Effects of Substitution on Cytotoxicity of Diphenyl Ditelluride in Cultured Vascular Endothelial Cells.

Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.

A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine, induces apoptosis in the human acute promyelocytic leukemia cell line NB4 via reactive oxygen species.

A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine (4), which has 1-(phenyldiazenyl)pyrrolidine (1) substituent in a benzene ring of tri(p-tolyl)bismuthane (2), was synthesized and tested for biological activity toward human tumor cell lines. 4 had a potent anti-proliferative effect on human cancer cell lines, although both 1 and 2 exhibited only weak activity. The sensitivity of leukemic cell lines to 4 was relatively high; IC(50) values for the human leukemia cell line NB4 and cervical cancer cell line HeLa were 0.88 µM and 5.36 µM, respectively. Treatment of NB4 cells with 4 induced apoptosis, loss of mitochondrial membrane potential (ΔΨ(mt)) and the generation of cellular reactive oxygen species (ROS). 1 and 2 did not induce apoptosis and had only a marginal effect on ΔΨ(mt) and the generation of ROS. N-acetyl cysteine (NAC) reduced the generation of ROS and conferred protection against 4-induced apoptosis, indicating a role for oxidative stress. 4 did not inhibit the polymerization of tubulin in vitro. 1-[2-(di-p-tolylstibanophenyl)diazenyl]pyrrolidine (3), which has the same chemical structure as 4 but contains antimony in place of bismuth, did not show any cytotoxic activity. The results suggest that the conjugated structure of the diazenylpyrrolidine moiety and bismuth center are key to the bioactivity of 4.

{2-[(Dimethyl-amino)-meth-yl]phen-yl}bis-(4-methyl-phen-yl)bis-muthane.

The title compound, [Bi(C(7)H(7))(2)(C(9)H(12)N)], was obtained by treating chlorodi(p-tol-yl)bis-muthane with o-lithio-N,N-dimethyl-benzyl-amine. An intra-molecular Bi⋯N nonbonding inter-action is observed in the distorted trigonal triaryl-bis-muth coordination of the title compound.

Pentavalent organoantimony compounds as mild N-arylating agents for amines: Cu-mediated Ullmann-type N-arylation with tetraarylantimony(V) acetates.

Simple and mild Cu-mediated arylation of various amines by use of tetraarylantimony acetate (Ar(4)SbOAc) is described. The Ullmann-type condensation of Ar(4)SbOAc with aliphatic and electron rich aromatic amines proceeded efficiently in the presence of copper(II) acetate. The arylation can be carried out under aerobic conditions without care of exogenous oxygen. This simple procedure exceeds the conventional Ullmann condensation which often requires harsh reaction conditions.

Effect of periodic replacement of the heteroatom on the spectroscopic properties of indole and benzofuran derivatives.

The electronic structures of a homologous series of indole and benzofuran derivatives, in which the nitrogen or oxygen atom is replaced by group 15 and group 16 heavier heteroatoms, have been investigated by means of various spectroscopic techniques coupled with density functional calculations. It was found that the excitation energies of the group 16 benzoheteroles systematically shift to the red in the order of benzofuran (6), benzothiophene (7), benzoselenophene (8), and benzotellurophene (9). In contrast, the electronic absorption spectra of the group 15 benzoheteroles, 1-phenyl derivatives of indole (1b), phosphindole (2b), arsindole (3b), stibindole (4b), and bismuindole (5b), did not exhibit this type of spectral shift. X-ray analysis and density functional theory (DFT) studies revealed that 2b-5b adopt a bent conformation both in the crystalline and in the solution phases. In contrast, planar structures were calculated for the group 16 heterocycles. Using the observed spectroscopic properties and time-dependent density functional theory (TDDFT) calculations, the electronic absorption spectra of the present heterocycles were assigned. A molecular orbital analysis was performed to rationalize the effect of replacement of the heteroatom on the electronic structures. The observed magnetic circular dichroism (MCD) sign patterns of these heterocycles are interpreted according to Michl's perimeter model.

Rhodium catalyzed 1,4-conjugate addition of 1,5-azastibocines with electron deficient olefins.

The rhodium-catalyzed reaction of Sb-aryl-1,5-azastibocines with alpha,beta-unsaturated ketones and esters is described. Exclusive formation of 1,4-conjugate adduct was achieved in aqueous NMP (N-methyl-2-pyrrolidinone) in the presence of 5 mol% of [RhCl(cod)](2), and no formation of Heck adduct was observed in this condition. Reactions with various enones and enoates were also demonstrated to prove generality of the 1,4-conjugate addition.

Carbonylative cross-coupling reaction of ethynylstibane with aryl iodides.

Palladium-catalyzed carbonylative cross-coupling reaction of ethynylstibane (PhSbPh(2)) and aryl iodides (Ar-I) is described. The reaction of the stibanes and the halides under 1 atm of carbon monoxide in N,N-dimethylacetamide using a combination of 5 mol% Pd(OAc)(2) and 4 equivalents (20 mol%) of PPh(3) brought about carbonylative cross-coupling reaction to afford arylethynylketones [ArC(O)Ph] in good yields along with a small amount of directly coupled products, aryl acetylens (ArPh). Formation of the side product was completely suppressed by conducting the reaction under high CO pressure (20 atm) conditions. The present method provides a variety of carbonylated products in good yield even with electron-deficient aryl iodides which usually give inferior results due to their tendency to undergo decarbonylation in the cross-coupling reaction of ethynylstibanes and acyl halides.

Microwave-assisted cross-coupling reaction of alkynylstibanes with aryl iodides in the presence of ammonium salt.

The scope of microwave-assisted coupling reaction of alkynylstibane and aryl iodides to form diarylalkynes is presented. Highly efficient reaction took place smoothly in dimethyl sulfoxide in the presence of cetyltrimethylammonium bromide with much shorter time (1 min) and lower catalyst loading (0.5 mol%) than the conventional method (heating for 24 h with 10 mol% catalyst).

Catalytic action of triarylstibanes: oxidation of benzoins into benzyls using triarylstibanes under an aerobic condition.

Benzoins are simply oxidized to benzils in excellent yields with a catalytic amount of triarylstibanes under an aerobic condition. This catalytic oxidation is heteroatom-specific in the antimony compound and no reaction take place with other group 15 reagents such as triphenylphosphane, -arsane and -bismuthane. The reaction should involve an oxidation-reduction cycle between stibane Sb(III) and stiborane Sb(V) under air.

A versatile route to 3-benzoheteroepines containing group 15 and 16 heavier elements involving several novel ring systems, and their thermal stabilities.

The C-unsubstituted 3-benzoheteroepines (2a-g) containing group 15 (P, As, Sb, and Bi) and group 16 (S, Se, and Te) heavier elements were prepared by the reaction of the corresponding metal reagents with (Z,Z)-o-bis(beta-lithiovinyl)benzene (5) which was derived in two steps from a common o-phthalaldehyde (3). The heteroepines (2) thus obtained were thermally labile towards heteroatom extrusion, and their half-lives on heating estimated from (1)H-NMR spectral analysis showed that the 3-benzoheteroepines (2) were far less stable than the corresponding 1-benzoheteroepines (1). The 2,4-bis(trimethylsilyl)-3-benzoheteroepines (17) containing Sb, Bi, and Te were also prepared from o-diiodobenzene (9) in 6 steps and were found to be more stable than the corresponding C-unsubstituted heteroepines (2).

Synthesis of optically active organoantimony compounds having an (S)-alpha-methylbenzyldimethylamine group and its evaluation for asymmetric reaction.

Novel, enantiomerically pure organoantimony compounds having a C-chiral amine moiety, (S)-(alpha-methyl-2-di-p-tolylstibanobenzyl)dimethylamine [AMSb] (2) and its (eta(6)-arene)chromium complex [AMSb-Cr(CO)(3)] (4), were prepared from common (S)-(alpha-methylbenzyl)dimethylamine (1) via its ortho-lithiated intermediates in short steps. The catalytic activity and enantioselectivity of the ligands 2 and 4 for asymmetric reaction are evaluated, and the optically active (eta(6)-arene)chromium complex 4 has been shown to be an effective ligand for rhodium-catalyzed asymmetric hydrosilylation of ketones.