Young-A Lee

Synthesis and antitumor activity of novel polyphosphazene-(diamine)platinum(II) conjugates

Abstract A novel class of water-soluble polyphosphazene-(diamine)platinum(II) conjugate drugs [N=P(S)Am·PtA 2 )] n have been designed and synthesized by incorporating the antitumor (diamine)platinum(II) moiety (A 2 Pt 2+ ) to a polyphosphazene back-bone along with a solubilizing groups (S) employing dicarboxylic amino acid (Am) as a spacer group. After characterization of these polymer conjugates by means of multinuclear ( 1 H, 31 P, 195 Pt) NMR and IR spectroscopies, elemental analysis and GPC, their antitumor activity were evaluated both in vitro and in vivo against murine leukemia L1210 cell lines and in vitro against five human tumor cell lines. Most of the title polymer conjugates have shown higher in vivo antitumor activity than cisplatin, and in particular [N=P(OH)(Glu·Pt(DACH))] n (Glu=glutamate, DACH= trans (±)-1,2-diaminocyclohexane) exhibit extraordinary high activity (ILS(%)>500) without cross-resistance to cisplatin as well as good water solubility, and therefore, was subjected to preclinical studies for human clinical trials.

Synthesis and structural properties of (diamineplatinum(II) complexes of itaconic acid

Abstract New zwitterioni (diamine)platinum(II) complexes A2Pt(ita) (A2 = 2,2-dimethyl-1,3-propanediamine (dmpa), tetrahydro-4H-pyran-4,4-diylbis(methylamine) (thpdma), trans-(±)-1,2-diaminocyclohexane (dach), ethylenediamine (en); ita = itaconate) have been synthesized and characterized by means of NMR spectroscopy and X-ray analysis. The platinum atom adopts a square-planar arrangement, in which the itaconate ligand is coordinated to the platinum atom through one carboxylate and the ethylate groups. The ethylene group occupies the fourth coordination site of the square plane, which intersects the midpoint of the Cue5f8C bond axis, but the bond axis is not perpendicular to the square plane because of i ts chelated ri ng strain. Such a chelation mode is retained without linkage isomerism in aqueous solution up to 70°C.

Synthesis, structure, and thermal behavior of discrete Co(II), Ag(I), and Pd(II) complexes with 2,3-bis(2-pyridyl)quinoxaline. Insight into coordination modes

Abstract The reactions of 2,3-bis(2-pyridyl)quinoxaline (bpq) with CoCl2·6H2O, Ag(CH3CN)4BF4, and PdCl2(C6H5CN)2 produce [CoCl2(bpq)]2·2CHCl3, [Ag(bpq)CH3CN]2(BF4)2·2CH3CN, and [PdCl2(bpq)], respectively. All the products are discrete 1:1 (metal:bpq) adducts, where the chelation mode of the bpq is dependent upon the metal atoms. The structure of [CoCl2(bpq)]2·2CHCl3 is a centrosymmetric Cl-bridged four-membered dimer, [Co2Cl2], in which the bpq is bonded to the cobalt(II) atom in an anisobidentate mode with the nitrogen donors of pyridine and pyrazine rings. For [Ag(bpq)CH3CN]2(BF4)2·2CH3CN, each bpq ligand connects two tetrahedral silver(I) ions in a tridentate mode, resulting in a cationic cyclic dimer. The structure of [PdCl2(bpq)] approximates to a molecular rocking chair with an isobidentate bpq through the nitrogen donors of 2-pyridyl rings. The compounds exhibit significant and characteristic relationships between the structures and their thermal properties. For [CoCl2(bpq)]2·2CHCl3, the solvate chloroform molecules are safely contained up to 144°C, but drastically evaporate above this temperature. The striking feature of [Ag(bpq)CH3CN]2(BF4)2·2CH3CN is that the skeletal cyclic dimer is basically retained after dissociation of the coordinated acetonitriles in the solid state.

Synthesis and antitumor activity of (diamine)platinum(ii) complexes of benzylmalonate derivatives

(Diamine)platinum(II) complexes of benzylmalonate derivatives as a leaving group designed in a wide range of lipophilicity and water-solubility were prepared and their antitumor activities were attempted to correlate to their lipophilicity or solubility. A good relationship was observed between their in vitro toxicity and solubility of the title complexes with the same carrier ligand, DACH (trans-(+/-)-1,2-diaminocyclohexane): The most soluble complexes are most cytotoxic whereas the least soluble complexes are least cytotoxic. However, no relationship could be established between their in vivo activity and their lipophilicity or solubility presumably due to other pharmacokinetic factors involved in vivo. The molecular structure of (IPA)2Pt(DBM).2CH3OH (IPA = isopropylamine; DBM = dibenzylmalonate) was determined by X-ray diffraction: space group P2(1)/n, a = 11.433 (3), b = 14.461 (4), c = 17.478 (4) A, beta = 97.25 (3) degrees, z = 4, R = 0.0437.

Facile synthesis and structural properties of (diamine)tetracarboxylatoplatinum(IV) complexes

Abstract (Diamine)tetracarboxylatoplatinum(IV) complexes, A2Pt(OOCR)4 (A2=trans-(±)-1,2-diaminocyclohexane (dach), 2,2-dimethyl-1,3-propanediamine (dmpda), ethylenediamine (en), 2 NH3, 2 cyclopropylamine (cpa); R=CH3, C2H5), have been facilely synthesized by reacting (diamine)tetrahydroxoplatinum(IV) with carboxylic anhydrides in dichloromethane, and their structural properties were examined by X-ray analysis and 1H NMR spectroscopy. The reactant (dach)Pt(OH)4 crystallizes in the triclinic space group P 1 (No. 2) with two molecules in an asymmetric unit and the local geometry around the platinum(IV) atom is a regular octahedron, but the carboxylated product (dach)Pt(O2CCH3)4 crystallizes in monoclinic space group P21/c (No. 14) and the platinum(IV) atom is in a distorted octahedral environment. The most interesting structural aspect of the title complexes is that the equatorial Pt(IV)–carboxylate bonds are slightly longer than the axial ones, probably due to the difference in trans influence of the nitrogen and oxygen donating atoms. The 1H NMR spectra also show that the axial and equatorial acetate groups are not equivalent.

Unusual Fluorenylidene‐philic Interactions for Effective Conformational Induction

Control of the conformation of the fluorenylidene moiety is achieved through an intramolecular interaction between the fluorenylidene moiety and the axial ligand during the oxidative addition and successive substitution of [PtII (fm)] to give [PtIV (X)(X)(fm)] (fm=9-fluorenylidenemalonate; see scheme). The conformation of the fm moiety can be effectively induced by the fluorenylidene-philicity of the axial X/X ligands, OOCCH3 >OCH3 >OH.

Synthesis and properties of diamine(isopropylidenemalonato) platinum(II): Crystal structure of O(CH2CH2)2C(CH2NH2)2Pt(OOC)2CC(CH3)2

Abstract New platinum(II) complexes of A 2 Pt(IPM) [A 2 = tetrahydro-4H-pyran-4,4-di(methylamine) (THPDMA), 2,2-dimethyl-1,3-propanediamine (DMPDA), trans -(±)-diaminocyclohexane (DACH); A = NH 3 , isopropylamine (IPA), cyclopropylamine (CPA); IPM = isopropylidenemalonate] have been synthesized and characterized by means of X-ray crystallography and various spectroscopies. The crystal structure of (THPDMA)Pt (IPM) · 5H 2 O was determined. The platinum atom adopts a typical square planar arrangement with two nitrogen atoms in the cis positions. The molecular structures are retained in aqueous solution at room temperature. However, the present complexes change to dimethyl sulphoxide (DMSO) adducts on standing for a long time or increasing temperature in DMSO : the monodentate amine complex produces (A)(DMSO)Pt(OOC) 2 Cue5fbC(CH 3 ) 2 , whereas the chelate amine analogue affords A 2 Pt + (DMSO)(OOC)C(COO − )ue5fbC(CH 3 ) 2 .

Oxidation of Pt(II) to Pt(IV) complex with hydrogen peroxide in glycols

Abstract The reaction of cis, cis-[PtII(9-fm)(dmpda)] (9-fm=9-fluorenylidenemalonate, dmpda=2,2-dimethyl-1,3-propanediamine) with hydrogen peroxide in ethyleneglycol produces cis,trans,cis-[PtIV(9-fm)(OCH2CH2OH)(OH)(dmpda)]. Its crystal structure shows that the local geometry around the platinum atom approximates a typical octahedral arrangement with the added OCH2CH2OH/OH ligands in trans coordination sites. The molecules are packed in a two-dimensional assembly via van der Waals interactions, where the hydrophobic fluorenyl groups are arranged on both faces of the assembly plate whereas the hydrophilic groups fill up the inner part of the plate. The compound bearing both “inorganic OH” and “organic OH” is a potential precursor for further various functionalizations.

An organometallic mercaptopyridine complex with unusual bond shift fluxionality: metal-mediated tautomerism of (pentamethylcyclopentadienyl)bis(pyridine-2-thiolato)rhodium(III)

Abstract Studies have been carried out on unique molecular non-rigidity of Cp*RhIII(PyS)2 (PyS=pyridine-2-thiolato). One PyS ligand bonds to the rhodium ion in an S-monodentate mode (Rhue5f8S(2)=2.3799(9) A) while the other ligand chelates to the metal in an N,S-bidentate mode (Rhue5f8S(1)=2.4380(9); Rhue5f8N(1)=2.089(2) A). Both PyS ligands possess a significant contribution from the thiol tautomer in the solid state. Even though the conformation and configuration of the molecule are still retained in solution, an unusual metal-mediated tautomeric non-rigidity for the PyS region is observed in the solution around room temperature.

A unique castle-wall type strand. Deca-coordinate cerium(III) complex with 3,3′-dihydroxy-2,2′-bipyridine

Abstract The reaction of cerium(III) nitrate with 3,3′-dihydroxy-2,2′-bipyridine (L) produces a coordination polymer of [Ce(NO 3 ) 3 (L)(H 2 O) 2 ] unit. L connects two Ce(III) ions via the oxygen donors of hydroxyl groups to give a castle-wall type strand. The Ce(III) ion is surrounded by deca oxygen donors including the bridged hydroxyl groups. Among the Ce(III)–O bonds, the bond length is the order of L>H 2 O>NO 3 − .