Platinum Moiety Research Articles

Improved targeting of platinum chemotherapeutics: the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models

AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum–polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O–Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.

Platinum‐Based Anticancer Agents: Innovative Design Strategies and Biological Perspectives

AbstractFor Abstract see ChemInform Abstract in Full Text.

Toward Highly Metallized Polymers: Synthesis and Characterization of Silicon-Bridged [1]Ferrocenophanes with Pendent Cluster Substituents

The acetylide-substituted sila[1]ferrocenophanes [Fe(η-C5H4)2Si(Me)C⋮CR] (R = Ph (2a), nBu (2b)) reacted with [Co2(CO)8], [{MoCp(CO)2}2], or [Ni(cod)2]/L selectively at the triple bond to give pendent organocobalt [Fe(η-C5H4)2Si(Me){Co2(CO)6C2R}] (R = Ph (4a), nBu (4b)) or organomolybdenum [Fe(η-C5H4)2Si(Me){Mo2Cp2(CO)4C2Ph}] (9) clusters or mononuclear organonickel [Fe(η-C5H4)2Si(Me){Ni(L)C2Ph}] (L = dmpe (11), L = dppe (12)) complexes. The bis(acetylide)-substituted sila[1]ferrocenophanes [Fe(η-C5H4)2Si(C⋮CR)2] (R = nBu (6a), Ph (6b)) reacted with [Co2(CO)8] in an analogous fashion, forming the novel pentametallic silicon-bridged [1]ferrocenophanes with two pendent cobalt clusters [Fe(η-C5H4)2Si{Co2(CO)6C2R}2] (R = nBu (7a), R = Ph (7b)). Compound 7b subsequently underwent rapid hydrolytic ring-opening to yield an unusual, highly metallized silanol, [(η-C5H5)Fe(η-C5H4)Si(OH){Co2(CO)6C2Ph}2] (8b). This reaction was found to be much slower for the hexynyl analogue (7a). The organonickel complexes (11 and 12) described in this work represent the first examples of mononuclear complexes prepared directly from an alkyne and [Ni(cod)2]. We postulate that steric factors prevent the addition of a second nickel fragment to the alkyne. The synthesis of a sila[1]ferrocenophane with a pendent platinum moiety was also attempted. However, reaction of 2a with [Pt(PEt3)3] instead gave the platinasila[2]ferrocenophane [Fe(η-C5H4)2Pt(PEt3)2Si(Me)C⋮CPh] (15) via oxidative insertion of the platinum(0) fragment into a strained ipso-cyclopentadienyl carbon−silicon bond of the sila[1]ferrocenophane.

Synthesis and antitumor activity of novel thermosensitive platinum(II)–cyclotriphosphazene conjugates

Thermosensitive cyclotriphosphazenes bearing alkoxy poly(ethylene glycol) and amino acid esters as side groups could be functionalized to chelate the antitumor (diamine)platinum(II) moiety through the dicarboxylate group of the amino acid substituent on the cyclic phosphazene ring. Surprisingly, like the precursor cyclotriphosphazenes, these (diamine)platinum(II)–cyclotriphosphazene conjugates were also found to exhibit variable lower critical solution temperatures (LCST) in the wide range of 12 to 92 °C. Furthermore, the present conjugates have shown outstanding in vitro and in vivo antitumor activities due to controlled release of the antitumor (diamine)platinum(II) moiety with hydrolytic degradation of the phosphazene ring. A few of these conjugates have shown LCSTs below body temperature, and it has been shown from a model animal experiment that the conjugates with a LCST below body temperature may be applied to local drug delivery by direct intratumoral injection.

Platinum-based anticancer agents: innovative design strategies and biological perspectives.

The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA-Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA-Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future.

Folate-targeted PEG as a potential carrier for carboplatin analogs. Synthesis and in vitro studies.

Like most low molecular weight drugs, carboplatin has a short blood circulation time, which reduces tumor uptake and intracellular DNA binding. Drugs conjugated to PEG carriers benefit from prolonged blood circulation, but suffer from reduced cell permeability. In this work we attempted to develop long-circulating PEGylated carboplatin analogues with improved cell permeation abilities, by conjugating the platinum moiety to folate-targeted PEG carriers capable of utilizing the folate receptor-mediated endocytosis (FRME). Two bifunctional FA-PEG conjugates, FA-PEG-Pt and FA-PEG-FITC, were prepared, and their cell uptake, DNA binding, and cytotoxicity were studied by fluorescent microscopy, FACS, and platinum analysis. Folate-targeted PEG conjugates enter the cells efficiently by the FRME pathway but form relatively few DNA adducts and have higher IC(50) values than carboplatin and their nontargeted analogues. Nontargeted PEG-Pt conjugates have a lower cellular uptake but produce higher levels of DNA binding and improved cytotoxicity. Carboplatin, used as a control, has the fastest cellular uptake, but after 16 h of postincubation a large percentage of the drug is excreted from the cells. The findings of this study suggest that folate-targeted conjugates such as FA-PEG-Pt, may not be an optimal prodrug for the carboplatin family compounds, because the conjugates or the active moieties are neutralized or blocked during the FRME process and do not manage to effectively reach the nuclear DNA.

Double Porphyrin Platinum Conjugates

Platinum-containing groups and porphyrins in the same molecule not only show additivity of the dark toxicity of the platinum moiety and the phototoxicity of the porphyrin system but also a selective enrichment of porphyrin platinum conjugates in tumor tissues compared to platinum-only drugs. Porphyrin platinum conjugates containing amino-porphyrin non-leaving groups and porphyrin-carboxylate leaving groups were synthesized and tested with the mammary carcinoma cell line MDA-MB-231.

(Aminoethanol)dichloroplatinum(II) complexes: influence of the hydroxyethyl moiety on 5′-GMP and DNA binding, intramolecular stability, the partition coefficient and anticancer activity

The influence of tethered hydroxyl groups on the binding behavior of the three (aminoethanol)dichloroplatinum complexes, dichloro(N,N′-bis(2-hydroxyethyl)ethylenediamine)-platinum(II) (1), dichloro(N-(2-hydroxyethyl)ethylenediamine)platinum(II) (2) and cis-dichlorobis(2-hydroxyethylamine)platinum(II) (3) towards 5′-GMP and DNA was investigated by 1H NMR and rb measurements, respectively. At pH 7.2, the sequence of reactivity with 5′-GMP is 1>2>>3. Complex 3 reacts very slowly with 5′-GMP and DNA and the amount and lifetime of the intermediate 5′-GMP monoadduct are much larger than for 1 and 2. At pH 5.5, the reaction of 3 with 5′-GMP is markedly accelerated and very small amounts of monoadduct are observed, indicating a pH-dependent ability of the pendant hydroxyl group to interact with the platinum moiety. In addition, the effect of the hydroxyethyl functionality on octanol/water partitioning and in vitro anticancer activity was studied. No correlation between lipophilicity and anticancer activity was detected. Furthermore, the lipophilicity and anticancer activity could not be directly correlated to 5′-GMP or DNA binding activity.

Carboxylation of 2-Hydroxyethyl-Substituted Tetrachloro(ethane-1,2-diamine)platinum(IV) Complexes — A New Synthetic Approach to Anticancer Platinum Compounds

The present study has focused on a general reaction procedure for the derivatization of hydroxyethyl-substituted tetrachloro(ethane-1,2-diamine)platinum(IV) compounds at peripheral hydroxyl groups using acyl chlorides. A new class of platinum(IV) complexes could be synthesized which now opens the possibility for the first time to couple the cytotoxic platinum(IV) moiety to carrier molecules like proteins and antibodies in a very selective way. Moreover, it is now possible to synthesize platinum(IV) complexes with ligands in the equatorial plane which are not very stable in the presence of oxidizing agents.

Strand-specific binding of RPA and XPA to damaged duplex DNA.

The nucleotide excision repair (NER) pathway is a major pathway used to repair bulky adduct DNA damage. Two proteins, xeroderma pigmentosum group A protein (XPA) and replication protein A (RPA), have been implicated in the role of DNA damage recognition in the NER pathway. The particular manner in which these two damage recognition proteins align themselves with respect to a damaged DNA site was assessed using photoreactive base analogues within specific DNA substrates to allow site-specific cross-linking of the damage recognition proteins. Results of these studies demonstrate that both RPA and XPA are in close proximity to the adduct as measured by cross-linking of each protein directly to the platinum moiety. Additional studies demonstrate that XPA contacts both the damaged and undamaged strands of the duplex DNA. Direct evidence is presented demonstrating preferential binding of RPA to the undamaged strand of a duplex damaged DNA molecule.

Formation and cleavage of platinacycles containing a fluorinated imine. Crystal structure of [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)PPh 3

The reaction of [Pt 2Me 4(μ-SMe 2) 2] with the ligand 3,4,5-C 6H 2F 3CHNCH 2C 6H 5 ( L) yielded the cyclometallated platinum(II) compound [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)SMe 2] ( 1), in which the imine acts as a [C,N]-bidentate ligand. Compounds [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)DMSO] ( 2) (DMSO=dimethyl sulfoxide) and [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)PPh 3] ( 3) were obtained from a displacement reaction of SMe 2 for DMSO or PPh 3, respectively. Oxidative addition of methyl iodide to compounds 1– 3 produced, respectively, [PtMe 2I(3,4,5-C 6HF 3CHNCH 2C 6H 5)SMe 2] ( 4a/ 4b) as two isomers, [{PtMe 2I(3,4,5-C 6HF 3CHNCH 2C 6H 5)} 2] ( 5) and [PtMe 2I(3,4,5-C 6HF 3CHNCH 2C 6H 5)PPh 3] ( 6). Platinum(II) metallacycles can be cleaved upon reaction with an excess of PPh 3 or with the diphosphine dppe to yield, respectively, compounds [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)(PPh 3) 2] ( 7) and [PtMe(3,4,5-C 6HF 3CHNCH 2C 6H 5)dppe] ( 8) in which the imine acts as a monodentate [C] ligand. Analogous compounds could not be obtained for platinum(IV) since in this case neither PPh 3 nor dppe can cleave the metallacycle. The reaction of 4a/ 4b with dppe produced [{PtMe 2I(3,4,5-C 6HF 3CHNCH 2C 6H 5)} 2dppe] ( 11), a binuclear compound in which the diphosphine bridges two platinum(IV) moieties with the imine acting as a [C,N]-bidentate ligand. All compounds were characterised by analytical and spectroscopic techniques and compound 3 was also characterised crystallographically.

Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety.

A combination of demethylcantharidin, a modified component of a traditional Chinese medicine (TCM), with a platinum moiety has produced a series of TCM-based platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, which demonstrate selective cytotoxicity toward SK-Hep-1 (human liver) cell line, and circumvention of cross-resistance. The inclusion of demethylcantharidin rendered the compounds highly active as protein phosphatase (PP2A) inhibitors. The new TCM-Pt compounds may possess a novel dual mechanism of antitumor action: inhibition of PP2A and platination of DNA.

Pt-Re small cluster interaction with H2

The interaction of small Pt-Re clusters with H2 is reported here through ab initio multicon-figuration self-consistent field (MC-SCF) calculations, plus extensive multireference configuration interaction (MR-CI), variational and perturbative calculations. These calculations provide a cluster model for the activation of hydrogen by Pt-Re bimetallic catalysts. It was found that the 6S(5d56s2) Re atom ground state needs an important activation to induce very weak capture of separated hydrogen atoms, whereas in the lowest excited states the activation energies are small or zero, with a very reasonable depth of well. The four lowest states of Pt-Re were found to be 4 Σ+, 6Πyz, Σ + and 6Πxz. Pt-Re interaction with H2 has been studied from both metal ‘sides’. It was established that Pt-Re with the platinum side in the ground electronic 4Σ+ state and in the lowest 6Π+ excited states is able to capture H2 molecules without activation, whereas in the 6Πyz and 6Πxz excited states there is no capture. The rhenium side of Pt-Re in its four lowest states considered cannot capture the H2 molecule. The interaction of Pt2-Re with H2 was studied also. For the ground 2B2 electronic state and the low lying 2A1 electronic state the platinum moiety can spontaneously capture and break H2. The rhenium side of Pt2-Re(B2), however, can capture H2 only after surmounting a small barrier, and the excited Pt2-Re(2A1) can spontaneously capture H2. For Pt2-Re in its low lying 4A1 electronic state both metal sides capture and break H2 after surmounting a small barrier.

Second-harmonic generation and absorption spectra of platinum organometallic complexes incorporated in PMMA films

Pt-acetylides with different end-side groups have been synthesized and incorporated in poly(methylmethacrylate) (PMMA) films for second-order nonlinear optics through high-temperature corona-poling. By using two complementary optical techniques, i.e. in-situ second-harmonic generation (SHG) and angle-resolved spectroscopy, the order parameter and the molecular hyperpolarizability β of the chromophores have been characterized inside the polymer matrix. The relaxation of orientational after order poling fits a bi-exponential equation in agreement with the Debye model for guest/host systems. A comparison with the azo-dye Disperse Red 1 (DR1) is discussed within the two-level model and the role of the platinum moiety for conjugated molecules.

Ternary adduct {[W(CN)8]3−,[Pt(en)2]2+,[W(CN)8]3−} in aqueous solution and crystal structure of [Pt(en)2]3[W(CN)8]2·4H2O with infinite linear W · · · Pt chains

A new donor–acceptor system based on [W(CN)8]3− and [Pt(en)2]2+ has been characterised in aqueous solution and in the solid state. Spectroscopic studies indicate formation of the ternary adduct {[W(CN)8]3−,[Pt(en)2]2+,[W(CN)8]3−} in aqueous solution. The aggregate has been described as a mixed-valence species with weak-to-moderate coupling between metal centres. The solid [Pt(en)2]3[W(CN)8]2·4H2O exhibits the simultaneous presence of {WV, PtII, WV} ←→ {WIV, PtIV, WIV} electronic isomers and can be interpreted in terms of ground state borderline electronic localised-to-delocalised species. The structure of [Pt(en)2]3[W(CN)8]2·4H2O consists of one-dimensional infinite chains formed by tungsten and platinum moieties linked through hydrogen bonding from ethane-1,2-diamine nitrogens and water molecules to nitrogens of all cyano ligands.

Synthesis and Antitumor Activity of Polyphosphazene/Methoxy-Poly(ethylene glycol)/(Diamine)platinum(II) Conjugates

The antitumor platinum moiety, (dach)Pt2+ (dach = trans(±)-1,2-diaminocyclohexane), was introduced to a poly(organophosphazene) using dicarboxylate spacers, glutamate or aspartate. After characterization of the polymeric conjugates by means of multinuclear (1H, 31P) NMR spectroscopy, elemental analysis, and gel-permeation chromatography (GPC), their in vitro hydrolytic behavior was examined in buffer solutions at different pHs and temperatures by monitoring with GPC. Hydrolytic properties of the conjugates were dependent on pH and temperature of the polymer solutions, and their degradation occurred more rapidly at lower pH and higher temperature. The antitumor activity of the conjugates was evaluated both in vitro and in vivo against the murine leukemia L1210 cell line and found to be dependent on the structures of the conjugates, and some of them exhibited higher in vivo activity than cisplatin and carboplatin.

NMR solution structure of a DNA dodecamer containing a transplatin interstrand GN7-CN3 cross-link

The DNA duplex d(CTCTCG*AGTCTC).d(GAGAC-TC*GAGAG) containing a single trans- diammine-dichloroplatinum(II) interstrand cross-link (where G* and C* represent the platinated bases) has been studied by two-dimensional NMR. All the exchangeable and non-exchangeable proton resonance lines were assigned (except H5'/H5") and the NOE intensities were transformed into distances via the RELAZ program. By combining the NOESY and COSY data (330 constraints) and NMR-constrained molecular mechanics using JUMNA, a solution structure of the cross-linked duplex has been determined. The duplex is distorted over two base pairs on each side of the interstrand cross-link and exhibits a slight bending of its axis ( approximately 20 degrees ) towards the minor groove. The platinated guanine G* adopts a syn conformation. The rotation results in a Hoogsteen-type pairing between the complementary G(6)* and C(19)* residues which is mediated by the platinum moiety and is stabilized by a hydrogen bond between O6(G(6)*) and N4H(C(19)*). The rise between the cross-linked residues and the adjacent residues is increased owing to the interaction between these adjacent residues and the ammine groups of the platinum moiety. These results are discussed in relation to the slow rate of closure of the monofunctional adducts into interstrand cross-links.

New Concepts Relevant to Cisplatin Anticancer Activity from Unique Spectral Features Providing Evidence That Adjacent Guanines in d(GpG), Intrastrand-Cross-Linked at N7 by a cis-Platinum(II) Moiety, Can Adopt a Head-to-Tail Arrangement

N7−Pt−N7 d(GpG) intrastrand cross-link adducts are formed in DNA by the anticancer drug, cisplatin. By creating adducts with slow dynamic motion, we have identified a new abundant conformer with the guanine bases in a head-to-tail (HT) arrangement and with both sugars in the N pucker of A-form DNA instead of the S pucker of B-form DNA. Both features are unprecedented for such cross-links. The HT form is one of two abundant thermodynamic and kinetic products formed by addition of d(GpG) to [(S,R,R,S)-BipPt(H2O)2]2+ (Bip = 2,2‘-bipiperidine with S, R, R, and S configurations at the asymmetric N, C, C, and N chelate ring atoms). The second form has the common head-to-head conformation (HH1) with the backbone propagating in the normal direction, both G's anti and with N and S puckers for the 5‘- and 3‘-G residues, respectively. This form has a typical NMR shift pattern: upfield 5‘-G H8, downfield 3‘-G H8, and downfield 31P NMR signal. In contrast, the HT (S,R,R,S)-BipPt(d(GpG)) form has several unusual or un...

Synthesis and hydrolytic properties of polyphosphazene/(diamine)platinum/saccharide conjugates

An antitumor (diamine)platinum moiety was introduced to poly(organophosphazene) by using dicarboxylate spacers, glutamate or aspartate. A liver targeting β-galactosyl group was also bound to 5-carboxyl-1-pentoxy residue of poly(organophosphazene) by carboxy activation with mixed anhydride method. After characterization of these polymeric conjugates by means of multinuclear ( 1H, 3 1P) NMR and IR spectroscopies, elemental analysis and gel-permeation chromatography (GPC), their in vitro hydrolytic behavior were measured by monitoring with GPC in sodium acetate buffer solutions. Hydrolytic properties of the conjugates were dependent on pH and temperature. Over 70% of the platinum moiety was released from the conjugates after incubation for 4 days both in acidic and basic buffer solutions whereas the conjugates were stable in the neutral pH solution.

Synthesis of two maleimide derivatives of cis-configurated platinum(II) complexes for the preparation of chemoimmunoconjugates

By attaching maleimide groups to anticancer drugs are obtained which bind selectively to thiolated carrier proteins. Two maleimide ester derivatives of platinum(II) complexes which consist of an active cis-configurated platinum(II) moiety and a maleimide group capable of binding to thiolated carriers were prepared, i.e. N-( O-(3-maleimidobenzoyl)-2-hydrpxyethyl)-1,2-diaminoethanedichloropl atinum(II) ( 7) and N-( O-(2-maleimidophenyl)acetyl)-2-hydroxyethyl)-1,2-diaminoethanedichloroplatinum(II) ( 8), 7, and 8 were characterized through 1H and 11C NMR spectroscopy, IR spectroscopy, elemental analysis and mass spectrometry (FAB).