Platinum(II) Complexes with 1,10‐Phenanthroline and Hydrophilic Alkoxyacetate Ligands as Potential Antitumor Agents

Four platinum complexes, formulated as [Pt(phen)(OCOCH₂OR)₂] (phen=1,10‐phenanthroline, R=Me, Et, ⁱPr, or ^tBu), have been synthesized and well characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectroscopy. Replacing chloride groups of the precursor Pt(phen)Cl₂ with alkoxyacetate anions greatly improved the aqueous solubility and cytotoxicity of the resulting platinum complexes. The in vitro cytotoxicity study revealed that complexes 1 – 3 were active in vitro towards four human tumor cell lines, especially complex 1 which exhibited prominent in vitro cytotoxic activity against HCT‐116 cell lines comparable to cisplatin and oxaliplatin. Flow cytometry assay indicated that representative complexes 1 and 2 exerted cytotoxicity on HCT‐116 cell lines through inducing cell apoptosis and blocking cell cycle progression in the S or G2/M phases. The interaction of representative complexes with pET28a plasmid DNA was tested by agarose gel electrophoresis, which demonstrated that complexes 1 and 2 were capable of distorting plasmid DNA mainly by covalent binding and degradation effect.     

Low valence states of iron complexes of aliphatic and mixed aliphatic-aromatic diimine ligands

Electrochemical reductions of iron(II) diimine complexes [FeL₃²⁺, where L = CH₃NC(R)C(R′) NCH₃, aliphatic diimine series with R,R′ = H,H; H,CH₃ and CH₃,CH₃ and L = C₅H₄NC(R)N(R′), mixed diimine series with R,R′ = H,CH₃ and CH₃] were investigated through polarography and cyclic voltammetry in acetonitrile, with tetraethylammonium perchlorate supporting electrolyte (0.2 M) as a function of temperature. In the 0 to ?2.4 V vs. Ag/AgCl potential range two to four polarographic waves were observed for the aliphatic series. The first two waves can be described as one-electron reversible reduction processes. They indicate that low valence states iron(I) and iron(0) are stabilized in acetonitrile. In the mixed ligand series three one-electron reversible reduction waves were observed, indicating that in addition to the low valence states stabilized in the aliphatic diimine series the formal reduction state Fe(–I) is also stabilized. The stabilization of the low oxidation states is due to the electron acceptor properties of the diimine ligands, inherent to the presence of the chromophoric iron diimine group. The half-wave potential data and the stabilization of the low valence states point to the importance of analyzing both σ and π effects. The molecular electronegativity values for the series of iron diimine complexes investigated evidences a synergistic interaction between the metal-ligand σ and π bonds. Diffusion coefficients, temperature effects on the heterogeneous electron transfer step, and electrocapillary curves were obtained for these complexes. No evidence for adsorption of the complexes on mercury electrodes was found for the one-electron reversible steps. When comparing polarographic data with those obtained on platinum disk working electrodes employed in the cyclic voltammetric experiments, we observed that for the symmetric aliphatic diimine ligands the observed cathodic currents are larger than expected on the basis of the previously calculated diffusion coefficients. In addition, the reduction waves are shifted 0.14 V to more negative potentials. The symmetric aliphatic diimine complexes exhibit adsorption of the electroactive species on the surface of the platinum electrodes in this potential range.     

Synthesis, spectroscopic, and cytotoxicity studies of some diamine and diimine platinum(II) complexes of diethyldithiocarbamate

Four new water soluble complexes of the formula [Pt(DA)(DDTC)]NO3 (where DA is 2,2'-bipyridine, 1,10-phenanthroline, 1,2-diaminopropane, or 1,2-diaminocyclohexane, and DDTC is diethyldithiocarbamate anion) have been synthesized by reaction of platinum-diamine/diimine diaqua complex with sodium diethyldithiocarbamate in molar ratio of 1:1. These complexes have been characterized by the chemical analysis, and ultraviolet-visible, infra-red and 1H NMR spectroscopy. The infrared and 1H NMR spectral studies of these complexes have ascertained the modes of binding of diamine/diimine and diethyldithiocarbamate to platinum. The molar conductance values of these platinum complexes in conductivity water suggest them to be 1:1 electrolytes. These four complexes and two other complexes containing ethylenediamine and 1,3-diaminopropane ligands have been tested against P-388 lymphocytic leukemic cells. Out of them only 2,2'-bipyridine and 1,10-phenanthroline complexes show 1.D.50 values less than cisplatin.     

Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines

The antitumor activity of the trinuclear Phase I clinical agent, BBR3464, is matched by that of polyamine-linked dinuclear complexes. The cytotoxicity and cellular accumulation of three polynuclear platinum complexes: [?trans-PtCl(NH3)2?2 mu-?trans-Pt(NH3)2(H2N(CH2)6-NH2)2?]4+ (BBR3464), [?trans-PtCl(NH3)2?2(H2N(CH2)3NH2(CH2)4NH2)]3+ (BBR3571), and [?trans-PtCl(NH3)2?2(H2N(CH2)6-NH2)]2+ (BBR3005), were studied in a series of murine L1210 cell lines and compared with cisplatin. Besides murine L1210 cell lines sensitive (/0) and resistant (/DDP) to cisplatin, the efficacy of the compounds in a cell line rendered resistant to BBR3464 (/3464) was examined. Finally, to examine possible uptake pathways of these novel charged complexes, cytotoxicity in a cell line resistant to the polyamine synthesis inhibitor, methylglyoxal-bis(guanylhydrazone) (/MGBG), was studied. Cytotoxicity profiles of BBR3571 most closely matched that of BBR3464. Both agents showed significantly reduced cytotoxicity in L1210/ BBR3464. The cytotoxicity of neither agent was affected by the polyamine uptake-deficient cell line and indeed both complexes showed significantly enhanced cytotoxicity in L1210/MGBG relative to wild-type L1210/0. The cellular uptake of both BBR3464 and BBR3571 was enhanced in L1210/DDP. These studies suggest that the chemical feature of a diamine linker containing an internal charge contributes significantly to the anticancer profiles of both the trinuclear platinum complex, BBR3464, which incorporates a charged platinum into a diamine linker, and the dinuclear platinum complex, BBR3571, which incorporates only a naturally occurring polyamine as diamine linker.     

Chemical ligand non-innocence in pyridine diimine Rh complexes

The formation and reactivity of pyridine diimine rhodium(I) alkyl complexes without β-hydrogens (Me, Bz, CH₂SiMe₃) is described. In contrast to the corresponding cobalt complexes, the rhodium complexes could not be activated to polymerise ethene. Rh ethyl complexes could not be prepared. Examples of hydrogen transfer to and from the ligand were observed, illustrating the active role the pyridine diimine ligand can play in the reactions of its complexes. Decomposition via loss of free ligand was observed in many cases, indicating that the pyridine diimine ligand is not a very suitable one for Rh^I.     

Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes

Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α′-diamino-p-xylene, L² = 4,4′-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.     

Antiviral properties and cytotoxic activity of platinum(II) complexes with 1,10-phenanthrolines and acyclovir or penciclovir

Platinum compounds containing an aromatic diimine (1,10-phenanthroline or 2,9-dimethyl-1,10-phenanthroline; phen and Me(2)phen, respectively) and antiviral guanosine-type ligands (acyclovir or penciclovir; acy and pen, respectively) have been synthesised. These compounds maintain the antiviral activity against Herpes Symplex Virus (HSV) and have greater efficacy than free acyclovir or penciclovir against Cytomegalovirus (CMV); in both cases the species with Me(2)phen are more active. The same complexes are effective against tumor cell proliferation which also results to be dependent upon the nature of the diimine ligand: all compounds containing Me(2)phen being more active than those containing phen. Although in vivo some complexes significantly reduce tumor cell proliferation, nevertheless, they do not appear to significantly affect the life time expectancy of the treated mice. The greater cytotoxicity of compounds with Me(2)phen may result from a higher reactivity towards cellular components, such as glutathione, which could cause release of the diimine, known to be highly cytotoxic.     

DNA binding and cleavage activity of [Ru(NH3)4(diimine)]Cl2 complexes

The interaction of a series of mixed ligand complexes of the type [Ru(NH₃)₄(diimine)]Cl₂, where diimine=2,2^′-bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp), 4,7-dimethyl-1,10-phenanthroline (4,7-dmp), 2,9-dimethyl-1,10-phenanthroline (2,9-dmp), 3,4,7,8-tetra-methyl-1,10-phenanthroline (Me₄phen), with calf thymus DNA has been studied using absorption, emission and circular dichroic spectral measurements and viscometry and electrochemical techniques. On interaction with DNA the complexes show hypochromism and red-shift in their MLCT band suggesting that the complexes bind to DNA. The magnitude of the binding constant (K_b) obtained from absorption spectral titration varies depending upon the nature of the diimine ligand: Me₄phen > 5,6-dmp > 4,7-dmp > phen suggesting the use of diimine ‘face’ of the octahedral complexes in binding to DNA. The interaction of phen complex possibly involves phen ring partially inserted into the DNA base pairs. In contrast, the methyl-substituted phen complexes would involve hydrophobic interaction of the phen ring in the grooves of DNA, which is supported by hydrogen bonding interactions of the ammonia ligands with the intrastrand nucleobases. Also the shape and size of the phen ligand as modified by the methyl substituents determine the DNA binding site sizes (0.12-0.45 base pairs). The relative emission intensities (I/I₀) of the DNA-bound complexes parallel the variation in K_b values. Almost all the metal complexes exhibit induced CD bands on binding to B DNA, with the 4,7-dmp and Me₄phen complexes inducing certain structural modifications on the biopolymer. DNA melting curves obtained in the presence of metal complexes reveal a monophasic melting of the DNA strands, the Me₄phen complex exhibiting a slightly enhanced tendency to stabilize the double-stranded DNA. There were slight to appreciable changes in the relative viscosities of DNA, which are consistent with enhanced hydrophobic interaction of the methyl-substituted phen rings. Upon interaction with CT DNA, the Me₄phen, 4,7-dmp and 5,6-dmp complexes, in contrast to bipy, phen and 2,9-dmp complexes, show a decrease in anodic peak current in their cyclic voltammograms suggesting that they exhibit enhanced DNA binding. DNA cleavage experiments show that all the complexes induce cleavage of pBR322 plasmid DNA, the Me₄phen and 5,6-dmp complexes being remarkably more efficient than other complexes.     

Bifunctional Platinum(II) Complexes with Bisphosphonates Substituted Diamine Derivatives: Synthesis and In vitro Cytotoxicity

A series of N,N′‐dibisphosphonate‐containing 1,3‐propanediamine derivatives ( L1 – L6 ) and their corresponding dichloridoplatinum(II) complexes ( 1 – 6 ) have been synthesized and characterized by elemental analysis, ¹H‐NMR, ¹³C‐NMR, ³¹P‐NMR and HR‐MS spectra. The in vitro antitumor activities of compounds L1 – L6 and 1 – 6 were tested by WST‐8 assay with Cell Counting Kit‐8, indicating that platinum‐based complexes 1 – 6 showed higher cytotoxicity than corresponding ligands L1 – L6 against A549 and MG‐63, especially complex 2 which displayed comparable cytotoxicity to those of cisplatin and zoledronate after 48 h incubation. In addition, complexes 1 – 6 were more active in vitro on osteosarcoma cell line MG‐63 than normal osteoblast cell line hFOB 1.19. The structure‐activity relationship has been summarized based on the in vitro cytotoxicity of three series of platinum complexes from this and our previous studies. The in vitro bone affinity of platinum complexes was also tested by hydroxyapatite (HAP) chromatography in terms of capacity factor K′. Besides, in this paper, representative complex 2 , which has been proved to be a promising antitumor agent with high cytotoxicity and bone HAP binding property, was investigated for its mechanism of action producing cell death against MG‐63.     

Anticancer activity of new imidazole derivative of 1R,2R-diaminocyclohexane palladium and platinum complexes as DNA fluorescent probes

The aim of this study was synthesis of two new water-soluble fluorescent palladium and platinum complexes with formulas of [Pt(DACH)(FIP)](NO₃)₂ and [Pd(DACH)(FIP)](NO₃)₂, respectively, where FIP is 2-(furan-2-yl)-1H-imidazo[4,5-f][1,10] phenanthroline and DACH is 1R,2R-diaminocyclohexane. Fluorescence spectroscopy, circular dichroism (CD), thermal denaturation measurement, ionic strength, and kinetic study displayed groove binding of Pt complex on DNA, while due to binding of Pd complex, B form of DNA convert to Z form. Due to electrostatic interaction of Pd complex with DNA, the DNA form is converted and it provides enough space for Pd complex to insert between base stacking of DNA. UV–vis study shows two complexes could denature the DNA at low concentrations in exothermic process and Pt complex is more active than Pd complex. Finally, the anticancer and growth inhibitory activities of synthesized complexes were investigated against human colon cancer cell line HCT116 after incubation time of 24 h using MTT assay and higher activity was observed for the platinum complex. Interaction of the two metal derivative complexes was studied by molecular docking and molecular dynamics simulation. The results showed that Pt complexes have higher negative docking energy and higher tendency for interaction with DNA, and exert more structural change on DNA.     

Structure-antitumour activity relationships for new platinum complexes

Fourteen platinum (Pt) coordination complexes with different ligands, which include both Pt(II) and Pt(IV) complexes, were prepared, characterized and tested for their in vitro cytotoxic effects on KB cells and for their antitumour activity against some tumour systems (L1210 and P388 leukaemia, ADJ/PC6A plasma cell tumour and Yoshida sarcoma).The majority of the ligands were derivatives of aniline or pyridine, but complexes with tranylcypromine, guanethidine and octodrine were also synthetized.Depending on cytotoxicity the Pt-compounds could be divided into 3 groups. The compounds with a high cytotoxicity (ED₅₀ = 0.1–1 μg/ml) were also active against L1210 and P-388 leukaemia; a correlation between cytotoxicity and antitumour activity was not always observed.In these complexes the oxidation state of the Pt appears to be critical for their activity.     

Toxicity of platinum(II) amino acid (N,O) complexes parallels their binding to DNA as measured in a new solid phase assay involving a fluorescent HMG1 protein construct readout

 The compound [Pt(lysine)Cl₂] (Kplatin) was previously identified in a study of platinum amino acid complexes as a potential antitumor drug candidate. The DNA binding properties, high mobility group (HMG)-domain protein affinity for the platinated DNA, and cytotoxicity against HeLa cells of Kplatin and three related (N,O) chelated platinum(II) amino acid complexes, [Pt(arginine)Cl₂] (Rplatin), K[Pt(N_e-acetyllysine)Cl₂] (NacKplatin), and K[Pt(norleucine)Cl₂] (Norplatin), are reported. The four complexes have identical PtCl₂(N,O) coordination environments. A new solid phase screening methodology was devised in which platinated DNA probes are covalently attached to a nylon support and tested for their ability to bind a fluorescently labeled HMG-domain protein. The fluorescent HMG-domain protein was generated by expressing a fusion of the green fluorescent protein (GFP) with recombinant rat HMG1. Binding revealed by the solid phase method correlated well with the results of gel mobility shift and HeLa cytotoxicity assays. These results suggest that the net charge on the complex, rather than the nature of the side chain, is the most important factor underlying the DNA binding properties and toxicity of amino acid (N,O) chelated platinum complexes. This property explains why Kplatin was previously selected from the pool of platinum amino acid complexes based on the ability of its DNA adducts to bind HMG1. Received: 3 February 1999 / Accepted: 7 April 1999     

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5′-GMP

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by ¹H NMR, ¹⁹⁵Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5′-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.     

Structure-activity relationship studies for three new asymmetric cis-platinum(II) aminoethanol-based complexes

The design and synthesis of three asymmetrical platinum(II) analogues of cisplatin with substituents on the amine, varying in polarity and steric bulk is presented. Their biological activities, as studied using in vitro cytotoxicity studies in cisplatin sensitive and the corresponding cisplatin resistant cell lines, cellular uptake experiments and in a reaction with model DNA base GMP, are presented. All compounds exhibit promising cytotoxicity in the cisplatin sensitive cell lines albeit lower than cisplatin. On the other hand, the complexes partly overcome cisplatin resistance in the resistant cell lines. A direct correlation between cytotoxicity and cellular uptake was found. Conversely, the rate of reaction of all compounds with the model base GMP was found to be very similar and faster than cisplatin. It was therefore concluded that the difference in activity observed for these complexes is due to differential cellular uptake rather than the reactivity towards the cellular target of platinum complexes, nuclear DNA.     

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5'-GMP

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by ¹H NMR, ¹⁹⁵Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5′-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.     

Antiproliferative effect and genotoxicity of novel synthesized palladium complexes with organoarsenic ligands

Three new palladium complexes with general formula [PdCl₂L₂], where L = heterofunctional organoarsenic ligand: (2-isopropoxyphenyl)diphenylarsine (1), (2-methoxyphenyl)-diphenylarsine (2) and (2-hydroxyphenyl)diphenylarsine (3) have been synthesized and fully characterized, including X-ray crystallographic data. Their potential antitumor effect and genotoxicity have been studied as well. The viability test performed on human tumor (MLS) and normal (Hfl-1) cell lines indicates significant cytotoxicity of complexes, which is higher in tumor cells than in normal cells. The lethal doses are comparable with those of standard metal-based chemotherapeutical drugs (carboplatin and oxaliplatin). These palladium complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. A new static cytometric method was developed and simultaneously the classic AnnexinV test was performed. Complex 2 has an important capacity to induce apoptosis in tumor cells. The apoptotic process is triggered due to the interaction of these complexes with secondary structure of DNA in treated cells. The alkaline single-cell gel assay shows that the level of DNA damages induced by compounds 2 and 3 are significantly higher in tumor cells as in normal cells. These studies shown that complexes 1, 2 and 3 have biologic activity, the effect of complex 2 being superior to its platinum analogues, attributable to its structure.     

Dinuclear platinum anticancer complexes with fluorescent N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones: cellular processing in two cisplatin-resistant cell lines reflects the differences in their resistance profiles

The biological activity of N,N-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl is 2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) and their dinuclear platinum complexes has been evaluated in the U2-OS human osteosarcoma cell line and its cisplatin-resistant U2-OS/Pt subline. All the compounds have been found to exhibit high cytotoxicity in the sensitive cell line, and to overcome cisplatin resistance in U2-OS/Pt cells. Cellular processing of N,N-bis(2-aminoethyl)-1,4-diaminoanthraquinone and the respective dinuclear platinum complex in the sensitive and resistant U2-OS cells has been studied over time using digital fluorescence microscopy. Cellular processing of the compounds has been found to be similar in sensitive and resistant U2-OS cells, which is in agreement with the lack of cross-resistance in the U2-OS/Pt cell line. Both the platinum complex and the free ligand quickly enter the cell and accumulate in the nucleus. The platinum complex is excreted from the cell via the Golgi apparatus, while the weakly basic anthraquinone ligand accumulates in the Golgi complex, where it is taken up by lysosomes and then transported to the cell surface. The cellular distribution of the fluorescent anthraquinones and their dinuclear platinum complexes in the sensitive/resistant pair of U2-OS osteosarcoma cell lines is compared with the earlier studied cellular processing in the sensitive/resistant pair of A2780 ovarian carcinoma cell lines. In the A2780cisR cell line, the platinum complexes (and not the free ligands) are sequestered in lysosomes, which is not the case in A2780 sensitive cells. The differences in cellular distribution of the compounds in these two sensitive/resistant pairs of cell lines most likely result from different resistance profiles in A2780cisR and U2-OS/Pt cells. Lysosomes of A2780cisR cells are less acidic than lysosomes of A2780 sensitive cells, which is likely to be the cause of a defect in endocytosis. The disruption of normal endocytosis might facilitate sequestration of the platinum complexes in lysosomes, which partly confers the cross-resistance of these complexes with cisplatin in the A2780cisR cell line. In contrast, sequestration in acidic vesicles does not occur in U2-OS/Pt cells that do not exhibit enhanced lysosomal pH and which are likely to have normal endocytosis.     

Palladium(II) saccharinate complexes with bis(2-pyridylmethyl)amine induce cell death by apoptosis in human breast cancer cells in vitro

The outcomes of breast cancer patients are still poor although new compounds have recently been introduced into the clinic. Therefore, novel chemical approaches are required. In the present study, palladium(II) and corresponding platinum(II) complexes containing bis(2-pyridylmethyl)amine (bpma) and saccharine were synthesized and tested against human breast cancer cell lines, MCF-7 and MDA-MB-231, in vitro. Cytotoxicity was first screened by the MTT assay and the results were further confirmed by the ATP assay. The palladium complexes 1 and 3 yielded stronger cytotoxicity than the corresponding platinum complexes 2 and 4 at the same doses. The palladium complex 3 was found to be the most cytotoxic one. Therefore, a more comprehensive study was carried out with this complex only. The mode of cell death was determined morphologically under fluorescent microscope and biochemically with detection of active caspase-3 and PARP cleavage by Western blot. Changes in apoptosis-related gene expressions were measured with qPCR. It was demonstrated that complex 3 caused cell death by apoptosis determined by fluorescence imaging and Western blot. As a sign of apoptosis, PARP was cleaved in both of the cell lines. In addition, caspase-3 was cleaved in MDA-MB-231 cells while this cleavage was not observed in MCF-7. The results show that the complex 3 is a promising anti-cancer compound against breast cancer with an IC₅₀ value of 3.9 μM for MCF-7 and 4.2 μM for MDA-MB-231 cells, which warrants further animal experiments.     

Synthesis and anticancer activity of dichloroplatinum(II) complexes of podophyllotoxin

A series of dichloroplatinum(II) complexes of podophyllotoxin (PPT) were prepared, and their cytotoxicity against sensitive (A-549, HeLa, HCT-8, Hep-G2, K562) and resistant (ADM/K562) cell lines were evaluated. Complex cis-[4α-O-(2″,3″-diaminopropanoyl)-podophyllotoxin] dichloride platinum(II) (12) displayed most potent cytotoxicity with IC₅₀ value in the range 0.071–2.98 μM. Complex 12 induces cell cycle arrest in the G₂/M phase, and inhibits the formation of microtubules in HeLa cells. Furthermore, this complex exhibits potent DNA cleavage capabilities.     

In vitro cytotoxicity study on platinum (II) complexes with epoxysuccinates as leaving groups

A series of novel cisplatin-type platinum complexes were designed, characteristic of epoxysuccinates as leaving groups. The pertinent compounds were prepared and characterized by IR, (1)H NMR, and ESI-MS spectra with elementary analyses. The in vitro cytotoxic activities of compounds toward SPC-A1 human lung adenocarcinoma cell line and BGC823 human stomach adenocarcinoma cell line were determined. Biological tests have confirmed that complexes containing 4R,5R-DMID [abbreviation of (4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane] as carrier ligands have greater cytotoxicity toward tumor cells than the corresponding compounds with other carrier ligands. Most platinum complexes with trans-epoxysuccinates usually have higher cytotoxicity than those with cis-epoxysuccinates. Complex 4a shows the most effective among those tested platinum complexes in both cell lines, and its cytotoxicity approached that of cisplatin.