Syntheses and structural studies of platinum(II) complexes of O-methylselenomethionine and related ligands

The complexes dichloro[2-(phenylselanyl)ethanamine]platinum(II), dichloro[2-(benzylselanyl)ethanamine]platinum(II) and dichloro(O-methylselenomethionine)platinum(II) have been prepared and the structure of dichloro(O-methylselenomethionine)platinum(II) has been determined by single crystal X-ray diffraction. The Pt(II) is in a square planar environment and is coordinated by two cis chloride ligands and a chelating O-methylselenomethionine ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and they are at least threefold less toxic than cisplatin in both cell lines.     

Syntheses, crystal structure and cytotoxicity of diamine platinum(II) complexes containing maltol

The cationic complexes (1,2-diaminoethane)(maltolato)platinum(II) ([Pt(en)(ma)]+) and (1R,2R-1,2-diaminocyclohexane)(maltolato)platinum(II) ([Pt(R,R-DACH)(ma)]+) have been prepared and the structure of [Pt(R,R-DACH)(ma)]NO3 has been determined by single crystal X-ray diffraction. The geometry of the metal in [Pt(R,R-DACH)(ma)]NO3 is essentially square planar and the maltolate ligand has a geometry similar to other chelate complexes involving this ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and the IC50 values are approximately 32 microM in HeLa cells and 26 microM in K562 cells. In these cell lines the cytotoxicity of cisplatin is higher than the maltolate complexes by a factor of 2 to 3 whereas the cytotoxicity of carboplatin is lower than the maltolate complexes.     

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.     

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.     

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.     

Preparation, characterization, and antitumor activity of new cisplatin analogs with homopiperazines: crystal structure of [PtII(1-methylhomopiperazine)(methylmalonato)].2H2O

A series of new platinum(II) and (IV) complexes with homopiperazine have been synthesized and characterized by elemental analysis, infrared, and 195Pt nuclear magnetic resonance spectroscopic techniques. The complexes are of two types: [PtIILX] (where L = homopiperazine (hpip), 1-methylhomopiperazine (mhpip), or 1,4-dimethylhomopiperazine (dmhpip), and X = 1,1-cyclobutanedicarboxylato (CBDCA), or methylmalonato ligand) and [PtIV(L-)trans-(Y)2Cl2] (where Y = hydroxo, acetato, or chloro ligand). Among the complexes synthesized, the crystal structure of [PtII(mhpip)(methylmalonato)].2H2O was determined by the single crystal X-ray diffraction method. The crystallographic parameters were orthorhombic, P2(1)2(1)2(1) (no. 19), a = 7.2014(14), b = 7.3348(15), c = 26.971(5) A, and Z = 4. The structure refinements converged to R1 = 0.0641 and wR2 = 0.1847. In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogens of the mhpip ligand, whereas the remaining cis positions are coordinated with two oxygen atoms of the methylmalonato group. The mhpip ligand is in a boat conformation and forms five and six membered chelating rings with platinum. The intricate network of intermolecular hydrogen bonds holds the crystal lattice together. Some of these synthesized cisplatin analogs have good in vitro cytotoxic activity against the cisplatin-sensitive human ovarian A2780 (IC50 = 0.083-17.8 microM) and the isogenic cisplatin-resistant 2780CP (IC50 = 20.1-118.1 microM) cell lines.     

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.     

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.     

Antitumor dinuclear platinum(II) complexes derived from a novel chiral ligand

A new chiral ligand, 2-(((1R,2R)-2-aminocyclohexyl)amino)acetic acid (HL), was designed and synthesized to prepare a series of novel dinuclear platinum(II) complexes with dicarboxylates or sulfate as bridges. The evaluation of these metal complexes in vitro cytotoxicity against human HCT-116, MCF-7 and HepG-2 cell lines were made. All compounds showed antitumor activity to HCT-116 and MCF-7. Particularly, compounds M3 and M5 not only exhibited better activity than carboplatin against MCF-7 and HepG-2, but also showed very close activity to oxaliplatin against HCT-116.     

Cis-platinum (II) complexes of carboxymethyl-dextran as potential antitumor agents. II. In vitro and in vivo activity

Cis-diamminedichloro platinum (II) (cis-DDP) and cis-diamminediaquo platinum (II) nitrate (cis-aq) were complexed to a macromolecular carrier carboxymethyl dextran (CM-dex). Two carriers were used in this study, one derived from dex-T-10 (Mr-10000) and the other from dex-T-40 (Mr-40000). The two platinum (II) drugs formed soluble complexes with both carriers. Uncomplexed and complexed drugs were tested and found to be cytotoxic in vitro against 5 murine and 2 human derived tumor cell lines. The two free platinum (II) drugs were cytotoxic against these cells to a similar extent. In comparison to the free drugs the complexes were somewhat less active, up to 3 fold, against murine 38C-13, L1210, EL-4 and RDM-4 leukemias, as well as against human HeLa and osteogenic sarcoma, and as active as the free drugs against murine F9 embryonal carcinoma. There were no major differences in the in vitro cytotoxic activity between CM-dex T-10 and CM-dex T-40 complexes. Differences due to the molecular size of the carrier were observed in vivo: The CM-dex T-10 complexes were significantly less toxic than the free drugs, whereas the reduction of toxicity by complexing to CM-dex T-40 was less profound. As for the efficacy, when tested in vivo against a cis-DDP sensitive tumor (F9) the T-40 complexes were equally or even more effective than the respective free drugs. The T-10 complexes were less effective than the free drugs at equal drug doses but their effectivity increased at increasing drug levels. These complexes were, however, very effective in inhibiting tumor growth upon repeated injections, leading to 100% survival.     

Design,synthesis and biological evaluation of six dinuclear platinum(II) complexes

Six dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1′R,2R,2′R)-N¹,N^1′-(1,4-phenylenebis(methylene))dicyclohexane-1,2-diamine, have been designed, synthesized and characterized. In vitro cytotoxicity evaluation of these metal complexes against human A549, HCT-116, MCF-7 and HepG-2 cell lines have been carried out. All compounds showed antitumor activity to HepG-2, HCT-116 and A549. Particularly, compounds A1 and A2 exhibited significant better activity than other four compounds and A2 even showed comparable cytotoxicity to cisplatin against HepG-2 cell line.     

2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design,synthesis, and antitumor activity

Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1’s substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.     

Antitumor activity of phenylene bridged binuclear bis(imino-quinolyl)palladium(II) and platinum(II) complexes

Antitumor effects of a known bis(imino-quinolyl)palladium(II) complex 1 and its newly synthesized platinum(II) analogue 2 were evaluated against human breast (MCF-7) and human colon (HT-29) cancer cell lines. The complexes gave cytotoxicity profiles that were better than the reference drug cisplatin. The highest cytotoxic activities were pronounced in complex 2 across the two examined cancer cell lines. Both compounds represent potential active drugs based on bimetallic complexes.     

Platinum(II) complexes with l-methionylglycine and l-methionyl-l-leucine ligands: synthesis, characterization and in vitro antitumoral activity

Four dipeptide complexes of the type [PtX(2)(dipeptide)] x H(2)O (X=Cl, I, dipeptide=l-methionylglycine, l-methionyl-l-leucine) were prepared. The complexes were characterized by (1)H, (13)C, (195)Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, (1)H and (13)C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with (13)C and (195)Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The (1)H NMR spectrum for the platinum(II) complex with l-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DeltaG( not equal)=72 kJ mol(-1) at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with l-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.     

Synthesis and characterization of palladium(II) and platinum(II) complexes with Schiff bases derivatives of 2-pyridincarboxyaldehyde. Study of their interaction with DNA

Several Schiff bases ligand derivatives of 2-pyridincarboxyaldehyde and different amines, together with their palladium(II) and platinum(II) complexes have been synthesised and characterised. The aim of this study is to probe the influence of substituents beared on the pyridyl/toulene ring at different position to their possible antitumor activity. The amines used were o-, m-, p-toluidine and 4-hydroxyaniline. All the compounds were characterised by elemental analysis, FT-IR spectroscopy, 1H and 195Pt NMR spectroscopy and matrix assisted laser desorption/ionization time-of-flight mass spectroscopy. The formation of DNA adducts were analysed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the compounds with plasmid DNA pBR322 were also obtained. In all cases changes in the second and tertiary structure of DNA could be observed as a consequence of the covalent interaction of the palladium(II) or platinum(II) ions with the N of the nucleobases. However, there are not significant differences in the behavior of the complexes related to the position of the methyl groups or the presence of the OH group. Values of IC50 were also calculated for the platinum(II) complexes for several pairs of ovarian tumor cell lines which were either sensitive or resistant to cisplatin. Finally in vitro apoptosis studies for platinum(II) complexes with ovarian tumor cell lines A2780/A2780cisR were carried out. The results indicated interesting antiproliferative activity and significant apoptosis induction.     

Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes

Five dinuclear platinum(II) complexes with a novel chiral ligand, 2-(((1R,2R)-2-aminocyclohexylamino)methyl)phenol (HL), were designed, prepared and spectrally characterized. In vitro cytotoxicity of all the resulting platinum(II) compounds was evaluated against human HEPG-2, A549 and HCT-116 cell lines, respectively. Results indicated that all compounds showed positive biological activity. Particularly, compound D4 has lower IC₅₀ values than carboplatin toward HEPG-2 and A549, while compound D5 shows better activity than carboplatin against A549.     

Synthesis of 17beta-estradiol platinum(II) complexes: biological evaluation on breast cancer cell lines

The synthesis of a novel series of 17beta-estradiol-linked platinum(II) complexes is described. The new molecules are linked with an alkyl chain at position 16alpha of the steroid nucleus and bear a 16beta-hydroxymethyl side chain. They are made from estrone in five chemical steps with an overall yield exceeding 28%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast cancers. The derivatives incorporating a 2-(2'-aminoethyl)pyridine ligand displayed good activity against the cell lines particularly when the connecting arm is 10 carbon atoms long.     

Novel cyclopalladated and coordination palladium and platinum complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazones): structural studies and cytotoxic activity against human A2780 and A2780cisR carcinoma cell lines

The preparation of new palladium(II) and platinum(II) complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazone), 1, and alpha-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies (IR, (1)HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC(50) values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.     

Synthesis and cytotoxic activities of estrone and estradiol cis-dichloroplatinum(II) complexes

Sixteen platinum(II) complexes of estrone and estradiol were synthesized in this work to evaluate their cytotoxic activity against several cancer cell lines including estrogen dependent and independent ones. The synthesis of all the complexes was done in three steps. The reaction of steroids with dibromoalkanes was followed by a reaction of the bromoalkyl steroids with 2-(aminomethyl)pyridine or 2-(2-aminoethyl)pyridine. The last step was a reaction of steroidal diamino ligands with potassium tetrachloroplatinate to obtain the desired platinum(II) complexes. Cytotoxicity assays showed that most of the complexes prepared are active against the cancer cell lines used—CEM, U-2 OS, MCF7, MCF7 AL, MDA-MB-468, BT-474, BT-549, and BJ fibroblasts. The six-membered platinum complexes are more active than five-membered ones.     

Relevance of the leaving group for antitumor activity of new platinum(II) compounds containing anthracene derivatives as a carrier ligand

A new anticancer-active platinum(II) compound [Pt(A9pyp)(dmso)(cbdca)], containing the E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone ligand (abbreviated as A9pyp) has been synthesized by the replacement of the anionic chloride ligands in cis-[Pt(A9pyp)(dmso)Cl₂] by the dianionic chelating cyclobutanedicarboxylate ligand (abbreviated as cbdca). The in vitro relevance of the leaving group of these new platinum(II) compounds has been investigated. Measurements of the time-dependent intracellular accumulation of both compounds in human ovarian carcinoma cell lines show that the leaving group affects their cellular uptake. In addition, the leaving group also influences DNA platination, and, therefore, has an effect on the biological activity against a pair of human ovarian carcinoma cell lines, i.e. sensitive and resistant to cisplatin.