This document summarizes the synthesis and biological evaluation of ferrocene-functionalized multinuclear organometallic complexes containing Ir, Rh, Ru, and Os metal centers as potential anticancer compounds. Two series of complexes were synthesized by coupling ferrocene ligands to metal dimers. Biological testing showed the Ru(II)-cymene complexes had the best antiproliferative activity against several cancer cell lines. Future work will further evaluate the anticancer activity and determine structure-activity relationships of the complexes, as well as study their aqueous stability, redox properties, and potential protein and DNA targeting abilities.
In-vitro biological activities of the free new H4L ( indole-7-thiocarbohydrazone) ligand and its Ni(II), Pd(II) , Pt(II),
Cu(II), Ag(I), Zn(II) and Cd(II) complexes are screened against two cancerous cell lines, that revealed significant
activity only for [Cu2Cl2(H4L)2(PPh3)2] after 72 h treatment by the highest tested concentrations. The Copper(I)
complex was characterized by X-ray Crystallography and the NMR spectra, whereas it has been confirmed to have
momentous cytotoxicity against ovarian, breast cancerous cell lines (Caov-3, MCF-7). The apoptosis-inducing
properties of the Cu(I) complex have been investigated through fluorescence microscopy visualization, DNA
fragmentation analysis and propidium iodide flow cytometry.
COPPER (II) PHENANTHROLINE COMPLEXES: SYNTHESIS, SPECTROSCOPIC STUDY AND ELEC...EDITOR IJCRCPS
Reaction of copper chloride [CuCl2] with NaaiR´ in acetone medium following ligand(1-10 phenanthroline) addition leads to
[Cu(NaaiR/)(phen)] where NaaiR/ = naphthylazo imidazole /benzimidazole /pyridine = -C10H4-N=N- / -C3H2-NN-1-R/, (R =
imidazole) / -C7H4-NN-1-H (Benzimidazole), / -C3H4-N-(Pyridine), abbreviated as -N,N/-chelator, where -N(imidazole) and -N(azo)
represent N and N/, respectively; R/ = H(a), Me (b)]. The 1H NMR spectral measurements suggest the molecular structure of the
chelated complex with the protons at the aromatic region and naphthyl protons at higher ∂ value. 13C NMR spectrum suggest the
molecular skeleton. The voltammogramalso shows a small anodic peak at 0.2 V, possibly due to the Cu(I)/Cu(0) couple.
Keywords: Copper(II), Naphthylazoimidazole, NMR, IR, ESIMS.
Oxidative stress has increasingly been considered a factor in numerous diseases and cancers because of its extensive presence throughout the body. Reactive Oxygen Species (ROS), generated continuously from oxidative phosphorylation and received from various exogenous sources, are constantly used as a key molecule for signal transduction, but under conditions of oxidative stress, when they can no longer be suppressed, they have the potential to damage the cell’s DNA. In many cases, repair mechanisms mitigate the damage, and if the damage becomes irreparable, then the cell will undergo apoptosis. In rare cases, though, DNA can get damaged to a point where the cell becomes cancerous and can eventually form a tumor. While ROS often take a significant amount of time to accumulate, once they have done so and are unable to be suppressed by cellular countermeasures, it is very likely for DNA damage to occur, and in cancerous cells, they actually enhance rapid proliferation, chronic inflammation, metastasis, and angiogenesis. This is why it is necessary to boost or introduce cellular countermeasures to mitigate the dangers of ROS. Current research on oxidative stress is mainly focusing on the benefits of antioxidants, which are commonly used by the cell to reduce ROS, and triggering apoptosis in tumors through enhanced oxidative stress conditions. This review will discuss the role of oxidative stress in tumorigenesis and cancer proliferation as well as the possible treatments, especially antioxidants and ROS-inducing drugs.
Superoxide dismutase is an enzyme that helps break down potentially harmful oxygen molecules in cells. This might prevent damage to tissues. It is being researched to see if it can help conditions where harmful oxygen molecules are believed to play a role in disease.
In-vitro biological activities of the free new H4L ( indole-7-thiocarbohydrazone) ligand and its Ni(II), Pd(II) , Pt(II),
Cu(II), Ag(I), Zn(II) and Cd(II) complexes are screened against two cancerous cell lines, that revealed significant
activity only for [Cu2Cl2(H4L)2(PPh3)2] after 72 h treatment by the highest tested concentrations. The Copper(I)
complex was characterized by X-ray Crystallography and the NMR spectra, whereas it has been confirmed to have
momentous cytotoxicity against ovarian, breast cancerous cell lines (Caov-3, MCF-7). The apoptosis-inducing
properties of the Cu(I) complex have been investigated through fluorescence microscopy visualization, DNA
fragmentation analysis and propidium iodide flow cytometry.
COPPER (II) PHENANTHROLINE COMPLEXES: SYNTHESIS, SPECTROSCOPIC STUDY AND ELEC...EDITOR IJCRCPS
Reaction of copper chloride [CuCl2] with NaaiR´ in acetone medium following ligand(1-10 phenanthroline) addition leads to
[Cu(NaaiR/)(phen)] where NaaiR/ = naphthylazo imidazole /benzimidazole /pyridine = -C10H4-N=N- / -C3H2-NN-1-R/, (R =
imidazole) / -C7H4-NN-1-H (Benzimidazole), / -C3H4-N-(Pyridine), abbreviated as -N,N/-chelator, where -N(imidazole) and -N(azo)
represent N and N/, respectively; R/ = H(a), Me (b)]. The 1H NMR spectral measurements suggest the molecular structure of the
chelated complex with the protons at the aromatic region and naphthyl protons at higher ∂ value. 13C NMR spectrum suggest the
molecular skeleton. The voltammogramalso shows a small anodic peak at 0.2 V, possibly due to the Cu(I)/Cu(0) couple.
Keywords: Copper(II), Naphthylazoimidazole, NMR, IR, ESIMS.
Oxidative stress has increasingly been considered a factor in numerous diseases and cancers because of its extensive presence throughout the body. Reactive Oxygen Species (ROS), generated continuously from oxidative phosphorylation and received from various exogenous sources, are constantly used as a key molecule for signal transduction, but under conditions of oxidative stress, when they can no longer be suppressed, they have the potential to damage the cell’s DNA. In many cases, repair mechanisms mitigate the damage, and if the damage becomes irreparable, then the cell will undergo apoptosis. In rare cases, though, DNA can get damaged to a point where the cell becomes cancerous and can eventually form a tumor. While ROS often take a significant amount of time to accumulate, once they have done so and are unable to be suppressed by cellular countermeasures, it is very likely for DNA damage to occur, and in cancerous cells, they actually enhance rapid proliferation, chronic inflammation, metastasis, and angiogenesis. This is why it is necessary to boost or introduce cellular countermeasures to mitigate the dangers of ROS. Current research on oxidative stress is mainly focusing on the benefits of antioxidants, which are commonly used by the cell to reduce ROS, and triggering apoptosis in tumors through enhanced oxidative stress conditions. This review will discuss the role of oxidative stress in tumorigenesis and cancer proliferation as well as the possible treatments, especially antioxidants and ROS-inducing drugs.
Superoxide dismutase is an enzyme that helps break down potentially harmful oxygen molecules in cells. This might prevent damage to tissues. It is being researched to see if it can help conditions where harmful oxygen molecules are believed to play a role in disease.
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Anticancer Activity of New Di-Nuclear Copper (I) ComplexTaghreed Al-Noor
In-vitro biological activities of the free new H4L ( indole-7-thiocarbohydrazone) ligand and its Ni(II), Pd(II) , Pt(II),
Cu(II), Ag(I), Zn(II) and Cd(II) complexes are screened against two cancerous cell lines, that revealed significant
activity only for [Cu2Cl2(H4L)2(PPh3)2] after 72 h treatment by the highest tested concentrations. The Copper(I)
complex was characterized by X-ray Crystallography and the NMR spectra, whereas it has been confirmed to have
momentous cytotoxicity against ovarian, breast cancerous cell lines (Caov-3, MCF-7). The apoptosis-inducing
properties of the Cu(I) complex have been investigated through fluorescence microscopy visualization, DNA
fragmentation analysis and propidium iodide flow cytometry.
Novel Hybrid Molecules of Quinazoline Chalcone Derivatives: Synthesis and Stu...Ratnakaram Venkata Nadh
Abstract: Background: A new series of quinazoline linked chalcone conjugates were synthesized
and evaluated for their in vitro cytotoxicity.
Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt
condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4-
dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three
potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of
1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50
values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line,
respectively.
Results and Conclusion: Based on these biological results, it is evident that compound 13h has the
potential to be considered for further detailed studies either alone or in combination with existing
therapies as potential anticancer agents.
ABSTRACT- The present study was conducted to investigate the effect of cadmium chloride on Histoarchiteceture of head kidney of fresh water fish Heteropneustes fossilis. The fishes were exposed to 0.5 ppm of cadmium chloride for 21 days. The most remarkable changes in head kidney, due to cadmium chloride were lysed condition of interrenal and chromaffin cells. The traces of cytoplasm had dark brown to black coloured cytoplasm. Most of cells are deformed and necrotic condition. Their size was significant at (P< 0.01 and 0.001) increased after cadmium chloride. All these changes will be recovered by herbal compound i.e. Ashwagandha. The damaged tissues were recovered in already treated group.
Key-words- Ashwagandha, Cadmium chloride, Chromaffin cells, Heteropneustes fossilis, Histopathology, Interrenal cells
A seminar report on the chemical frontiers of living matter seminar series - ...Glen Carter
This seminar report highlights a select few presentations of cutting-edge research being done in various labs across the Paris Science et Lettre (PSL) network.
Membrane Potential: An Emerging and Important Player in Cancer Metastasisasclepiuspdfs
The voltage across the plasma membrane which emanates due to the presence of different ion channels/transporters with specific ion selectivity and permeability is known as membrane.[1] It is the main biophysical indication in non-excitable cells controlling some essential cellular activities, such as proliferation and differentiation. Hence, the plurality of different ion channels/transporters indicated on various cells is finely tailored toward maintaining the membrane potential
Antioxidant Activity and Cytotoxicity against Cancer Cell Lines of the Extrac...Juan Hernandez
Xylaria species associated with termite nests or soil have been considered rare species in nature and the few which have been reported upon have been found to act as a rich source of bioactive metabolites. This study evaluated 10 ethyl acetate extracts of five new Xylaria species associated with termite nests or soil for their antioxidant activity, and cytotoxicity against different cancer and normal cell lines. DPPH and ABTS radical scavenging activities of the extracts demonstrated strong capacity with low IC50 values. The highest observed activities belonged to X. vinacea SWUF18-2.3 having IC50 values of 0.194 ± 0.031 mg/mL for DPPH assay and 0.020 ± 0.004 mg/mL for ABTS assay. Total phenolic content ranged from 0.826 ± 0.123 to 3.629 ± 0.381 g GAE/g crude extract which correlated with antioxidant activities. The high total phenolic content could contribute to the high antioxidant activities. Cytotoxicity was recorded against A549, HepG2, HeLa and PNT2 and resulted in broad spectrum to specific activity depending on the cell lines. The highest activities were observed with X. subintraflava SWUF16-11.1 which resulted in 11.15 ± 0.32 to 13.17 ± 2.37% cell viability at a concentration of 100 µg/mL. Moreover, LC-MS fingerprints indicated over 61 peaks from all isolates. There were 18 identified and 43 unidentified compounds compared to mass databases. The identified compounds were from various groups of diterpenoids, diterpenes, cytochalasin, flavones, flavonoids, polyphenols, steroids and derivatives, triterpenoids and tropones. These results indicate that Xylaria spp. has abundant secondary metabolites that could be further explored for their therapeutic properties
Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia.
1. Ferrocene-functionalised Multinuclear
Organometallic Anticancer Compounds with
Ir, Rh, Ru, and Os Co-centres
Kelvin Tong,a Mario Kubanik,a Muhammad Hanif,a Stephen Jamieson,b Christian Hartingera
E-mail: kton030@aucklanduni.ac.nz
aSchool of Chemical Sciences, The University of Auckland, Private Bag 92019 Auckland 1142, New Zealand
bAuckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019 Auckland 1142, New Zealand
Ruthenium-based Anticancer Drugs
The discovery of cisplatin in the 20th century has revolutionised the field of
metal based anticancer drug and cancer chemotherapy. While seeking for
potential successors, the properties of ruthenium(II) arene complexes
have attracted much attentions. The characteristic piano-stool geometry is
promising as it enables the compound to be tuned according to our
“flavours”.
• R = The aromatic “seat” that provides lipophilicity
to bring the complex across cell membranes
easily.
• X = usually a halogen leaving group
• Y and Z = can be bioactive ligands that
coordinate to the Ru(II) centre in either mono- or
bidentate fashion.
Synthetic Chemistry
Series 1 M Ar X Series 2 M Ar X
1a Ru Cym Cl 2a Ru Cym Cl
1b Ru Cym Br 2b Ru Cym Br
1c Ru Cym I 2c Ru Cym I
1d Os Cym Cl 2d Os Cym Cl
1e Os Cym I 2e Os Cym I
1f Ru Biph Cl 2f Rh Cp* Cl
1g Os Biph Cl 2g Ir Cp* Cl
1h Rh Cp* Cl
1i Ir Cp* Cl
Firstly, ferrocene is coupled with the bioactive ligand using different
coupling reagents. Followed by reacting the desired metal dimer with the
ferrocenyl ligand in which its Y and Z coordination sites can coordinate to
the metal in a bidentate manner.
Why Multinuclear Metal Complexes?
Biological Studies
Introducing multiple metal centres to a complex can potentially enhance its
pharmacological properties and broaden its spectrum of bioactivity. This
means a single compound can offer multiple pathways to fight tumour
cells. Therefore, this can overcome the persisting issue of drug resistance
in cancer cells, making chemotherapies more effective.
Why To Choose Ferrocene?
Under strong oxidising conditions, the cytotoxic ferrocenium cation is
formed which aids killing cancer cells. There have been various attempts in
introducing ferrocene into different anticancer compounds and many have
shown improved activity.
To date, 1 ligand and 7 corresponding complexes have been evaluated in
cancer cell lines such as HCT116 (human colorectal carcinoma), H460
(human large cell lung carcinoma) and SiHa (human cervix carcinoma).
It appears that the Ru(II)-cymene complexes 1a-c have better
antiproliferative activity compared to the osmium analogues as indicated by
their low IC50 values (concentration needed to reduce cancer cell growth by
50%). In particular, they are most active in the HCT116 cell line.
Compound HCT116 H460 SiHa
Ligand 1 >64 >64 >64
1a 10.79 ± 6.13 15.22 ± 4.35 19.61 ± 9.33
1b 16.94 ± 2.24 22.47 ± 5.43 18.79 ± 2.36
1c 8.65 ± 1.26 16.01 ± 1.14 14.26 ± 1.44
1d 17.61 ± 11.59 35.42 ± 25.28 26.98 ± 13.12
1e 12.59 ± 2.14 27.42 ± 4.71 23.01 ± 5.03
1f 20.35 ± 6.25 28.86 ± 2.20 23.24 ± 0.87
1g 33.86 ± 2.52 >30 36.86 ± 2.36
IC50(μM) of selected complexes
Aqueous Stability
Conclusions and Future Work
References and Acknowledgements
Top, S. et al., Chemistry-A European Journal. 2003, 21, 5223-5236
Ang, W. et al., Journal of Organometallic Chemistry. 2011, 5, 989-998
I would like to thank the members of Lab6@NZ for their support, especially
my supervisor Christian Hartinger for providing countless research advices.
Biological evaluation of selected complexes shows that they are
considerably potent, especially in the HCT116 cell line with low IC50 values.
Currently, the aqueous stability, DMSO stability and acid stability of these
complexes are still being investigated using NMR and ESI-MS methods.
Their redox properties are also looked at using cyclic voltammetry.
Future work involves the complete evaluation of anticancer activity of these
complexes and if possible, establishing the structure-activity relationships
for these two series of compounds.
Ferrocifen is a remarkable
example derived from the breast
cancer drug tamoxifen. The
ferrocene moiety can enhance
the formation of ROS (reactive
oxygen species) which promotes
cell cycle arrest and cellular
senescence.
Compounds Synthesised
The aqueous stability of complex 2a was investigated using 1H-NMR
spectroscopy. 50% DMSO was used to dissolve the compound due to the
poor solubility of the complex. DMSO exchange occurred after 3 hours.
However, the 100mM saline solution can suppress hydrolysis for a
minimum of 3 hours. This implies that while the compound is being
transported in the blood stream,
it can remain stable for a
moderate period of time.
T=48h
T=3h
T=10min
50% DMSO in D2O + 100mM NaCl
Hydrolysis
DMSO species
Protein Targeting
DNA Targeting
Cancer
Cell Cycle Arrest