Organometallic compounds based on bioactive ligand systems have shown promising antiproliferative properties. The use of 8-hydroxyquinoline and its derivatives as bioactive ligands resulted in ...organometallic complexes with potent anticancer activity, but they lack aqueous solubility for further development. We report here the preparation of a series of MII/III(cym/Cp*)Cl complexes (η6-p-cymene (cym): M = Ru, Os; η5-pentamethylcyclopentadienyl (Cp*): M = Rh, Ir) with hydroxyquinoline-derived co-ligands and in a subsequent step the substitution of the chlorido ligands for amphiphilic 1,3,5-triaza-7-phosphatricyclo-3.3.1.1decane (PTA). Solubility studies indicated that the introduced PTA ligand significantly improved the aqueous solubility of all complexes. The complexes were shown to be stable in aqueous and DMSO solution over a period of at least 3 d. As would be expected for such modification of complexes, the higher solubility resulted in significantly decreased cytotoxicity in cancer cells. The antiproliferative activity was still more pronounced than that of RAPTA-C Ru(cym)(PTA)Cl which, however, has been demonstrated to have antimetastatic and antiangiogenic properties in vivo.
The introduction of a PTA ligand into organometallic hydroxyquinoline complexes significantly increases their aqueous solubility, and gives high stability but reduces their cytotoxic activity to an extent found for the prototype PTA anticancer agent RAPTA-C. Display omitted
•Preparation of organometallic anticancer agents•Substitution of chlorido ligands with an amphiphilic phosphine leads to high aqueous solubility.•The complexes showed high stability in aqueous solution.•Introduction of the PTA ligand decreased the anticancer activity of the complexes.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active ...photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite–ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes Ru
II
(cym)(HQ)Cl
1
(cym = η
6
-
p
-cymene, HQ = 8-hydroxyquinoline) and Ru
II
(cym)(PCA)ClCl
...2
(PCA =
N
-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that
2
accumulates in greater quantities in cells than
1
. Inhibition studies of selected cellular accumulation mechanisms indicated that both
1
and
2
may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that
1
and
2
are subjected to efflux through a mechanism that does not involve
p
-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl
2
resulted in a higher accumulation of
1
and
2
whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes
1
and
2
were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with
2
showed higher Ru contents than those treated with
1
. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.
Graphical abstract
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral RuIII(azole) through ...to RuII(arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC–ICP‐MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono‐ or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano‐stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Using ferrocene-based ligand systems, a series of heterobimetallic architectures of the general formula Pd m L n x+ were designed with the aim of installing an opening and closing mechanism that ...would allow the release and binding of guest molecules. Palladium complex formation was achieved through coordination to pyridyl groups, and using 2-, 3-, and 4-pyridyl derivatives provided access to defined PdL, PdL2, and Pd2L4 structures, respectively. The supramolecular complexes were characterized using nuclear magnetic resonance (NMR) and infrared spectroscopy, mass spectrometry, and elemental analysis, and for some examples density functional theory calculations and single-crystal X-ray diffraction analysis. 1H NMR spectroscopy was used to investigate disassembly and reassembly of the metallosupramolecular structures. The former was induced by cleavage of the relatively labile Pd–Npyridyl bonds with the introduction of the competing ligands N,N′-dimethylaminopyridine (DMAP) and Cl– (using tetrabutylammonium chloride) to yield Pd(DMAP)42+ and PdCl42–, respectively. The process was found to be reversible for several of the heterodimetallic compounds, with the addition of H+ or Ag+ triggering complex reassembly. Guest binding studies with several architectures revealed interactions with the anionic guests p-toluenesulfonate and octyl sulfate, but not with neutral molecules. Furthermore, the release of guests was reversibly induced with Cl– ions as a stimulus.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Abstract
Metal complexes bind to a wide variety of biomolecules and the control of the reactivity is essential when designing anticancer metallodrugs with a specific mode of action in mind. In this ...study, we used the highly cytotoxic compound RuII(cym)(8-HQ)Cl (cym = η6-p-cymene, 8-HQ = 8-hydroxyquinoline), the more inert derivative RuII(cym)(8-HQ)(PTA)(SO3CF3) (PTA = 1,3,5-triaza-7-phosphaadamantane), and RuII(cym)(PCA)ClCl (PCA = pyridinecarbothioamide) as a complex with a different coordination environment about the Ru center and investigated their stability, interactions with proteins, and behavior in medium (αMEM) and human serum by capillary zone electrophoresis. The developed method was found to be robust and provides a quick and low-cost technique to monitor the interactions of such complexes with biomolecules. Each complex was found to behave very differently, emphasizing the importance of the choice of ligands and demonstrating the applicability of the developed method. Additionally, the human serum albumin binding site preference of RuII(cym)(8-HQ)Cl was investigated through displacement studies, revealing that the compound was able to bind to both sites I and site II, and the type of adducts formed with transferrin was determined by mass spectrometry.
Graphical Abstract
Graphical Abstract
Tracking the binding of Ru(cym)(8-HQ)Cl to human serum albumin over time using capillary electrophoresis.
Display omitted
•Half-sandwich organoruthenium compounds are extensively investigated as cancer treatments.•Bidentate bioactive ligands with a wide variety of donor atom combinations are ...investigated.•Bidentate bioactive ligands endow in some Ru compounds multimodal anticancer activity.•The bioactivity of the organometallics is often determined by the bidentate ligands.•The complexes have been categorized into 5 structural design concepts.
The small molecule anticancer agent cisplatin and its Pt(II) analogs carboplatin and oxaliplatin are widely used to treat a variety of tumorigenic diseases. Despite their structural simplicity, side effects and disadvantages, they are cornerstones of cancer chemotherapy. Several strategies have been pursued to enhance the activity and reduce the side effects of metal-based drugs, for example, to use bioactive ligands that equip them with novel modes of action, enhance delivery, allow for selective activation, create synergistic effects or improve tumor accumulation. Many of these strategies have been developed for or adapted in the design of half-sandwich organoruthenium compounds. For such compounds decorated with bioactive ligands that coordinate monodentately to the Ru center, we have identified five design concepts (Coord. Chem. Rev. 2021, 439, 213890): (i) the bioactive ligand coordinates directly to the Ru center or (ii) after functionalization with a coordinating group, (iii) the ligand(s) and the Ru center solely define the overall shape of the molecule, (iv) the bioactive ligand is released, and (v) the bioactive ligand acts as a vector to the tumor (cell). Herein, we use these five concepts and explore their application to half-sandwich organoruthenium anticancer compounds in which the bioactive ligand is coordinated to the Ru center through a bidentate chelating motif.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes RuII(cym)(HQ)Cl 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and RuII(cym)(PCA)ClCl 2 (PCA = ...N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes RuII(cym)(HQ)Cl 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and RuII(cym)(PCA)ClCl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVETo generate a national multiple sclerosis (MS) prevalence estimate for the United States by applying a validated algorithm to multiple administrative health claims (AHC) datasets.
METHODSA ...validated algorithm was applied to private, military, and public AHC datasets to identify adult cases of MS between 2008 and 2010. In each dataset, we determined the 3-year cumulative prevalence overall and stratified by age, sex, and census region. We applied insurance-specific and stratum-specific estimates to the 2010 US Census data and pooled the findings to calculate the 2010 prevalence of MS in the United States cumulated over 3 years. We also estimated the 2010 prevalence cumulated over 10 years using 2 models and extrapolated our estimate to 2017.
RESULTSThe estimated 2010 prevalence of MS in the US adult population cumulated over 10 years was 309.2 per 100,000 (95% confidence interval CI 308.1–310.1), representing 727,344 cases. During the same time period, the MS prevalence was 450.1 per 100,000 (95% CI 448.1–451.6) for women and 159.7 (95% CI 158.7–160.6) for men (female:male ratio 2.8). The estimated 2010 prevalence of MS was highest in the 55- to 64-year age group. A US north-south decreasing prevalence gradient was identified. The estimated MS prevalence is also presented for 2017.
CONCLUSIONThe estimated US national MS prevalence for 2010 is the highest reported to date and provides evidence that the north-south gradient persists. Our rigorous algorithm-based approach to estimating prevalence is efficient and has the potential to be used for other chronic neurologic conditions.
Understanding an animal’s diet is a crucial component of conservation, but diet data are often labor intensive to collect and are frequently scarce. Atlantic Puffins ( Fratercula arctica ; hereafter ...Puffins) are vulnerable to global extinction and have declined in some parts of their UK and Irish range. Differences in population trajectories may relate to diet, but Puffin diet data are currently only collected at a handful of colonies. We explored whether citizen science could address this data gap by inviting visitors to Puffin colonies in 2017 to submit their photographs of Puffins carrying prey. In total, 602 people submitted 1402 images from 35 colonies. We identified the species group, size, and number of prey items in each bill load. Photograph quality was excellent, with 89% of birds in images providing useable diet information. In total 11,150 prey items were counted and measured from 1198 Puffins across 27 colonies. We demonstrated a lack of bias in the sample of photos provided by citizen scientists and described how Puffin chick diet varies in prey composition, prey length, number of prey per bill load, and load biomass over large spatial scales and throughout the breeding season. The diet of Puffin chicks from regions where severe declines have occurred, most notably Shetland, were characterized by a lower prey biomass, higher numbers of fish per load, and a high proportion of small, transparent sandeels consistently through the season. By contrast, in regions where Puffin populations are thought to be increasing, load biomass was high, the number of prey per load low, and larger non-transparent sandeels were the dominant prey, which persisted right through the breeding season. Results from our study show colonies and regions where birds may be expending more effort (collecting more prey items) for lesser returns (lower load biomass) and emphasize the value of collecting diet data across large spatial scales.
PDF
