Azolato-Bridged Dinuclear Platinum(II) Complexes Exhibit Androgen Receptor-Mediated Anti-Prostate Cancer Activity.

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{-Pt(NH)}(μ-OH)(μ-azolato)]X, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling.

Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of Antitumor Activity in Mice.

Tetrazolato-bridged dinuclear platinum(II) complexes ([{-Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-,)]; tetrazolato-bridged complexes) show remarkable cytotoxic effects and antitumor activity . Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH, CFH, or CF), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and antitumor efficacy. Fluorination had a little effect on the properties of the derivatives ; however, marked differences in cytotoxicity and tumor growth inhibition activity were observed.

Data on synthesis and structure-activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes.

In this data file, the synthetic procedures for the preparation of a series of anticancer tetrazolato-bridged dinuclear platinum(II) complexes ([{-Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-2,3)] ( = 1 or 2, tetrazolato-bridged complexes)) and of the bridging ligands of 5-substituted 1-tetrazoles (5-R-1-tetrazoles) are described. These compounds were characterized by H-, C-, F- and Pt-NMR spectroscopy and mass spectrometry.

Different Effects of Cisplatin and Transplatin on the Higher-Order Structure of DNA and Gene Expression.

Despite the effectiveness of cisplatin as an anticancer agent, its trans-isomer, transplatin, is clinically ineffective. Although both isomers target nuclear DNA, there is a large difference in the magnitude of their biological effects. Here, we compared their effects on gene expression in an in vitro luciferase assay and quantified their effects on the higher-order structure of DNA using fluorescence microscopy (FM) and atomic force microscopy (AFM).

Synthesis and structure-activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes: A small modification at tetrazole C5 markedly influences the in vivo antitumor efficacy.

We synthesized and characterized 15 new derivatives of the highly anticancer-active platinum(II) complex [{cis-Pt(NH)}(μ-OH)(μ-tetrazolato-N2,N3)] (5-H-Y) by making substitutions at tetrazole C5. We then evaluated the comprehensive structure-cytotoxicity relationships of a total of 23 derivatives in two murine lymphocytic leukaemia cell lines, sensitive and resistant to cisplatin. We also report the in vivo antitumor efficacy of three ester derivatives, two of which exhibited much higher efficacy than oxaliplatin against mouse homografted Colon-26 colorectal tumor.

Kinetic analysis of and platinum(II) migration in the reactions of tetrazolato-bridged dinuclear platinum(II) complexes with nucleotides.

The series of tetrazolato-bridged complexes with the formula [{cis‑Pt(NH)}(μ-OH)(μ-5-H-tetrazolato-N1,N2)] (5-H-X) or [{cis‑Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-N2,N3)] (R=H (5-H-Y), CH (1), CHCOOCHCH (2), CHCOO (3), n=2 (5-H-Y, 1, 2) or 1 (3)) are promising candidate complexes for formulation as next-generation platinum-based anticancer drugs that form multimodal bindings with DNA molecules. These multimodal bindings involve both non-covalent and covalent interactions, the latter of which are acknowledged to be essential for platinum-based drugs to exert their anticancer activity. In the present study, the tetrazolato-bridged complexes reacted with two molar equivalents of guanosine-5'-monophosphate (GMP) to yield the 1:2 reaction products [{cis‑Pt(NH)(GMP-N7)}(μ-5-R-tetrazolato-N1,N3)].

Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-Bridged Dinuclear Platinum(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect.

Derivatives of the highly antitumor-active compound [{cis-Pt(NH)}(μ-OH)(μ-tetrazolato-N2,N3)] (5-H-Y), which is a tetrazolato-bridged dinuclear platinum(II) complex, were prepared by substituting a linear alkyl chain moiety at C5 of the tetrazolate ring. The general formula for the derivatives is [{cis-Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-N2,N3)], where R is (CH)CH and n = 0 to 8 (complexes 1-9). The cytotoxicity of complexes 1-4 in NCI-H460 human non-small-cell lung cancer cells decreased with increasing alkyl chain length, and those of complexes 5-9 increased with increasing alkyl chain length.

Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy.

Self-Assembly of 4-(Diethylboryl)pyridine: Crystal Structures of the Cyclic Pentamer and Hexamer and Their Solvent-Dependent Selective Crystallization.

Two distinct oligomeric structures were obtained by the self-assembly of 4-(diethylboryl)pyridine (1). In the (1)H NMR spectrum of 1 in CDCl3, at least two sets of signals were observed for the pyridyl α- and β-hydrogen atoms. ESI-MS, VPO, and TLC analysis revealed that 1 assembles mainly into a mixture of cyclic pentamers and hexamers in solution via intermolecular boron-nitrogen coordination bonds.

Highly efficient uptake into cisplatin-resistant cells and the isomerization upon coordinative DNA binding of anticancer tetrazolato-bridged dinuclear platinum(II) complexes.

We examined the cytotoxicity and cellular uptake in L1210 murine leukemia cells, as well as the coordinative reaction with the guanine derivative 9-ethylguanine (9EtG), of a series of μ-hydroxo-μ-tetrazolato dinuclear platinum(II) complexes (tetrazolato-bridged complexes), [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N1,N2)](2+) (5-H-X) and [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)](n+), where R = H (5-H-Y), CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), or CH2COO(-) (4), and n = 2 (5-H-Y, 1-3) or 1 (4). Most tetrazolato-bridged complexes overcame cross-resistance to cisplatin and were more efficiently taken up into cisplatin-resistant cells (L1210R) than into parental cisplatin-sensitive cells (L1210), whereas cisplatin uptake into L1210R was decreased compared with that into L1210. The cellular uptake was most likely controlled by the total charge of the complexes.

The structure of 3-(diethylborylethynyl)pyridine: a nonplanarly arranged cyclic trimer.

3-(Diethylborylethynyl)pyridines 2 assemble into a cyclic trimer stabilized via intermolecular boron–nitrogen coordination bonds both in solution and in the crystalline state. The outstanding structural features of the methoxy derivative 2b in the crystalline state are that (1) two pyridine rings (P1 and P2) of the cyclic trimer of 2b are almost coplanar, and the third pyridine ring (P3) is largely bent away from P1 and P2, and (2) P3 of the cyclic trimer stacks in a face-to-face fashion with one of the pyridine rings (P3’) of an adjacent cyclic trimer. The crystallographic study revealed that the conformation of the cyclic trimer is flexible enough to be affected by the crystal packing.

Second- and higher-order structural changes of DNA induced by antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes with different types of 5-substituent.

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.

Synthesis of antitumor azolato-bridged dinuclear platinum(ii) complexes with in vivo antitumor efficacy and unique in vitro cytotoxicity profiles.

We synthesised four tetrazolato-bridged dinuclear Pt(ii) complexes, [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)](n+), where R is CH3 (1), C6H5 (2), CH2COOC2H5 (3), or CH2COO(-) (4) and n = 2 (1-3) or 1 (4). Their structures were characterised by (1)H, (13)C, and (195)Pt NMR spectroscopy, mass spectrometry, and elemental analysis, and the crystal structure of 1 was determined by X-ray crystallography. The cytotoxicities of the complexes to human non-small-cell lung cancer (NSCLC) cell lines sensitive and resistant to cisplatin were assayed.

A red-emissive aminobenzopyrano-xanthene dye: elucidation of fluorescence emission mechanisms in solution and in the aggregate state.

We have designed and synthesized a new class of rhodamine dyes with an extended π-conjugated system and named them 3',3''-bis(oxospiroisobenzofuran)-3,7-bis(diethylamino)benzopyrano-xanthene (ABPX01) dyes. ABPX01 exhibits fluorescence emission in both dilute solution and the aggregate state, whereas conventional rhodamine dyes show aggregation-induced quenching (AIQ). The chemical species of ABPX01 in solution were determined by spectrophotometric measurements and density functional theory (DFT) calculations to study the relationship among chemical species, color, and fluorescence emission.

DNA conformation and repair of polymeric natural DNA damaged by antitumor azolato-bridged dinuclear Pt(II) complex.

Design of new antitumor Pt drugs is currently also focused on those new Pt complexes which form on DNA major adducts that can hardly be removed by DNA repair systems. An attempt of this kind has already been done by designing and synthesizing new antitumor azolato-bridged dinuclear Pt(II) complexes, such as [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-pyrazolate)](2+) (AMPZ). This new Pt(II) complex exhibits markedly higher toxic effects in some tumor cell lines than conventional mononuclear cisplatin.

Energetics, conformation, and recognition of DNA duplexes containing a major adduct of an anticancer azolato-bridged dinuclear Pt(II) complex.

Background: The design of anticancer metallodrugs is currently focused on platinum complexes which form on DNA major adducts that cannot readily be removed by DNA repair systems. Hence, antitumor azolato-bridged dinuclear Pt(II) complexes, such as [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-pyrazolate)](2+) (AMPZ), have been designed and synthesized. These complexes exhibit markedly higher toxic effects in tumor cell lines than mononuclear conventional cisplatin.

A circular dichroism study uncovers a two-step interaction of antitumor azolato-bridged dinuclear platinum(II) complexes with calf thymus DNA.

The interactions of four antitumor azolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-azolato)](2+), with calf thymus DNA were monitored dose- and time-dependently, by using circular dichroism. Complexes 1-4 reacted with DNA via a two-step interaction that comprised a prompt diffusion-controlled reaction, which induced a B- to C-form transition, and a relatively slow temperature-dependent reaction.

An in vivo highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex largely circumvents in vitro cisplatin resistance: two linkage isomers yield the same product upon reaction with 9-ethylguanine but exhibit different cytotoxic profiles.

Cytotoxicity assays of azolato-bridged dinuclear Pt(II) complexes, [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-azolato)](2+), where the azolato was pyrazolato (1), 1,2,3-triazolato-N1,N2 (2), tetrazolato-N1,N2 (3), or tetrazolato-N2,N3 (4), were performed in cisplatin-sensitive and -resistant human non-small-cell lung cancer cell lines (PC-9 and PC-14). These complexes largely circumvented the cisplatin resistance in both cell lines, with resistance factors for 1-4 in the range of 0.5-0.

[Drug discovery research in in-vivo antitumor-active azolato-bridged dinuclear Pt(II) complexes].

Cis-diamminedichloridoplatinum(II) (cisplatin), which was first introduced as a clinical anticancer agent in the 1970s, is still among the most-utilized agents in current cancer chemotherapy. The discovery of cisplatin antitumor activity has catalyzed drug discovery research on antitumor platinum coordination compounds with improved efficacy. Some of new compounds show fewer side effects or expanded clinical applications.

Next-generation anticancer metallodrugs.

More than 99% of currently approved clinical drugs are organic compounds. In contrast, the percentage of metal-containing drugs (metallodrugs) is very low. In cancer chemotherapy, however, platinum coordination compounds represented by cisplatin and derivatives thereof are essential anticancer agents with proven effects against a variety of tumors.

Highly efficient DNA compaction mediated by an in vivo antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

We investigated the effects of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-tetrazolato-N(1),N(2))](2+) (1) and [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-tetrazolato-N(2),N(3))](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.

Unique platinum-DNA interactions may lead to more effective platinum-based antitumor drugs.

Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors.