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Papers by Andjela Franich
Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of ma... more Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of malonic (mal, Pt1), 2-methylmalonic (Me-mal, Pt2), 2,2-dimethylmalonic (Me2-mal, Pt3) or 1,1- cyclobutanedicarboxylic (CBDCA, Pt4) acid while 5,6-epoxy-1,10-phen is bidentately coordinated 5,6-epoxy-5,6-dihydro-1,10-phenanthroline were synthesized and characterized by elemental microanalysis, IR, UV-Vis and NMR (1H and 13C) spectroscopic techniques. In vitro anticancer activity of novel platinum(II) complexes have been investigated on human and murine cancer cell lines, as well as normal murine cell line by MTT assay. The obtained results indicate that studied platinum(II) complexes exhibited strong cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. Complex Pt3 display stronger selectivity toward carcinoma cells in comparison to other tested platinum(II) complexes exhibiting beneficial antitumor activity mainly via the induction of apoptosis, as well as inhibition of cell proliferation and migration. Further study showed that Pt3 complex also carry significant in vivo antitumor activity in orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All results imply that these novel platinum(II) complexes have a good anti-tumor effect on breast and colorectal cancer in vivo and in vitro and the affinity to become possible candidates for treatment in anticancer therapy.
Journal of Biological Inorganic Chemistry, Oct 29, 2021
Abstract The mechanism of action of most approved drugs in use today is based on their binding to... more Abstract The mechanism of action of most approved drugs in use today is based on their binding to specific proteins or DNA. One of the achievements of this research is a new perspective for recognition of binding modes to DNA by monitoring of changes in measured and stoichiometric values of absorbance at 260 nm. UV–Vis and IR spectroscopy, gel electrophoresis and docking study were used for investigation of binding properties of three dinuclear platinum(II) complexes containing different pyridine-based bridging ligands, [{Pt(en)Cl} 2 ( μ -4,4’-bipy)]Cl 2 ·2H 2 O ( Pt1 ), [{Pt(en)Cl} 2 ( μ -bpa)]Cl 2 ·4H 2 O ( Pt2 ) and [{Pt(en)Cl} 2 ( μ -bpe)]Cl 2 ·4H 2 O ( Pt3 ) to DNA (4,4’-bipy, bpa and bpe are 4,4′-bipyridine, 1,2- bis (4-pyridyl)ethane and 1,2- bis (4-pyridyl)ethene, respectively). In contrast to the system with well-known intercalated ligand (EtBr), covalently bound ligand ( cis -Pt) and with minor groove binder (Hoechst 33258), which do not have significant differences in measured and stoichiometric values, the most pronounced deviations are recorded for two dinuclear platinum(II) complexes ( Pt1 and Pt2 ), as a consequence of complex binding to the phosphate backbone and bending of DNA helix. The hydrolysis of complexes and changes in DNA conformation were also analysed as phenomena that may have an impact on the changes in absorbance. Graphic abstract
Applied Organometallic Chemistry, Dec 2, 2020
The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ... more The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ‐1,6‐nphe)](ClO4)2 (Pt2) (en is a bidentate‐coordinated ethylenediamine and 1,6‐nphe is the bridging 1,6‐naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The DNA‐binding evaluation of complexes Pt1 and Pt2 was done by UV–Vis, fluorescence emission spectroscopy, and their interaction with bovine serum albumin (BSA). The cytotoxic activity of these complexes was determined against mouse breast (4T1) and colon (CT26) cancer cell lines, human breast (MDA‐MB‐468), colon (HCT‐116), and lung (A549) cancer cell lines as well as mouse mesenchymal stem cells (mMSC). Complex Pt1 showed higher cytotoxic capacity toward solid cancer cell lines compared with Pt2 and lower cytotoxic capacity toward mMSC cells compared with cisplatin. Furthermore, molecular mechanism studies showed that Pt1 complex induced 4T1 and A549 cell apoptosis therefore increasing expression of pro‐apoptotic caspase‐3 and decreasing expression of anti‐apoptotic Bcl‐2 and Ki‐67. Antitumor capacity of Pt1 complex might be manifested at least in two ways: by facilitating apoptosis and by inhibiting tumor cells proliferation.
Journal of Biological Inorganic Chemistry, Mar 11, 2020
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoa... more New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl} 2 (μ-L)] 2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H 2 O)} 2 (μ-L)] 4+ , interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl} 2 (μ-4,4′-bipy)]Cl 2 •2H 2 O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs. Keywords Dinuclear platinum(II) complexes • Minor groove covering • Dual anticancer and anti-angiogenic activity Andjela A. Franich and Marija D. Živković contributed equally to this work.
Serbian Journal of Experimental and Clinical Research, Jun 22, 2021
Book of Proceedings: 1st International Conference on Chemo and BioInformatics,, 2021
Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of ma... more Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of malonic (mal, Pt1), 2-methylmalonic (Me-mal, Pt2), 2,2-dimethylmalonic (Me2-mal, Pt3) or 1,1- cyclobutanedicarboxylic (CBDCA, Pt4) acid while 5,6-epoxy-1,10-phen is bidentately coordinated 5,6-epoxy-5,6-dihydro-1,10-phenanthroline were synthesized and characterized by elemental microanalysis, IR, UV-Vis and NMR (1H and 13C) spectroscopic techniques. In vitro anticancer activity of novel platinum(II) complexes have been investigated on human and murine cancer cell lines, as well as normal murine cell line by MTT assay. The obtained results indicate that studied platinum(II) complexes exhibited strong cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. Complex Pt3 display stronger selectivity toward carcinoma cells in comparison to other tested platinum(II) complexes exhibiting beneficial antitumor activity mainly via t...
Serbian Journal of Experimental and Clinical Research, 2021
The interactions of metal complexes with important biomolecules such as deoxyribonucleic acid (DN... more The interactions of metal complexes with important biomolecules such as deoxyribonucleic acid (DNA) or bovine serum albumin (BSA) are responsible for their antitumor activity due to different modes of interaction with DNA and their transport through the blood system to cells and tissues via serum albumin. Therefore, the dinuclear palladium(II) complexes, [{Pd(en)Cl}2(μ-1,5- nphe)](NO3)2 (Pd1) and [{Pd(1,3-pd)Cl}2(μ-1,5-nphe)](NO3)2 (Pd2) (en is ethylenediamine, 1,3-pd is 1,3-propylenediamine and 1,5-nphe is the bridging 1,5-naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The UV-Vis and fluorescence emission spectroscopy were applied for evaluation of binding modes of Pd1 and Pd2 complexes to DNA as well as their interaction with BSA. The emission spectra indicate that the investigated Pd1 and Pd2 complexes can displace the ethidium bromide intercalator from DNA/EtBr molecules and act as intercalators showing strong interactions with DNA. ...
Book of Proceedings: 1st International Conference on Chemo and BioInformatics,, 2021
The series of nine dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-X)]2+ (where L is two NH3 or b... more The series of nine dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-X)]2+ (where L is two NH3 or bidentantly coordinated diamine ligand – ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2- dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd; (±)-1,3-pentanediamine,1,3-pnd, and X is a bridging pyrazine (pz) or pyridazine (pydz) ligand) have been synthesized and characterized. The antitumor potential of these complexes against CT26 cells were determined by in vitro and in vivo assays. A murine model of heterotopic colon cancer tumor was induced in immunocompetent BALB/c mice for investigating antitumor potential of the Pt(II) complexes in vivo. It was found that complexes Pt1, Pt2 and Pt7 shows significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells, while all these complexes show moderate apoptotic effect. Complexes Pt1 and Pt7 arrested CT26 cells in G2/M phase o...
Applied Organometallic Chemistry, 2020
The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ... more The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ‐1,6‐nphe)](ClO4)2 (Pt2) (en is a bidentate‐coordinated ethylenediamine and 1,6‐nphe is the bridging 1,6‐naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The DNA‐binding evaluation of complexes Pt1 and Pt2 was done by UV–Vis, fluorescence emission spectroscopy, and their interaction with bovine serum albumin (BSA). The cytotoxic activity of these complexes was determined against mouse breast (4T1) and colon (CT26) cancer cell lines, human breast (MDA‐MB‐468), colon (HCT‐116), and lung (A549) cancer cell lines as well as mouse mesenchymal stem cells (mMSC). Complex Pt1 showed higher cytotoxic capacity toward solid cancer cell lines compared with Pt2 and lower cytotoxic capacity toward mMSC cells compared with cisplatin. Furthermore, molecular mechanism studies showed that Pt1 complex induced 4T1 and A549 cell apoptosis therefore increasing expre...
JBIC Journal of Biological Inorganic Chemistry, 2020
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoa... more New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl} 2 (μ-L)] 2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H 2 O)} 2 (μ-L)] 4+ , interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl} 2 (μ-4,4′-bipy)]Cl 2 •2H 2 O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs. Keywords Dinuclear platinum(II) complexes • Minor groove covering • Dual anticancer and anti-angiogenic activity Andjela A. Franich and Marija D. Živković contributed equally to this work.
Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of ma... more Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of malonic (mal, Pt1), 2-methylmalonic (Me-mal, Pt2), 2,2-dimethylmalonic (Me2-mal, Pt3) or 1,1- cyclobutanedicarboxylic (CBDCA, Pt4) acid while 5,6-epoxy-1,10-phen is bidentately coordinated 5,6-epoxy-5,6-dihydro-1,10-phenanthroline were synthesized and characterized by elemental microanalysis, IR, UV-Vis and NMR (1H and 13C) spectroscopic techniques. In vitro anticancer activity of novel platinum(II) complexes have been investigated on human and murine cancer cell lines, as well as normal murine cell line by MTT assay. The obtained results indicate that studied platinum(II) complexes exhibited strong cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. Complex Pt3 display stronger selectivity toward carcinoma cells in comparison to other tested platinum(II) complexes exhibiting beneficial antitumor activity mainly via the induction of apoptosis, as well as inhibition of cell proliferation and migration. Further study showed that Pt3 complex also carry significant in vivo antitumor activity in orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All results imply that these novel platinum(II) complexes have a good anti-tumor effect on breast and colorectal cancer in vivo and in vitro and the affinity to become possible candidates for treatment in anticancer therapy.
Journal of Biological Inorganic Chemistry, Oct 29, 2021
Abstract The mechanism of action of most approved drugs in use today is based on their binding to... more Abstract The mechanism of action of most approved drugs in use today is based on their binding to specific proteins or DNA. One of the achievements of this research is a new perspective for recognition of binding modes to DNA by monitoring of changes in measured and stoichiometric values of absorbance at 260 nm. UV–Vis and IR spectroscopy, gel electrophoresis and docking study were used for investigation of binding properties of three dinuclear platinum(II) complexes containing different pyridine-based bridging ligands, [{Pt(en)Cl} 2 ( μ -4,4’-bipy)]Cl 2 ·2H 2 O ( Pt1 ), [{Pt(en)Cl} 2 ( μ -bpa)]Cl 2 ·4H 2 O ( Pt2 ) and [{Pt(en)Cl} 2 ( μ -bpe)]Cl 2 ·4H 2 O ( Pt3 ) to DNA (4,4’-bipy, bpa and bpe are 4,4′-bipyridine, 1,2- bis (4-pyridyl)ethane and 1,2- bis (4-pyridyl)ethene, respectively). In contrast to the system with well-known intercalated ligand (EtBr), covalently bound ligand ( cis -Pt) and with minor groove binder (Hoechst 33258), which do not have significant differences in measured and stoichiometric values, the most pronounced deviations are recorded for two dinuclear platinum(II) complexes ( Pt1 and Pt2 ), as a consequence of complex binding to the phosphate backbone and bending of DNA helix. The hydrolysis of complexes and changes in DNA conformation were also analysed as phenomena that may have an impact on the changes in absorbance. Graphic abstract
Applied Organometallic Chemistry, Dec 2, 2020
The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ... more The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ‐1,6‐nphe)](ClO4)2 (Pt2) (en is a bidentate‐coordinated ethylenediamine and 1,6‐nphe is the bridging 1,6‐naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The DNA‐binding evaluation of complexes Pt1 and Pt2 was done by UV–Vis, fluorescence emission spectroscopy, and their interaction with bovine serum albumin (BSA). The cytotoxic activity of these complexes was determined against mouse breast (4T1) and colon (CT26) cancer cell lines, human breast (MDA‐MB‐468), colon (HCT‐116), and lung (A549) cancer cell lines as well as mouse mesenchymal stem cells (mMSC). Complex Pt1 showed higher cytotoxic capacity toward solid cancer cell lines compared with Pt2 and lower cytotoxic capacity toward mMSC cells compared with cisplatin. Furthermore, molecular mechanism studies showed that Pt1 complex induced 4T1 and A549 cell apoptosis therefore increasing expression of pro‐apoptotic caspase‐3 and decreasing expression of anti‐apoptotic Bcl‐2 and Ki‐67. Antitumor capacity of Pt1 complex might be manifested at least in two ways: by facilitating apoptosis and by inhibiting tumor cells proliferation.
Journal of Biological Inorganic Chemistry, Mar 11, 2020
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoa... more New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl} 2 (μ-L)] 2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H 2 O)} 2 (μ-L)] 4+ , interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl} 2 (μ-4,4′-bipy)]Cl 2 •2H 2 O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs. Keywords Dinuclear platinum(II) complexes • Minor groove covering • Dual anticancer and anti-angiogenic activity Andjela A. Franich and Marija D. Živković contributed equally to this work.
Serbian Journal of Experimental and Clinical Research, Jun 22, 2021
Book of Proceedings: 1st International Conference on Chemo and BioInformatics,, 2021
Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of ma... more Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of malonic (mal, Pt1), 2-methylmalonic (Me-mal, Pt2), 2,2-dimethylmalonic (Me2-mal, Pt3) or 1,1- cyclobutanedicarboxylic (CBDCA, Pt4) acid while 5,6-epoxy-1,10-phen is bidentately coordinated 5,6-epoxy-5,6-dihydro-1,10-phenanthroline were synthesized and characterized by elemental microanalysis, IR, UV-Vis and NMR (1H and 13C) spectroscopic techniques. In vitro anticancer activity of novel platinum(II) complexes have been investigated on human and murine cancer cell lines, as well as normal murine cell line by MTT assay. The obtained results indicate that studied platinum(II) complexes exhibited strong cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. Complex Pt3 display stronger selectivity toward carcinoma cells in comparison to other tested platinum(II) complexes exhibiting beneficial antitumor activity mainly via t...
Serbian Journal of Experimental and Clinical Research, 2021
The interactions of metal complexes with important biomolecules such as deoxyribonucleic acid (DN... more The interactions of metal complexes with important biomolecules such as deoxyribonucleic acid (DNA) or bovine serum albumin (BSA) are responsible for their antitumor activity due to different modes of interaction with DNA and their transport through the blood system to cells and tissues via serum albumin. Therefore, the dinuclear palladium(II) complexes, [{Pd(en)Cl}2(μ-1,5- nphe)](NO3)2 (Pd1) and [{Pd(1,3-pd)Cl}2(μ-1,5-nphe)](NO3)2 (Pd2) (en is ethylenediamine, 1,3-pd is 1,3-propylenediamine and 1,5-nphe is the bridging 1,5-naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The UV-Vis and fluorescence emission spectroscopy were applied for evaluation of binding modes of Pd1 and Pd2 complexes to DNA as well as their interaction with BSA. The emission spectra indicate that the investigated Pd1 and Pd2 complexes can displace the ethidium bromide intercalator from DNA/EtBr molecules and act as intercalators showing strong interactions with DNA. ...
Book of Proceedings: 1st International Conference on Chemo and BioInformatics,, 2021
The series of nine dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-X)]2+ (where L is two NH3 or b... more The series of nine dinuclear platinum(II) complexes, [{Pt(L)Cl}2(μ-X)]2+ (where L is two NH3 or bidentantly coordinated diamine ligand – ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2- dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd; (±)-1,3-pentanediamine,1,3-pnd, and X is a bridging pyrazine (pz) or pyridazine (pydz) ligand) have been synthesized and characterized. The antitumor potential of these complexes against CT26 cells were determined by in vitro and in vivo assays. A murine model of heterotopic colon cancer tumor was induced in immunocompetent BALB/c mice for investigating antitumor potential of the Pt(II) complexes in vivo. It was found that complexes Pt1, Pt2 and Pt7 shows significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells, while all these complexes show moderate apoptotic effect. Complexes Pt1 and Pt7 arrested CT26 cells in G2/M phase o...
Applied Organometallic Chemistry, 2020
The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ... more The dinuclear platinum(II) complexes, [{PtCl(NH3)2}2(μ‐1,6‐nphe)](ClO4)2 (Pt1) and [{Pt(en)Cl}2(μ‐1,6‐nphe)](ClO4)2 (Pt2) (en is a bidentate‐coordinated ethylenediamine and 1,6‐nphe is the bridging 1,6‐naphthyridine ligand) were synthesized and characterized by different spectroscopic methods. The DNA‐binding evaluation of complexes Pt1 and Pt2 was done by UV–Vis, fluorescence emission spectroscopy, and their interaction with bovine serum albumin (BSA). The cytotoxic activity of these complexes was determined against mouse breast (4T1) and colon (CT26) cancer cell lines, human breast (MDA‐MB‐468), colon (HCT‐116), and lung (A549) cancer cell lines as well as mouse mesenchymal stem cells (mMSC). Complex Pt1 showed higher cytotoxic capacity toward solid cancer cell lines compared with Pt2 and lower cytotoxic capacity toward mMSC cells compared with cisplatin. Furthermore, molecular mechanism studies showed that Pt1 complex induced 4T1 and A549 cell apoptosis therefore increasing expre...
JBIC Journal of Biological Inorganic Chemistry, 2020
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoa... more New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl} 2 (μ-L)] 2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H 2 O)} 2 (μ-L)] 4+ , interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl} 2 (μ-4,4′-bipy)]Cl 2 •2H 2 O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs. Keywords Dinuclear platinum(II) complexes • Minor groove covering • Dual anticancer and anti-angiogenic activity Andjela A. Franich and Marija D. Živković contributed equally to this work.