Gold(I)-NHC complexes of antitumoral diarylimidazoles: structures, cellular uptake routes and anticancer activities

Five new heterocyclic gold carbene complexes were prepared, four chlorido-[1,3-dimethyl-4,5-diarylimidazol-2-ylidene]gold complexes 6a-d and a chlorido-[1,3-dibenzylimidazol-2-ylidene]gold complex 11, and three of them were characterised by X-ray single crystal analyses. They were tested for cytotoxicity against a panel of four human cancer cell lines and non-malignant fibroblasts, for tubulin interaction, and for the pathways of their uptake into 518A2 melanoma cells. All complexes showed cytotoxic activity in the micromolar IC₅₀ range with distinct selectivities for certain cell lines. In stark contrast to related metal-free 1-methyl-4,5-diarylimidazoles, the complexes 6 and 11 did not noticeably inhibit the polymerisation of tubulin to give microtubules. The cellular uptake of complexes 6 occurred mainly via the copper transporter (Ctr1) and the organic cation transporters (OCT-1/2). Complex 11 was accumulated preferentially via the organic cation transporters and by Na⁺/K⁺-dependent endocytosis. The new gold carbene complexes seem to operate by a mechanism different from that of the parent 1-methylimidazolium ligands.     

Relationship between the structure of diamine platinum(II) complexes and their cytostatic activity as measured on plant roots

The amine substituent effect in compounds [Pt(diamine)Cl₂] on inhibition of maize and cucumber root growth and branching has been investigated. The diamines used were ethylenediamine (en),N-methylethylenediamine (men),N,N-dimethylethylenediamine (N,N-dmen),N,N-dimethylethylenediamine (N,N-dmen),N,N,N,N-tetramethylethylenediamine (tmen), 1,2-propanediamine (1,2-pn), 2-methyl-1,2-propanediamine (ibn), 2,3 dimethyl-2,3-butanediamine (C-tmen), 1,3-propanediamine (1,3-pn), 2,2-dimethyl-1,3-propanediamine (C₂-dm-1,3 pn),N,N-dimethyl-1,3-propanediamine (N,N-dm-1,3-pn). Increased substitution of hydrogen atoms of the amine part with CH₃ groups reduces the cytostatic activity of complexes. The substitution of hydrogen atoms of NH₂ and vicinal CH₂ groups displays similar results. C-2 dimethylation (C-dm-1,3-pn) does not change the activity of the complex compared with (1,3-pn). It was observed that maize and cucumber roots differ in their relative sensitivity to various complexes. All complexes containing pn and their substituted analogs inhibited cucumber root growth weaker than that in maize. A comparison of obtained data with earlier published results concerning antitumor activity of complexes shows that they correlate in a similar manner with increased substitution of amino groups. Therefore, roots may be used as cheap test objects for primary screening of cytostatics. The general tendency of a decrease in cytostatic activity goes parallel with the number of Nor vicinal C-methyl groups and seems to arise from a decrease in hydrogen-bonding potential; however, some other possible reasons are also discussed. The activity discrimination by different species in our experiments and clearly different results forN,N-dimethylation depending on the chelate ring size (en and pn derivatives) on maize cannot be attributed to slower ligand-exchange kinetics from methylation. It is possible to assume that the major role in cytostatic activity of platinum complexes belongs to a cell repair system, i.e. the ability to eliminate platinum diamine fragments from DNA, depending on the number and strength of hydrogen bonds formed by thecis-diamine fragment.     

In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake

In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an example of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.     

Synthesis,characterization and cytotoxic activities of the [RuCl2(NO)(dppp)(L)]PF6 complexes

The synthesis and characterization of ruthenium compounds of the type [RuCl₂(NO)(dppp)(L)]PF₆ [dppp = 1,3-bis(diphenylphosphino)propane; L = pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0 μM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized = 200 μM).     

Synthesis and cytotoxic activities of novel copper and silver complexes of 1,3-diaryltriazene-substituted sulfonamides

In this study, a series of 10 novel copper (II) and silver complexes of 1,3-diaryltriazene-substituted sulfonamides was synthesised. All the synthesised ligands and their metal complexes were assessed for in vitro cytotoxicity against human colorectal adenocarcinoma (DLD-1), cervix carcinoma (HeLa), breast adenocarcinoma (MDA-MB-231), colon adenocarcinoma (HT-29), endometrial adenocarcinoma (ECC-1), prostate cancer (DU-145 and PC-3), normal embryonic kidney (HEK-293), normal prostate epithelium (PNT-1A), and normal retinal pigment epithelium (ARPE-19) cells. Most of the metal complexes from the series showed to be more active against all cancerous cells than the uncomplexed 1,3-diaryltriazene-substituted sulfonamides, and lower cytotoxic effects observed on normal cells. Most of the Cu (II) and Ag (I) metal complexes from the presented series showed high cytotoxic activity against HeLa cells with IC₅₀ values ranging from 2.08 to >300?µM. Specifically, compound L₃-Ag showed one of the highest cytotoxicity against all cancer cell lines with IC₅₀ values between 3.30 to 16.18?µM among other tested compounds.     

Synthesis and biological evaluation of a new series of N-acyldiamines as potential antibacterial and antifungal agents

In continuation of our efforts to find new antimicrobial compounds, series of fatty N-acyldiamines were prepared from fatty methyl esters and 1,2-ethylenediamine, 1,3-propanediamine or 1,4-butanediamine. The synthesized compounds were screened for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and for their antifungal activity against four species of Candida (C. albicans, C. tropicalis, C. glabrata and C. parapsilosis). Compounds 5a (N-(2-aminoethyl)dodecanamide), 5b (N-(2-aminoethyl)tetracanamide) and 6d (N-(3-aminopropyl)oleamide) were the most active against Gram-positive bacteria, with MIC values ranging from 1 to 16 μg/mL and were evaluated for their activity against 21 clinical isolates of methicillin-resistant S. aureus. All the compounds exhibited good to moderate antifungal activity. Compared to chloramphenicol, compound 6b displayed a similar activity (MIC₅₀ = 16 μg/mL). A positive correlation could be established between lipophilicity and biological activity.     

Enhancing lipophilicity as a strategy to overcome resistance against platinum complexes?

Decreased influx represents one of the major resistance mechanisms of platinum complexes. In order to address the question if this mechanism of resistance can be overcome by enhancing the lipophilicity of platinum complexes, we investigated the influence of lipophilicity on cellular accumulation and cytotoxicity in a panel of oxaliplatin analogues with different carrier ligands. Cellular accumulation, DNA platination and cytotoxicity were measured in a cisplatin-sensitive and -resistant ovarian carcinoma (A2780/A2780cis) and in an oxaliplatin-sensitive and -resistant ileocecal colorectal adenocarcinoma (HCT-8/HCT-8ox) cell line pair. Platinum concentrations were determined by flameless atomic absorption spectrometry or adsorptive stripping voltammetry. Passive diffusion represented the main influx mechanism of oxaliplatin analogues during the first minutes of incubation as indicated by a correlation between lipophilicity and early influx rate. Afterwards, the predominant influx mechanism was lipophilicity-independent. More lipophilic complexes showed a reduced cytotoxic activity, although the early influx rate was increased. The resistance profiles of the two cell line pairs were found to be different: HCT-8ox cells were less resistant against more lipophilic complexes, whereas A2780cis cells exhibited a comparable degree of resistance against all investigated compounds. However, the reduction in resistance factor of HCT-8ox cells cannot be explained by increased influx suggesting that other resistance mechanisms are circumvented upon exposure to more lipophilic compounds. Though resistance against more lipophilic platinum complexes analogues is lower we conclude that enhancing lipophilicity is not a successful strategy to overcome platinum resistance as higher lipophilicity is also associated with lower cytotoxic activity.     

The synthesis and characterization of a series of cobalt(II) β-ketoaminato complexes and their cytotoxic activity towards human tumor cell lines

A series of square planar cobalt(II) compounds bearing tetradentate β-ketoaminato ligands with variation in the number of ―CF₃ ligand substituents has been prepared and structurally and spectroscopically characterized. The fluorinated β-ketoamine ligands were prepared utilizing a multistep reaction sequence employing a silylenol protecting group. An additional tetrahedral cobalt compound bearing two bidentate β-ketoaminato ligands was also prepared and characterized.Cytotoxic activity of the cobalt-containing complexes was evaluated using six human cell lines; including two different prostate cancer cell lines (PC-3 and VCaP), acute monocytic leukemia (THP-1), astrocytoma (U-373 MG), hepatocellular carcinoma (HepG2), and neuroblastoma (SH-SY5Y) cells. The cobalt compounds are more active than their corresponding ligands. The activity is cell type specific; the cobalt compounds exhibit strong activity against human prostate cancer and monocytic leukemia cells but weak or no activity against neuroblastoma, astrocytoma, and liver carcinoma cells. Activity generally increases with a greater number of ―CF₃ substituents, and square planar complexes exhibit greater activity than the tetrahedral derivative. The mechanisms of activity against human PC-3 prostate cancer cells involve caspase-3 and two different mitogen-activated protein kinases. The addition of a thiol antioxidant reduced cytotoxicity, suggesting the possible involvement of reactive oxygen species. These cobalt complexes may represent a novel class of cytotoxic drugs selective towards certain types of tumors.     

Synthesis,Characterization, Antimicrobial and Antimalarial Activities of Azines Based Schiff Bases and their Pd(II) Complexes

Herein, we report synthesis, characterization, antimicrobial and antimalarial activities of azines Schiff base ligands (L¹−L⁴) and their palladium (II) complexes ( C¹−C⁴ ) of [Pd(L)(OAc)₂] type. The azine ligands (L¹−L⁴) were prepared by condensation of carbonyl compounds with hydrazine hydrate and their complexes by the reaction of palladium acetate with L¹−L⁴ ligands in 1 : 1 molar ratio. The prepared ligands and their complexes were characterized by spectral characterization using ¹H &¹³C-NMR, FT-IR and mass spectral studies, which revealed that the ligands coordinates via azomethine nitrogen and heteroatom or aryl carbon with palladium. Moreover, Schiff bases and their palladium (II) complexes have been screened for their antibacterial (S. aureus, B. subtillis, and S. typhi, P. aeruginosa), antifungal (C. albicans, A. niger, and A. clavatus) and antimalarial (P. falciparum) activities. The Schiff base L⁴ showed good results for antibacterial against S. aureus (MIC, 50 μg/mL) and antimalarial against P. falciparum (IC₅₀, 0.83 μg/mL). The complex C¹ showed best antibacterial activity (MIC, 62.5 μg/mL) against S. typhi and the complex C⁴ exhibited remarkable antimalarial activity (IC₅₀, 0.42 μg/mL) among the tested compounds. Thus, azines based ligands and their Pd complexes can be good antimicrobial and antimalarial agents if explored further.     

Synthesis,characterization, cytotoxic activity,and cellular accumulation of dinuclear platinum complexes derived from N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol,aryl substituted N-benzyl-1,4-butanediamines,and N-benzyl-1,6-hexanediamines

This work describes the synthesis and characterization of six new dinuclear platinum complexes having N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines and N-benzyl-1,6-hexanediamines as ligands. They were prepared by the reaction of cis-[PtCl(2)(DMSO)(2)] (DMSO=dimethyl sulfoxide) with the appropriate ligand in water, except for one of them, which was prepared from K(2)PtCl(4). We also report the cytotoxic activity and cellular accumulation of three of these complexes in a human small-cell lung carcinoma cell line and its resistant subline. Resistant cells exhibited a lesser degree of cross-resistance to these compounds when compared to cisplatin. The accumulation of platinum in both cell lines followed the same pattern, i.e. approximately the same intracellular platinum concentration yielded the same cytotoxic effect independent of the nature of the platinum complex used.     

Tuning of lipophilicity and cytotoxic potency by structural variation of anticancer platinum(IV) complexes

A series of bis(carboxylato)dichlorido(ethane-1,2-diamine)platinum(IV) compounds with IC₅₀ values ranging between 142 μM and 18 nM was investigated with respect to their lipophilicity (by the shake flask method as well as microemulsion electrokinetic chromatography), reduction potential, as well as their cellular accumulation in cancer cells in vitro. In general, the antiproliferative properties of the complexes correlated with their lipophilicity as well as their accumulation, whereas differences in antiproliferative potency could not be explained by reduction potentials since they do not vary significantly within the investigated series of compounds. Only minor effects for complexes featuring polar end groups were detected.     

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.     

Synthesis, characterization, antibacterial and cytotoxic study of platinum (IV) complexes

Platinum (IV) complexes [Pt (L)2Cl2] [where, L= benzyl-N-thiohydrazide (L1), (benzyl-N-thio)-1,3-propanediamine (L2), benzaldehyde-benzyl-N-thiohydrazone (L3) and salicylaldehyde-benzyl-N-thiohydrazone (L4)] have been synthesized. The thiohydrazide, thiodiamine and thiohydrazones can exist as thione-thiol tautomer and coordinate as a bidentate N-S ligand. The ligands were found to act in monobasic bidentate fashion. Analytical data reveal that metal to ligand stoichiometry is 1:2. The complexes have been characterized by elemental analysis, IR, mass, electronic and 1H NMR spectroscopic studies. In vitro antibacterial and cytotoxic studies have been carried out for some complexes. Various kinetic and thermodynamic parameters like order of reaction (n), activation energy (Ea), apparent activation entropy (S#) and heat of reaction (DeltaH) have also been carried out for some complexes.     

Cd(II) and Cu(II) complexes of polydentate Schiff base ligands: synthesis, characterization, properties and biological activity

We report the synthesis of the Schiff base ligands, 4-[(4-bromo-phenylimino)-methyl]-benzene-1,2,3-triol (A₁), 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,2,3-triol (A₂), 3-(p-tolylimino-methyl)-benzene-1,2-diol (A₃), 3-[(4-bromo-phenylimino)-methyl]-benzene-1,2-diol (A₄), and 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,3-diol (A₅), and their Cd(II) and Cu(II) metal complexes, stability constants and potentiometric studies. The structure of the ligands and their complexes was investigated using elemental analysis, FT-IR, UV-Vis, ¹H and ¹³C NMR, mass spectra, magnetic susceptibility and conductance measurements. In the complexes, all the ligands behave as bidentate ligands, the oxygen in the ortho position and azomethine nitrogen atoms of the ligands coordinate to the metal ions. The keto-enol tautomeric forms of the Schiff base ligands A₁-A₅ have been investigated in polar and non-polar organic solvents. Antimicrobial activity of the ligands and metal complexes were tested using the disc diffusion method and the strains Bacillus megaterium and Candida tropicalis.Protonation constants of the triol and diol Schiff bases and stability constants of their Cu²⁺ and Cd²⁺ complexes were determined by potentiometric titration method in 50% DMSO-water media at 25.00 ± 0.02 °C under nitrogen atmosphere and ionic strength of 0.1 M sodium perchlorate. It has been observed that all the Schiff base ligands titrated here have two protonation constants. The variation of protonation constant of these compounds was interpreted on the basis of structural effects associated with the substituents. The divalent metal ions of Cu²⁺ and Cd²⁺ form stable 1:2 complexes with Schiff bases.The Schiff base complexes of cadmium inhibit the intense chemiluminescence reaction in dimethylsulfoxide (DMSO) solution between luminol and dioxygen in the presence of a strong base. This effect is significantly correlated with the stability constants K_CdL of the complexes and the protonation constants K_OH of the ligands; it also has a nonsignificant association with antibacterial activity.     

Mononuclear copper(II) nitrato complexes with methyl-substituted 4-nitropyridine N-oxide. Physicochemical and cytotoxic characteristics

Three new complexes, products of the interaction of Cu(NO₃)₂ and methyl-substituted 4-nitropyridine N-oxides were synthesized and characterized by elemental analysis, magnetic, spectroscopic (IR, FIR and EPR), thermal and X-ray methods. The complexes (magnetic moments 1.70-1.81 BM at 300 K) of general formula [Cu(H₂O)(NO₃)₂L₂], L = 2-methyl-4-nitropyridine N-oxide and [Cu(NO₃)₂ L′₂], where L′ = 2,6-dimethyl- and 2,3,6-trimethyl-4-nitropyridine N-oxide were obtained. The compounds were unstable upon dissolution. The X-ray single crystal structure of Cu(II) complex with 2,6-dimethyl-4-nitropyridine N-oxide was determined and analysed. The compounds and free ligands were tested in vitro on the cytotoxic activity against MCF-7 and SW-707 human cancer cell lines. The complexes with 4-nitropyridine N-oxide (a reference) and 2-methyl-4-nitropyridine N-oxide show a significant anti-proliferative activity against studied cell lines. A reciprocal relationship between the activity and the number of methyl groups was observed. Both ligands and complexes are cytotoxic active but to the different cell lines.     

Synthesis and antitubercular activity of lipophilic moxifloxacin and gatifloxacin derivatives

Fluoroquinolone (FQ) has a broad spectrum of activity against several bacteria, mycobacteria, parasites, and other diseases. Moxifloxacin and gatifloxacin are a new generation of fluoroquinolone agents with improved activity against Gram-negative and positive bacteria. As lipophilicity is an important consideration in the design and activity of novel antibacterial agents, we report in this work the synthesis and biological evaluation of 12 lipophilic moxifloxacin or gatifloxacin derivatives, by reaction of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 13 with several N-monoalkyl 1,2-ethanediamine or 1,3-propanediamine.     

Synthesis,DNA/protein binding and in vitro cytotoxic studies of new palladium metallothiosemicarbazones

A series of four new thiosemicarbazone complexes of palladium have been synthesized, characterized and evaluated for their DNA/protein binding with CT-DNA and BSA, respectively. The new complexes bound to CT-DNA by intercalation mode and in protein binding studies, the complexes bound to BSA binding mechanism was found as static quenching. Among them the complex 4 had a strong binding affinity with BSA. In addition, in vitro cytotoxic studies were carried out on lung cancer (A549) and liver cancer (HepG2) cell lines and found that the complexes exhibited better activity than their parent thiosemicarbazone analogues. The complex 3 exhibited better activity than other complexes and this fact supported by the increased accumulation of the complexes in to the cancer cells which are evident from inter cellular uptake studies.     

Synthesis and anticancer activity of bis-benzo[d][1,3]dioxol-5-yl thiourea derivatives with molecular docking study

New thiourea derivatives incorporating two benzo[d][1,3]dioxol-5-yl moieties have been synthesized through the reaction of two molecules of benzo[d][1,3]dioxol-5-yl isothiocyanate with one molecule of various diamino derivatives. The synthesized compounds were examined for their cytotoxic effects using SRB assay on three cancer cell lines HepG2, HCT116 and MCF-7. Most of compounds showed significant antitumor activity and some compounds showed strong results greater than the reference drug. As example, IC₅₀ values of 1,1′-(1,4-phenylene)bis(3-(benzo[d][1,3]dioxol-5-yl)thiourea) 5 were 2.38 µM for HepG2, 1.54 µM for HCT116 and 4.52 µM for MCF7, while the IC₅₀ values of standard drug doxorubicin were 7.46, 8.29 and 4.56 µM, respectively. Interestingly, these compounds were non cytotoxic toward the tested normal cell line (IC₅₀ value > 150 µM). The anticancer mechanisms were studied via EGFR inhibition assessment, annexin V-FITC apoptosis assessment, cell cycle analysis and study the effect on mitochondrial apoptosis pathway proteins Bax and Bcl-2 as well as molecular docking studies.     

Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2'-deoxyguanosine 5'-monophosphate and 2'-deoxyadenosine 5'-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.     

Synthesis,characterization, and biological activity of platinum II,III, and IV pivaloamidine complexes

Imino ligands have proven to be able to activate the trans geometry of platinum(II) complexes towards antitumor activity. These ligands, like aromatic N-donor heterocycles, have a planar shape but, different from the latter, have still an H atom on the coordinating nitrogen which can be involved in H-bond formation. Three classes of imino ligands have been extensively investigated: iminoethers (HN=C(R)OR′), ketimines (HN=CRR′), and amidines (HN=C(R)NR′R″). The promising efficacy of the platinum compounds with amidines (activity comparable to that of cisplatin for cis complexes and much greater than that of transplatin for trans complexes) prompted us to extend the investigation to amidine complexes with a bulkier organic residue (R = t-Bu). The tert-butyl group can confer greater affinity for lipophilic environments, thus potentiating the cellular uptake of the compound. In the present study we describe the synthesis and characterization of pivaloamidine complexes of platinum(II), (cis and trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}] and cis and trans-[PtCl₂{Z-HN=C(t-Bu)NH₂}₂]), platinum(III) ([Pt₂Cl₄{HN=C(t-Bu)NH}₂(NH₃)₂]), and platinum(IV) (trans-[PtCl₄(NH₃){Z-HN=C(t-Bu)NH₂}] and trans-[PtCl₄{Z-HN=C(t-Bu)NH₂}₂]). The cytotoxicity of all new Pt complexes was tested toward a panel of cultured cancer cell lines, including cisplatin and multidrug resistant variants. In addition, cellular uptake and DNA binding, perturbations of cell cycle progression, induction of apoptosis, and p53 activation were investigated for the most promising compound trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}]. Remarkably, the latter complex was able to overcome both acquired and intrinsic cisplatin resistance.