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We recently isolated 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) and 4-nitro-3-phenylphenol (PNMPP) from diesel exhaust particles (DEP) and identified them as vasodilators. Because these compounds are alkylphenolic derivatives that might mimic hormones, we evaluated their estrogenic activity by using recombinant yeast screens, myometrial contractility assays, and in vivo uterotrophic assays. Recombinant yeast screen assays showed that both PNMC and PNMPP possess estrogenic activity. Furthermore, ovariectomized 25-day-old immature female rats injected with PNMC and PNMPP subcutaneously for 2 days showed significant increases in uterine weight among those receiving 100 mg/kg PNMC and 0.1 and 1.0 mg/kg PNMPP. To clarify further the estrogenic activity of PNMC and PNMPP, rat uterine horns were monitored in organ bath chambers for myometrial contractility in response to oxytocin (OT). Significant differences occurred in the initial and maximum contractilities to OT at 0.25 and 25 mIU/ml in uterine horns obtained from animals treated with 100 mg/kg PNMC and in the maximum contractilities to OT at 0.025, 0.25, and 25 mIU/ml in those from rats treated with 0.1 mg/kg PNMPP. These results clearly demonstrated that PNMC and PNMPP in DEP have estrogenic activity both in vitro and in vivo and might therefore be considered as endocrine-disrupting chemicals.

Vasodilatory compounds in the weak acidic fraction of a benzene extract of diesel exhaust particles (DEP) were fractionated by column chromatography through silica gel, and the chemical structures of these compounds were analyzed using GC-MS and 1H-NMR. The compounds in DEP that cause vasodilation — 3- and 4-nitrophenol, 2-methyl-4-nitrophenol, 3-methy-4-nitrophenol, and 4-nitro-3-phenylphenol — were isolated and identified. All five of these nitrophenols had vasodilatory activities (10-4 to 10-6 M) in rat thoracic artery assays, and 4-nitro-3-phenylphenol was the most potent vasodilator among these compounds. In addition, nine other alkylnitrophenols were isolated from the benzene extract of DEP and characterized.

We recently isolated 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) and 4-nitro-3-phenylphenol (PNMPP) from diesel exhaust particles (DEP) and identified them as vasodilators and xenoestrogens. The estrogenic activity of PNMC and PNMPP was further examined by using immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in uterine luminal epithelium of ovariectomized 25-d-old immature female rats injected with PNMC and PNMPP subcutaneously for 2 d. Significant increases were observed in uterine luminal epithelium in PCNA positive cells of animals receiving 10 and 100 mg/kg PNMC and 0.1 mg/kg PNMPP compared with controls. These results clearly show the estrogenic activity of PNMC and PNMPP by cell proliferation on the uterine luminal epithelium.

In our continuing studies on estrogenic compounds in diesel exhaust particles (DEP), we have reported the systematic separation of alkyldibenzothiophenes from the estrogenic hexane fraction of DEP. In this study, another estrogenic fraction was further isolated and characterized. DEP were roughly fractionated by successive extraction with hexane, benzene, dichloromethane, methanol, 1 M ammonia and 1 M HCl. The hexane extract, which exhibited estrogenic activity, was further fractionated by column chromatography and high performance liquid chromatography (HPLC). From one of the obtained fractions that showed estrogenic activity, three alkyltrimethylbenzenes were identified by gas chromatography-mass spectrometry (GC-MS) and 1H-nuclear magnetic resonance (NMR) spectroscopy.

We recently isolated 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) and 4-nitro-3-phenylphenol (PNMPP) from diesel exhaust particles (DEP) and identified them as vasodilators. Because these compounds are alkylphenolic derivatives that might mimic hormones, we evaluated their estrogenic activity by using recombinant yeast screens, myometrial contractility assays, and in vivo uterotrophic assays. Recombinant yeast screen assays showed that both PNMC and PNMPP possess estrogenic activity. Furthermore, ovariectomized 25-day-old immature female rats injected with PNMC and PNMPP subcutaneously for 2 days showed significant increases in uterine weight among those receiving 100 mg/kg PNMC and 0.1 and 1.0 mg/kg PNMPP. To clarify further the estrogenic activity of PNMC and PNMPP, rat uterine horns were monitored in organ bath chambers for myometrial contractility in response to oxytocin (OT). Significant differences occurred in the initial and maximum contractilities to OT at 0.25 and 25 mIU/ml in uterine horns obtained from animals treated with 100 mg/kg PNMC and in the maximum contractilities to OT at 0.025, 0.25, and 25 mIU/ml in those from rats treated with 0.1 mg/kg PNMPP. These results clearly demonstrated that PNMC and PNMPP in DEP have estrogenic activity both in vitro and in vivo and might therefore be considered as endocrine-disrupting chemicals.

In a previous study, we focused on estrogenic activity of the hexane extract of diesel exhaust particles (DEP). The extract of hexane was first fractionated to acidic, phenolic and neutral portions according to their chemical properties, of which the neutral fraction was fractionated by column chromatography on silica gel. The chemical structures of compounds in these fractions were then analyzed. It was found that the neutral fraction of the hexane extract of DEP contains dibenzothiophene derivatives, one of which, 4,6-dimethyldibenzothiophene, possesses estrogenic activity.

In an earlier study using a recombinant yeast screen we found that a suspension of diesel exhaust particles (DEP) and some extracts of DEP are not estrogenic but possess anti-estrogenic activity. In the present study, estrogenic and anti-estrogenic activities of two types of DEP, type-1 (old type) and type-2 (new type) were compared. Whole DEP of both types were found to possess estrogenic and anti-estrogenic activities. The DEP were serially extracted with organic solvents and then with 1 M ammonia and 1 M HCl. In type-2 DEP, the ratio of dry weight of a hexane extract was higher than those of methanol and ammonia extracts, which were lower than those in type-1 DEP. In the hexane extract, estrogenic activity was found in both types of DEP. In the benzene and dichloromethane extracts, estrogenic and anti-estrogenic activities were found in both types of DEP. In the methanol extract, estrogenic activity was found in type-2 DEP, and extracts of both types decreased the activity of estrogen. Anti-estrogenic activity was found in extracts of ammonia and HCl from both types of DEP. It was found that both type-1 and type-2 DEP possess estrogenic and anti-estrogenic activities.

The compounds in diesel exhaust particles (DEP) that are responsible for vasodilatation were isolated and characterized for the first time. From benzene extract of DEP, 2-methyl-4-nitrophenol, 3-methyl-4-nitrophenl and 4-nitrophenol were isolated, and their vasodilatation activities were confirmed. 3-methyl-4-nitrophenol caused dilatation of rat thoracic artery, and the other two nitrophenols, also showed vasodilatation activities.

Reactions of 2-aminophenols, 2-aminothiophenol and o-phenylenediamines with 2-chloro-1,1,3,3-tetramethylformamidinium chloride proceeded easily via cyclization of guanidine intermediates to give the corresponding benzazoles having a dimethylamino group at 2-position.

2-(Arylmethoxy)methyl-2-oxazolines, on treatment with LDA in THF at low temperature, rearrange to afford products which are hydrolysed to ortho-methylmandelic acids or α-(1-methyl-2-naphthyl)glycolic acid.

Utilization of 1-(2-oxazolinyl) indoles, prepared from 1-cyano compounds, to the synthesis of 2-substituted indoles was investigated

Dialkyl (3-pyridyl) boranes (2) were synthesized by the iodination of lithium trialkyl (3-pyridyl) borates, prepared from trialkylboranes and 3-lithiopyridine. Although 2 was resistant to quaternization or ate-complex formation, betaines (4b-e) were obtained by the reaction of 2a with cyanide ion and alkylating agents in high yields. Further, protonolysis of 2a with propionic acid gave 3-pyridylboronic acid (5). Proton and carbon-13 nuclear magnetic resonance data for 2a, b and 4b are presented.

A synthetic scheme leading to an isomeric DE ring (14) of the anti-tumor alkaloid, camptothecin, has been achieved. However, the method failed to give the correct pyridone lactone (2) found in this alkaloid.

Dialkyl (3-pyridyl) boranes (2) were synthesized by the iodination of lithium trialkyl (3-pyridyl) borates, prepared from trialkylboranes and 3-lithiopyridine. Although 2 was resistant to quaternization or ate-complex formation, betaines (4b-e) were obtained by the reaction of 2a with cyanide ion and alkylating agents in high yields. Further, protonolysis of 2a with propionic acid gave 3-pyridylboronic acid (5). Proton and carbon-13 nuclear magnetic resonance data for 2a, b and 4b are presented.

A kinetically controlled cyclization using the lithio-salt of an oxazoline and 1,4-di-iodopentane gave cis- and trans-2-methyl cyclopentanecarboxylic acid in the ratio 9 : 1.

A kinetically controlled cyclization using the lithio-salt of an oxazoline and 1,4-di-iodopentane gave cis- and trans-2-methyl cyclopentanecarboxylic acid in the ratio 9 : 1.

Reaction of N-methylpyrrolidine and tosyl chloride in the presence of AgClO4 afforded N-methyl-N-tosylpyrrolidinium perchlorate (II) as a stable, crystalline salt, which can be used for the selective tosylation of an amino-group in the presence of a hydroxy-group.

Methylation of the NN-disubstituted sulphonamides (IIIa,b) by dimethoxycarbonium hexachloroantimonate (II) gave the crystalline N-methylated salts (IVa,b), which afforded methyl amine derivatives on acid hydrolysis.