Anticancer Platinum Complexes Research Articles

Pharmacokinetics of miriplatin in experimental dog models of hepatic or renal impairment

Miriplatin is an anticancer platinum complex for treatment of hepatocellular carcinomas by intra-hepatic arterial injection suspended in an iodinated ethyl ester of fatty acids from poppy seed oil as a carrier. Effects of liver and kidney function on( 14)C-miriplatin pharmacokinetics were assessed using dog models of hepatic and renal impairment introduced by thioacetamide exposure and 7/8 nephrectomy, respectively. Miriplatin was selectively delivered to the liver; platinum and radioactive component were gradually released into systemic circulation and excreted into urine. Microautoradiographic analysis of liver specimens showed( 14)C-miriplatin to be localized in blood vessels and/or macrophage-like cells. These features of miriplatin disposition were not affected by hepatic impairment. Thus, in clinical settings, hepatic impairment would not be expected to affect the intra-hepatic distribution and systemic pharmacokinetics of miriplatin. In dogs with renal impairment, although inconclusive, plasma concentrations of ultrafilterable platinum and radioactivity increased due to reduction in renal clearance.

Comparison of the effects of the oral anticancer platinum(IV) complexes oxoplatin and metabolite cis-diammine-tetrachlorido-platinum(IV) on global gene expression of NCI-H526 cells.

Platinum(IV) coordination complexes like oxoplatin (cis,cis,trans-diammine-dichlorido-dihydroxido-platinum[IV]) show high stability and therefore can be utilized orally for outpatient care. Although oxoplatin is capable of binding directly to DNA after prolonged incubation, platinum(IV) agents are considered to be largely inert prodrugs that are converted to highly cytotoxic platinum(II) compounds by reducing substances, enzymes, or microenviron-mental conditions. Reaction of oxoplatin with 0.1 M hydrogen chloride mimicking gastric acid yields cis-diammine-tetrachlorido-platinum(IV) (DATCP[IV]), which exhibits two-fold increased activity. The presence of chlorides as ligands in the axial position results in a high reduction potential that favors transformation to platinum(II) complexes. In this study, the intracellular effect of the highly reactive tetrachlorido derivative was investigated in comparison with an equipotent dose of cisplatin. Genome-wide expression profiling of NCI-H526 small cell lung cancer cells treated with these platinum species revealed clear differences in the expression pattern of affected genes and concerned cellular pathways between DATCP(IV) and cisplatin. Application of DATCP(IV) resulted in extensive downregulation of protein and ATP synthesis, cell cycle regulation, and glycolysis, in contrast to cisplatin, which preferentially targeted glutathione conjugation, pyruvate metabolism, citric acid cycle, and the metabolism of amino acids and a range of carbohydrates. Thus, the oxoplatin metabolite DATCP(IV) constitutes a potent cytotoxic derivative that may be produced by gastric acid or acidic areas prevailing in larger solid tumors, depending on the respective pharmaceutical formulation of oxoplatin. Furthermore, DATCP(IV) exhibits intracellular effects that are clearly different from the expected reduced product cisplatin(II). In conclusion, activation of the platinum(IV) complex oxoplatin seems to involve the generation of a cytotoxic six-coordinate species, dependent on prevailing conditions, and its effects need to be considered in addition to the effects of the potential final platinum(II) product.

ChemInform Abstract: Activating Platinum Anticancer Complexes with Visible Light.

AbstractReview: 17 refs.

Activating Platinum Anticancer Complexes with Visible Light

The next generation: Classical PtII anticancer compounds contain cis diam(m)ine ligands and are activated by ligand-substitution reactions. PtIV diam(m)ine diazido dihydroxo complexes are nontoxic to cells until activated by light. Replacement of the diam(m)ine ligands in a trans configuration by pyridine gives a complex that is potently cytotoxic when irradiated with visible light and which has potential as a photochemotherapeutic agent.

A Potent Trans‐Diimine Platinum Anticancer Complex Photoactivated by Visible Light

Activating platinum with light: An inert platinum(IV) diazido complex trans, trans,trans-[Pt(N3)2(OH)2(py)2] becomes potently cytotoxic to cancer cells when activated by low doses of visible light.

A Potent Trans‐Diimine Platinum Anticancer Complex Photoactivated by Visible Light

Platin mit Licht aktiviert: Der inerte PtIV-Diazidokomplex trans,trans,trans- [Pt(N3)2(OH)2(py)2] verwandelt sich bei der Bestrahlung mit geringen Dosen sichtbaren Lichts in einen potenten zytotoxischen Wirkstoff gegen Krebszellen. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Determination of the kinetic profile of a dinuclear platinum anticancer complex in the presence of sulfate: introducing a new tool for the expedited analysis of 2D [(1)H,( 15)N] HSQC NMR spectra.

Two-dimensional (2D) [(1)H, (15)N] heteronuclear single-quantum coherence (HSQC) NMR experiments of the kinetics of aquation and sulfation of the dinuclear platinum anticancer complex [{trans-PtCl(NH(3))(2)}(2)(μ-NH(2)(CH(2))(6)NH(2))](2+) (1,1/t,t, 1) in 15 mM sulfate solution are reported using conditions (298 K, pH 5.4) identical to those previously used for other anionic systems (phosphate and acetate), allowing for a direct comparison. Sulfate is the fourth most abundant anion in human plasma. The rate constant for the aquation step (k(H)) is higher than that previously found in the presence of phosphate, but the anation rate constants are similar. The rate constant for sulfate displacement of the aqua ligand (k(L)) is approximately three times higher than that of phosphate, and a further major difference between these two anions is the very high k(-L) for loss of sulfate, suggesting that when formed in plasma the sulfato species will be substitution labile. We also introduce a novel (free) plug-in, '2D NMR analysis', developed for the expedited integration and analysis of 2D [(1)H, (15)N] HSQC NMR spectra. We have found that this plug-in significantly reduces the amount of time taken in the analysis of experiments with no loss to the quality of the data.

Comparative study of the hydrolysis of a third- and a first-generation platinum anticancer complexes

The hydrolysis of cis-[Pt(NH3)2Cl2] (cisplatin) and of the third-generation platinum anticancer compound (cis-[PtCl2(NH3)-(2-picoline)] (picoplatin) has been studied quantum-mechanically using density functional theory (mPW1PW91). Due to its asymmetry, picoplatin is an interesting case, since hydrolysis may proceed through two distinct reaction paths and with the entering water molecule sin or anti to the methyl group of 2-picoline. Solvent effects were taken into account either by applying the polarizable continuum model (PCM) solvent approach or by introducing a cluster of water molecules solvating the complex. With the PCM approach, it emerges that the steric hindrance of 2-picoline has a minimum impact on the activation barriers for picoplatin hydrolysis, since the water molecule approach is far from being axial and far from the methyl group. Accordingly, the TS state geometry with 5-coordinated platinum is not significantly more distorted than in the cisplatin case. Our results point out that the use of separated reactants as reference for energy barrier gives satisfactory results for each compound and produces correct relative magnitudes of first and second hydrolysis rate constants for each compound. However, this model is not able to predict the generally faster hydrolysis experimentally observed for cisplatin with respect to picoplatin. The study of the first hydrolysis step for the two compounds in the presence of explicit water molecules shows that the entering water molecule is strongly interacting with the others through a complex hydrogen bond network. The discrete solvation model is able to correctly predict a slightly slower hydrolysis of picoplatin highlighting the need of explicit solvation to predict small differences (within an order of magnitude) in the observed rate constants.

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 142μM and 18nM 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.

ChemInform Abstract: Platinum—DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Anticancer Platinum Complexes as Non‐Innocent Compounds for Catalysis in Aqueous Media.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The first example of MEEKC-ICP-MS coupling and its application for the analysis of anticancer platinum complexes.

MEEKC is a powerful electrodriven separation technique with many applications in different disciplines, including medicinal chemistry; however, up to now the coupling to highly sensitive and selective MS detectors was limited due to the ion suppressive effect of the commonly used surfactant SDS. Herein, the first example of the coupling of MEEKC to ICP-MS is presented and an MEEKC method for the separation of Pt(II) and Pt(IV) anticancer drugs and drug candidates was developed. Different compositions of microemulsions were evaluated and the data were compared with those collected with standard ultraviolet/visible (UV/vis) spectroscopy detection. The MEEKC-ICP-MS system was found to be more sensitive than MEEKC-UV/vis and the analysis of UV/vis silent compounds is now achievable. The migration behavior of the Pt(II) and Pt(IV) compounds under investigation is correlated to their different chemical structures.

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Platinum-based compounds are widely used as chemotherapeutics for the treatment of a variety of cancers. The anticancer activity of cisplatin and other platinum drugs is believed to arise from their interaction with DNA. Several cellular pathways are activated in response to this interaction, which include recognition by high-mobility group and repair proteins, translesion synthesis by polymerases, and induction of apoptosis. The apoptotic process is regulated by activation of caspases, p53 gene, and several proapoptotic and antiapoptotic proteins. Such cellular processing eventually leads to an inhibition of the replication or transcription machinery of the cell. Deactivation of platinum drugs by thiols, increased nucleotide excision repair of Pt-DNA adducts, decreased mismatch repair, and defective apoptosis result in resistance to platinum therapy. The differences in cytotoxicity of various platinum complexes are attributed to the differential recognition of their adducts by cellular proteins. Cisplatin and oxaliplatin both produce mainly 1,2-GG intrastrand cross-links as major adducts, but oxaliplatin is found to be more active particularly against cisplatin-resistant tumor cells. Mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these two agents. This review describes the formation of Pt-DNA adducts, their interaction with cellular components, and biological effects of this interaction.

Anticancer platinum complexes as non-innocent compounds for catalysis in aqueous media

An efficient cyclization of alkyne-acids to enol-lactones catalyzed by anticancer platinum(II) and platinum(IV) compounds is described. These compounds are not only DNA-binding complexes; they can also catalyze reactions in solvents such as acetone, methanol, water or blood plasma.

New reactions of anticancer-platinum complexes and their intriguing behaviour under various experimental conditions

The anticancer platinum complexes here described react with organic substrates (such as acids, alkenes, alkynes) and catalyze transformations that can occur in biomolecules which contain unsaturated functions. We have analyzed the role of the platinum complexes in the observed reactions and studied the progress of the detected transformations upon variation of the reaction conditions.

Factors Affecting DNA–DNA Interstrand Cross‐Links in the Antiparallel 3′–3′ Sense: A Comparison with the 5′–5′ Directional Isomer

Reported herein is a study of the unusual 3'-3' 1,4-GG interstrand cross-link (IXL) formation in duplex DNA by a series of polynuclear platinum anticancer complexes. To examine the effect of possible preassociation through charge and hydrogen-bonding effects the closely related compounds [{trans-PtCl(NH(3))(2)}(2)(mu-trans-Pt(NH(3))(2){NH(2)(CH(2))(6)NH(2)}(2))](4+) (BBR3464, 1), [{trans-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (BBR3005, 2), [{trans-PtCl(NH(3))(2)}(2)(mu-H(2)N(CH(2))(3)NH(2)(CH(2))(4))](3+) (BBR3571, 3) and [{trans-PtCl(NH(3))(2)}(2){mu-H(2)N(CH(2))(3)-N(COCF(3))(CH(2))(4)}](2+) (BBR3571-COCF(3), 4) were studied. Two different molecular biology approaches were used to investigate the effect of DNA template upon IXL formation in synthetic 20-base-pair duplexes. In the "hybridisation directed" method the monofunctionally adducted top strands were hybridised with their complementary 5'-end labelled strands; after 24 h the efficiency of interstrand cross-linking in the 5'-5' direction was slightly higher than in the 3'-3' direction. The second method involved "postsynthetic modification" of the intact duplex; significantly less cross-linking was observed, but again a slight preference for the 5'-5' duplex was present. 2D [(1)H, (15)N] HSQC NMR spectroscopy studies of the reaction of [(15)N]-1 with the sequence 5'-d{TATACATGTATA}(2) allowed direct comparison of the stepwise formation of the 3'-3' IXL with the previously studied 5'-5' IXL on the analogous sequence 5'-d(ATATGTACATAT)(2). Whereas the preassociation and aquation steps were similar, differences were evident at the monofunctional binding step. The reaction did not yield a single distinct 3'-3' 1,4-GG IXL, but numerous cross-linked adducts formed. Similar results were found for the reaction with the dinuclear [(15)N]-2. Molecular dynamics simulations for the 3'-3' IXLs formed by both 1 and 2 showed a highly distorted structure with evident fraying of the end base pairs and considerable widening of the minor groove.

The Rational Design of Anticancer Platinum Complexes: The Importance of the Structure-Activity Relationship

The ideal drug discovery process of new platinum based drugs should take into account three basic fundaments: on one side the mechanisms of action and the corresponding target biomolecules, on the other side, the possible mechanisms of resistance of cancer cells and their biochemical pathways and, finally, the pharmacokinetic and toxicity properties (ADMET) that will condition the clinical usefulness of the new drugs. At the end of this rational process always we face the necessity to design a molecule with a structure and certain physical and chemical properties. The structure is then a key fundamental issue when thinking of new anticancer platinum compounds. When analyzing the influence of molecular structure on anticancer activity it is useful to make the dissection of platinum complexes into different significant subunits or moieties, of the molecular structure. Thus, the following structural and electron dependent parameters are important to facilitate the comparison among platinum complexes: a) Nature of the non-labile ligand or carrier ligand (NLG); b) Nature of the labile ligand or leaving group (LG); c) Oxidation state of platinum atom; d) Type of atoms (connecting atoms X, Y, Z, W) that link ligands to platinum atom; e) Nature of the axial groups (AG) in platinum(IV) complexes; f) Nuclearity or number of Pt atoms in the platinum complexes; g) Formal charges present in the molecule and h) Intrinsic bioactivity of some ligands or bioactivity induced by molecules attached to ligands by linkers (in order to get a double mechanism of action or a parallel biological activity).

Transferring the Concept of Multinuclearity to Ruthenium Complexes for Improvement of Anticancer Activity

Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.

A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery

Single crystal and powder X-ray diffraction have been used to examine the host-guest complex of cucurbit[7]uril (CB[7]) and the model dinuclear platinum anticancer complex trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt, dpzm= 4,4'-dipyrazolylmethane). The single crystal structure shows that the host-guest complex forms with the di-Pt dpzm ligand within the CB[7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB[7] carbonyls. Each host-guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]-di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB[7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB[7] and the CB[7]-di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160 degrees C. The DSC results showed that the free dpzm ligand melts between 186 and 199 degrees C, with a standard enthalpy of fusion of 27.92 kJ mol(-1). As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290 degrees C. Encapsulation by CB[7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 degrees C.

Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism.

The impressive impact of cisplatin on cancer on one side and severe side effects, as well as the development of drug resistance during treatment on the other side, were the factors motivating scientists to design and synthesize new more potent analogues lacking disadvantages of cisplatin. Platinum(IV) complexes represent one of the perspective groups of platinum-based drugs. In this review, we summarize recent findings on both in vitro and in vivo effects of platinum(IV) complexes with adamantylamine. Based on a literary overview of the mechanisms of activity of platinum-based cytostatics, we discuss opportunities for modulating the effects of novel platinum complexes through interactions with apoptotic signaling pathways and with cellular lipids, including modulations of the mitochondrial cell death pathway, oxidative stress, signaling of death ligands, lipid metabolism/signaling, or intercellular communication. These approaches might significantly enhance the efficacy of both novel and established platinum-based cytostatics.