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The protein binding rates (PBR) of platinum‐containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L‐OHP) have been reported as 98%, 25–50% and 98%, respectively. To investigate the protein‐binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP‐MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin‐binding on albumin in vitro, using CD spectrometry and native‐polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60–70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin. [ABSTRACT FROM AUTHOR]

Abstract: Here, we used circular dichroism (CD) and fluorescence microscopy (FM) to examine the interactions of a series of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]n+ (R=CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), CH2COO− (4), n=2 (1–3) or 1 (4)), which are derivatives of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y), with DNA to elucidate the influence of these interactions on the secondary or higher-order structure of DNA and reveal the mechanism of action. The CD study showed that three derivatives, 1–3, with a double-positive charge altered the secondary structures of calf thymus DNA but that 4, the only complex with a single positive charge, induced almost no change, implying that the B- to C-form conformational change is influenced by ionic attraction. Unexpectedly, single-molecule observations with FM revealed that 4 changed the higher-order structure of T4 DNA into the compact-globule state most efficiently, at the lowest concentration, which was nearly equal to that of 5-H-Y. These contradictory results suggest that secondary structural changes are not necessarily linked to higher-order ones, and that the non-coordinative interaction could be divided into two distinct interactions: (1) ionic attraction and (2) hydrogen bonding and/or van der Waals contact. The relationship between diffusion-controlled non-coordinative DNA interactions and cytotoxicities is also discussed. [Copyright &y& Elsevier]

Abstract: In order to reveal the solvolysis reactions of dinuclear ruthenium(II)-2,2′-bipyridine complexes with various bridged-ligands (BL), [{RuCl(bpy)2}2(μ-BL)]2+ ([Ru2Cl2-BL]2+), we have studied the kinetics of these complexes in H2O and H2O–dmso (1:1 v/v). In H2O–dmso (1:1 v/v), time-course UV–Vis absorption and IR spectra indicate that the labile Cl− ligands of [Ru2Cl2-BL]2+ are successively substituted by H2O followed by dmso, [{Ru(dmso-S)(bpy)2}2(μ-BL)]4+. Cytotoxicity assays of dinuclear ruthenium(II) complexes were performed in L1210 murine leukemia cell line. [Ru2Cl2-BL]2+ complexes exhibit much lower cytotoxicity compare to cisplatin. However, [{Ru(dmso-S)(bpy)2}2(μ-BL)]4+ complexes produced in H2O–dmso are found to much more cytotoxic than [Ru2Cl2-BL]2+ and in particular the cytotoxicity of [{Ru(dmso-S)(bpy)2}2(μ-dado)]4+ (dado=1,12-diaminododecane) is comparable to that of cisplatin. [Copyright &y& Elsevier]

We investigated the effects of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N¹,N²)]2+ (1) and [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N²,N³)]2+ (2) on the higher-order structure of a large DNA molecule (T4 phage DNA, 166 kbp) in aqueous solution through single-molecule observation by fluorescence microscopy. Complexes 1 and 2 cause irreversible compaction of DNA through an intermediate state in which coil and compact parts coexist in a single DNA molecule. The potency of compaction is in the order 2 > 1 ⪢ cisplatin. Transmission electron microscopic observation showed that both complexes collapsed DNA into an irregularly packed structure. Circular dichroism measurements revealed that the dinuclear platinum(II) complexes change the secondary structure of DNA from the B to C form. These characteristics of platinum(II) complexes are markedly different from those of the usual condensing agents such as spermidine(3+) and [CoIII(NH3)6]3+. The ability to cause DNA compaction by the platinum(II) complexes is discussed in relation to their potent antitumor activity. [ABSTRACT FROM AUTHOR]

It is known that a 1,2,3-triazolato-bridged dinuclear platinum(II) complex, [{ cis-Pt(NH3)2}2(µ-OH)(µ-1,2,3-ta- N1, N2)](NO3)2 (AMTA), shows high in vitro cytotoxicity against several human tumor cell lines and circumvents cross-resistance to cisplatin. In the present study, we examined a dose- and time-dependent effect of AMTA on the higher-order structure of a large DNA, T4 phage DNA (166 kbp), by adapting single-molecule observation with fluorescence microscopy. It was found that AMTA induces the shrinking of DNA into a compact state with a much higher potency than cisplatin. From a quantitative analysis of the Brownian motion of individual DNA molecules in solution, it became clear that the density of a DNA segment in the compact state is about 2,000 times greater than that in the absence of AMTA. Circular dichroism spectra suggested that AMTA causes a transition from the B to the C form in the secondary structure of DNA, which is characterized by fast and slow processes. Electrophoretic measurements indicated that the binding of AMTA to supercoiled DNA induces unwinding of the double helix. Our results indicate that AMTA acts on DNA through both electrostatic interaction and coordination binding; the former causes a fast change in the secondary structure from the B to the C form, whereas the latter promotes shrinking in the higher-order structure as a relatively slow kinetic process. The shrinking effect of AMTA on DNA is attributable to the possible increase in the number of bridges along a DNA molecule. It is concluded that AMTA interacts with DNA in a manner markedly different from that of cisplatin. [ABSTRACT FROM AUTHOR]

Abstract: It has recently become clear that a long DNA with a size of more than several tens of kilo base-pairs (kbp) exhibits a large on/off change in conformation between elongated coil and folded compact states. To explore the possible effect of anticancer drugs on the conformation of large DNA, we observed single DNA molecules with regard to changes in their higher-order structure upon the addition of cisplatin and its derivatives, diamminedinitratoplatinum(II) and tetrammineplatinum(II). We found that these cisplatin analogues significantly affected the conformation of individual DNA molecules by inducing a folding transition. [Copyright &y& Elsevier]

Abstract: To develop a solid catalyst which can be a model of catechol oxidase and/or catecholamine monoamine oxidase, the ion-exchange resins modified with metal-tetrakis(4-sulfophenyl)porphine (M-TSPP wherein M is Mn3+, Co3+, Fe3+ or Cu2+) were examined for a catalytic activity in the oxidative reaction of epinephrine (adrenaline, Ad). Among M-TSPP-modified resins (M-TSPPrs), Mn-TSPPr exhibited the strongest catalytic activity in the oxidation of Ad with O2 in the air to adrenochrome and adrenolutin. Mn-TSPP had little catalytic activity in an aqueous solution of Ad. The optimum conditions for the oxidation reaction catalyzed by Mn-TSPPr were determined. Oxidation of catecholamines and related compounds thereof were conducted under the optimum conditions thus determined, which revealed that Mn-TSPPr only catalyzes oxidation of catecholamines. [Copyright &y& Elsevier]

Abstract: Background: Urinary excretion of desmosine has been reported to be increased in patients with pulmonary fibrosis; however, several investigators have pointed out that measuring urinary desmosine is not a very useful indicator of lung wall destruction. We developed a sensitive time-resolved fluoroimmunoassay (TR-FIA) to identify trace amounts of desmosine in bronchoalveolar lavage fluid (BALF), and applied this method to analyze BALF samples from healthy subjects and patients with interstitial lung diseases. Methods: In the proposed TR-FIA, a polystyrene strip was coated with desmosine-conjugated gelatin. The strip was then incubated with rabbit anti-desmosine antibody and the test solution. The desmosine bound to the solid phase and free desmosine in the sample or standard solution were allowed to compete to bind to the anti-desmosine. The solid-phase antibody was detected by Eu-complex conjugated anti-rabbit IgG. Results: The detectable limit of desmosine was 50 fmol/ml in the TR-FIA developed in this study. TR-FIA showed low cross-reactivity against amino acids. BALF desmosine levels were significantly higher in patients with idiopathic pulmonary fibrosis and sarcoidosis compared with healthy subjects. Conclusions: Desmosine levels in BALF may be useful to investigate lung disease. [Copyright &y& Elsevier]

We describe a 1.2 Å X-ray structure of a double-stranded B-DNA dodecamer (the Dickerson Dodecamer, DDD, [d(CGCGAATTCGCG)]2) associated with a cytotoxic platinum(lI) complex, [{trans-Pt- (NH3)2(NH2(CH2)6(NH3+)}2-μ-{ trans-Pt(NH3)2(NH2(CH2)6NH2)2}] (TriplatinNC). TriplatinNC is a multifunctional DNA ligand, with three cationic Pt(ll) centers, and directional hydrogen bonding functionalities, linked by flexible hydrophobic segments, but without the potential for covalent interaction. TriplatinNC does not intercalate nor does it bind in either groove. Instead, it binds to phosphate oxygen atoms and thus associates with the backbone. The three square-planar tetra-am(m)ine Pt(ll) coordination units form bidentate N-O-N complexes with OP atoms, in a motif we call the Phosphate Clamp. The geometry is conserved among the 8 observed phosphate clamps in this structure. The interaction appears to prefer 02P over 01 P atoms (frequency of interaction is 02P > 01P, base and sugar oxygens > N). The high repetition and geometric regularity of the motif suggests that this type of Pt(ll) center can be developed as a modular nucleic acid binding device with general utility. TriplatinNC extends along the phosphate backbone, in a mode of binding we call ‘Backbone Tracking’ and spans the minor groove in a mode of binding we call ‘Groove Spanning’. Electrostatic forces appear to induce modest DNA bending into the major groove. This bending may be related to the direct coordination of a sodium cation by a DNA base, with unprecedented inner-shell (direct) coordination of penta-hydrated sodium at the 06 atom of a guanine. [ABSTRACT FROM AUTHOR]

Examines the isomerization on interaction of antitumor-active azole. Reactions of the dinuclear platinum with spectroscopy; Applicability of cisplatin in tumors; Geometry of the crystal structure.

Discusses the synthesis, characterization, crystal structures and cytotoxic studies of an antitumor-active azole-bridged dinuclear platinum(II) complexes. Characterization by solution NRM study; X-ray crystal structures; Cytotoxicity studies; Structure-activity relationships.

• Unusual intraligand substitution of N3 for N2 of 1,2,3-triazolate. • Pt(II) migration related to the mechanism of action of the dinuclear Pt(II) compounds. • Dimerization reaction to yield a unique tetranuclear Pt(II) compound. • Presented importance of 1,2,3-triazolate derivatives as a tridentate building block. The reaction of the anticancer azolato-bridged dinuclear platinum(II) compound [{ cis -Pt(NH 3) 2 } 2 (µ-OH)(µ-1,2,3-triazolato- N1 , N2)](NO 3) 2 (AMTA) in 0.2 M DCl-D 2 O solution was monitored at 298 K using 1H NMR spectroscopy. Acid hydrolysis of AMTA first provided a dinuclear Pt(II) cationic species [{ cis -Pt(NH 3) 2 Cl} 2 (µ-1,2,3-triazolato- N1 , N2)]+ (intermediate A) which then turned into [{ cis -Pt(NH 3) 2 Cl} 2 (µ-1,2,3-triazolato- N1 , N3)]+ (intermediate B) by migration of a Pt(II) ion, initially bound to N2, to N3. Hence, intramolecular ligand substitution of N3 for N2 occurred after substitution of two chloride ligands for the hydroxido bridge. Under the reaction conditions, the intermediate A and B were unambiguously detected, and both or either of the intermediate species then dimerized by a substitution of the chlorido ligand by N3 or N2 of a partner molecule to yield an unprecedented tetranuclear Pt(II) compound [{ cis -Pt(NH 3) 2 Cl}µ-{ cis -Pt(NH 3) 2 } 2 (µ-1,2,3-triazolato- N2 , N3) 2 - N1 , N1′ ]Cl 2 (NO 3) 2 (compound 1), whose 3D structure has been determined by X-ray crystal analysis. The fact that all triazolate nitrogen atoms coordinated to 3 different Pt(II) ions indicates that 1,2,3-triazolate derivatives could be important as a unique tridentate building block for metal-organic framework. [ABSTRACT FROM AUTHOR]