migration, as well as tube formation during angiogenesis. In vivo studies in a murine HeLa xenograft model further showed the gold compounds may inhibit tumor growth on par clinically used cisplatin, supporting the significant potential this new compound class has for further development as cancer therapeutic.
Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding
Publisher: Wiley
Date: 04-03-2022
Abstract: A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pd n Pt m L 4 ] 6+ ( DC1 : n =1, m =2 and DC2 : n =2, m =1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and Pd II ions. 1 H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1 , which features two identical cavities, binding two 2,6‐diaminoanthraquinone ( DAQ ) guest molecules was determined by single‐crystal X‐ray crystallography. In addition, DC1 was shown to bind two molecules of 5‐fluorouracil ( 5‐FU ) in a statistical (non‐cooperative) manner. In contrast, DC2 , which features two different cage cavities, was found to interact with two different guests, 5‐FU and cisplatin , selectively.
Synthesis and characterisation of the water soluble bis-phosphine complex [Ru(η6-cymene)(PPh2(o-C6H4O)-κ2-P,O)(pta)]+ and an investigation of its cytotoxic effects
Publisher: Elsevier BV
Date: 08-2010
Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host–guest chemistry
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2DT02720H
Abstract: A new [PdPtL 4 ] 4+ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach.
Thiourea-Derived Chelating Ligands and Their Organometallic Compounds: Investigations into Their Anticancer Activity
Publisher: MDPI AG
Date: 11-08-2020
DOI: 10.3390/MOLECULES25163661
Abstract: Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [MII(cym)(L)Cl]X (cym = η6-p-cymene) or [MIII(Cp*)(L)Cl]X (Cp* = η5-pentamethylcyclopentadienyl), where X = Cl− or PF6−, and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.
Exploiting reduced-symmetry ligands with pyridyl and imidazole donors to construct a second-generation stimuli-responsive heterobimetallic [PdPtL4]4+ cage
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3SC01354E
Abstract: A new method for the assembly of a heterobimetallic [PdPtL 4 ] 4+ cage which can interact with anionic guest molecules in a specific, selective host–guest orientation is described.
Related Organisations
Related Funding Activities
No related grants have been discovered for Christian Hartinger.