A tetra(L-lysine)-grafted poly(organophosphazene) for gene delivery.

In order to develop a new gene delivery vector, a novel cationic poly(organophosphazene) was synthesized by stepwise nucleophilic substitutions of poly(dichlorophosphazene) with a hydrophilic methoxy-poly(ethylene glycol) (MPEG) as a shielding group and a branched tetra(L-lysine), LysLys(LysEt)(2), as a cationic moiety. The cationic polymer has shown to form a polyplex by DNA condensation and very low in vitro cytotoxicity probably due to the shielding effect of MPEG, which provides a basis for improving the low gene transfection yield of cationic polyphosphazenes.

Flexibility of inorganic tennis ball structures inducing anion selectivity.

Inorganic tennis balls (ITBs), [[{Pt(betmp)(dach)}(2)Cu](2)(X)][X](3) (in which X=ClO(4) (-) (3), NO(3) (-) (4), Cl(-) (5) and Br(-) (6); dach=trans-1,2-diaminocyclohexane and betmp=bisethylthiomethylidenepropanedioate) and [[{Pt(dteym)(dach)}(2)Cu](2)(PF(6))][PF(6)](3) (7; dteym=1,3-dithiepane-2-ylidenemalonate), were prepared as crystals. Investigation of their X-ray crystal structures revealed that shapes of the cavities in ITBs show significant distortions that depend on the properties of the encapsulated anions. The CuCu* distance was observed to be longest in 7 and shortest in 5, the difference between them being 2.05 A. The flexibility of cavity structures of ITBs makes it possible to encapsulate various anions inside the cavity, while their distortions may be a reason for the difference in the encapsulating ability for anions, that is, anion selectivity. Especially, the distortions observed in 7 are so severe that the encapsulating ability of the cavity for PF(6) (-) is very low compared to other anions. The shapes of ITBs with ClO(4) (-) and BF(4) (-) ions inside their cavities are very similar; however, ClO(4) (-) is encapsulated by the cavity better than BF(4) (-), which is explicable by the difference of metal-anion interactions. This structural study on ITBs gives a clue to the origin of the anion selectivity of the cavity in ITBs previously investigated by (19)F NMR spectroscopy of the ITBs in methanol.

Self-assembly of rectangles and prisms via a molecular "clip".

Aromatic molecular "clips" bearing two symmetrically bound platinum moieties have been prepared. The molecular "clip" 4 readily self-assembled with linear linkers such as 4,4'-bipyridyl, 1,4-bis[2-(4-isocyano-3,5-diisopropylphenyl)ethynyl]benzene, and nicotinic acid to form molecular rectangles. The overall dimensions of the rectangle 7 were 7.3 Angstroms x 15.3 Angstroms. The molecular "clip" also self-assembled with tritopic pyridyl and isocyanide ligands to form trigonal prismatic frameworks. The characterization of the supramolecules by multinuclear NMR, electrospray mass spectrometry, and X-ray crystal structures is also reported.

Selective tumor targeting by enhanced permeability and retention effect. Synthesis and antitumor activity of polyphosphazene-platinum (II) conjugates.

Nanosized polyphosphazene-platinum (II) conjugates with a wide range of molecular weight from 24,000 to 115,000 were synthesized to study their tumor selectivity by enhanced permeability and retention (EPR) effect and their antitumor activity. It has been found from biodistribution study that the present polyphosphazene-Pt(II) conjugates exhibit high tumor selectivity by EPR effect with the tumor to tissue ratio (TTR) from 3.6 to 13 depending on the molecular size. These polymer conjugates have shown excellent in vivo antitumor activity against both murine and human cancer cell lines. In particular, xenograft trials of the conjugates have shown outstanding tumor inhibition effect on the stomach cancer cell line, YCC-3, which is one of the least responsive to the anticancer agents currently in clinical use, although the reason is not clearly explainable yet. The high in vivo activity seems to be attributed to the controlled-release of the antitumor active platinum (II) moiety, [GlyGluPt(dach] (dach=trans-(+/-)-1,2-diaminocyclohexane) from the phosphazene backbone by degradation in aqueous solution.

Tuning the intermolecular dative interactions by altering the ligand planarity and counter cations in vanadyl(IV) complexes.

A vanadyl(iv) complex, K2V(O)(dtoym)2, forms polymeric interactions via intermolecular dative bonds; the intermolecular dative interaction is tuned by changes of the ligand planarity and counter cations of the vanadyl complex.

Non-interpenetrating honeycomb-like 2D [6,3] network built by a novel trigonal metalloligand.

The combination of a novel trigonal metalloligand and linear linker affords the large non-interpenetrating honeycomb-like 2D [6,3] network in spite of the large hexagon lattice dimension.

Coordination modes vs. antitumor activity: synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids.

The trans-(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of multidentate L-glutamate (Glu) and L-aspartate (Asp) were prepared and their antitumor activity was examined in relation with their coordination modes. All these complexes were obtained as a mixture of (O,O')- and (O,N)-chelate isomers due to rapid isomerization of the initially formed (O,O')-isomer to the thermodynamically more stable (O,N)-isomer. The (O,O')/(O,N)-isomeric mixture with the mole ratio of 80/20 exhibited excellent antitumor activity while the pure (O,N)-isomer was only marginally active. Therefore, in order to prevent the linkage isomerization of the active (O,O')-isomer to the inactive (O,N)-isomer, we have designed N-substituted amino dicarboxylic acids as a leaving group and prepared a new series of complexes, [Pt(dach)(RGlu)] and [Pt(dach)(RAsp)] (dach=trans-(+/-)-1,2-diaminocyclohexane; R=acetyl (Ac), propionyl (Pro), pivaloyl (Piv), carbobenzyloxy (Cbz) or phthaloyl (Phth)) and characterized by means of elemental analyses, and 1H NMR, 195Pt NMR and IR spectroscopies. The N-substituted amino dicarboxylate ligands were found to coordinate to platinum(II) ion through only the (O,O')-chelation mode, and their Pt(II) complexes were chemically stable in aqueous solution. The present Pt(II) complexes of N-substituted amino dicarboxylic acids showed excellent antitumor activity against both murine leukemia L1210 and human tumor cells. Especially, the highly hydrophobic N-phthaloylglutamate complex, [Pt(dach)(PhthGlu)], exhibited an outstanding in vitro activity (IC50=2.22 microM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.

The non-templated empty cavity and its selective anion binding despite having similar shapes.

An inorganic tennis ball with an empty cavity was formed without any assistance of guest molecules, and found to bind various anions selectively depending on their size and copper-anion interaction strengths without much change of the shapes.

Synthesis, biodistribution and antitumor activity of hematoporphyrin-platinum(II) conjugates.

A new series of platinum(II) complexes of pegylated hematoporphyrin derivatives with controlled hydrophobic/hydrophilic balance were synthesized by introducing different kinds of poly(ethylene glycol) and amine ligands to the porphyrin ring. The antitumor activity of the porphyrin-platinum(II) conjugates was assayed in vitro and in vivo against leukemia L1210 cell line and various human tumor cell lines. The present complexes exhibited high antitumor activity and improved water solubility as well as considerable lipophilicity. In particular, complex 16 showed not only higher in vivo activity (T/C%=258) than cisplatin (T/C%=184) and carboplatin (T/C%=168), but also excellent solubility in water and organic solvent. The antitumor activity of complex 20 was superior to that of carboplatin against all human tumor cell lines tested. Moreover, some amphiphilic complexes (7 and 12) exhibited elevated tumor-localizing effect (tumor/muscle ratio>2).

Reactivity of 3d transition metal cations in diethylene glycol solutions. Synthesis of transition metal ferrites with the structure of discrete nanoparticles complexed with long-chain carboxylate anions.

Study of the reactivity of 3d transition metal cations in diethylene glycol solutions revealed several key features that made it possible to develop a new method for synthesis of the nanocrystalline transition metal ferrites. The 3-7 nm particles of [MFe2O4]n[O2CR]m, where M = Mn, Fe, Co, Ni, and Zn, ligated on their surface with long-chain carboxylate anions, have been obtained in an isolated yield of 75-90%. The key features are the following. Complexation of the first-row transition metal cations with diethylene glycol at a presence of alkaline hydroxide is sufficient to enable control over the rate of their hydrolysis. The reaction of hydrolysis leads to the formation of metal oxide nanocrystals in colloidal solution. The nanoparticles growth is terminated by an added long-chain carboxylic acid, which binds to their surface and acts as a capping ligand. The isolated nanocrystalline powders are stable against agglomeration and highly soluble in nonpolar organic solvents.

The First Inorganic "Tennis Ball" Encapsulating an Anion.

New balls please! Reaction of Cu(BF4 )2 with [(dach)PtII ] (dach=trans (±)-1,2-diaminocyclohexane) and bis(ethylthio)methylenepropanedioate (BETMP) gave [{(dach)Pt(BETMP)}2 Cu(BF4 )2 ] (1; shown schematically). Dimerization of 1 in methanol leads to the first inorganic "tennis ball" 2 [Eq. (1)]. A BF4- ion is encapsulated in the cavity of 2.

High-Dimensional Manganese(II) Compounds with Noncovalent and/or Covalent Bonds Derived from Flexible Ligands: Self-Assembly and Structural Transformation.

A hydrogen- and covalent-bonded 3D array, [Mn(bpe)(H(2)O)(4)](n)()(ClO(4))(2)(n)()(bpe)(4)(n)()(H(2)O)(2)(n)() (2) [bpe = 1,2-bis(4-pyridyl)ethane], a covalent-bonded 3D network, [Mn(bpe)(1.5)(H(2)O)(tp)](n)()(H(2)O)(n)() (3) [tp = terephthalate], and a covalent-bonded 2D sheet, [Mn(bpe)(N(3))(2)](n)() (4), have been synthesized and characterized by spectroscopic data and single-crystal X-ray diffraction studies. Complex 2 contains two types of packing bpe molecules: One type of bpe molecules (=N31-bpe and symmetry-related bpe) run along the chain direction, and the other type of bpe molecules (=N11-bpe and N21-bpe) are slanted to the chain linked by bridging bpe (=N1-bpe). The chain is coupled with hydrogen bonds via N31-bpe, while hydrogen bonds through packing bpe molecules of N11- and N21-bpe sew the chains, leading to a 3D interlocking network structure. The bpe ligands in 3 have an anti conformation for the bridging bpe and a gauche conformation for the capping bpe with a dihedral angle between the two pyridyl rings of 44.5 degrees. The tp ligand acts as a linker of three metal ions through the unidentate and bridging modes, leading to the formation of a 2D layer. The final molecular dimensionality in 3 is determined from adding bpe ligands to the 2D sheet connected by tp ligands, resulting in a covalent-bonded 3D array where the bridging bpe ligands link the tp-bridged layers. The manganese(II) center in 4 consists of four equatorial azido nitrogen atoms and two axial bpe nitrogen atoms. The one-dimensional chains formed by two azido bridging ligands are interconnected by bpe ligands, each of which has two pyridyl rings with a dihedral angle of 67 degrees, leading to a two-dimensional sheet. Variable-temperature magnetic susceptibility data of 2 and 4 have been fitted to the infinite-chain model (H = -J summation operatorS(A)(i)().S(A)(i)()(+1)) derived by Fisher under the molecular field approximation (J '). Obtained exchange parameters are J = -0.083 cm(-)(1), g = 2.0 for 2 and J = -12.5 cm(-)(1), g = 2.0, J ' = 1.3 cm(-)(1) for 4. In the case of 3, the magnetic nature was interpreted by the dimer model (H = -JS(1).S(2)), affording parameters J = -0.96 cm(-)(1), g = 1.99, J ' = -0.005 cm(-)(1). MO calculations on a hypothetical dimeric unit (NH(3))(5)Mn-bpe-Mn(NH(3))(5) are discussed to evaluate the magnetic nature for the bpe-bridged system 4.