Kenji Niiyama

Separation of carcinogenic fraction of bracken fern

Isolation of the carcinogen in the boiling water extract of bracken fern was conducted by following the active principle with a carcinogenicity bioassay. Fractionation of the bracken extract was carried out using adsorption on resin (Amberlite XAD-2 and TOYOPEARL HW-40 (c] and organic solvent extraction. A diet containing each of the fractions was given to 7 female Charles River Sprague-Dawley rats (CD rats) of 4 weeks old, except for the second fraction. All 7 rats given the last carcinogenic fraction developed mammary and intestinal tumors and 5 rats had urinary bladder tumors. Ptaquiloside (PT) which induced mammary cancer in female CD rats and rho-hydroxystyrene glycosides were isolated from this fraction.

A convenient synthetic method of a 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylate: A key intermediate for potent endothelin receptor antagonists

A convenient method for the synthesis of the title intermediate 4 was described. The key steps of this synthesis involved: (1) regioselective addition reaction of arylzinc reagent to quinolic anhydride in 42% isolated yield, (2) conversion of a ketoacid to an enone, which was achieved in 65% yield by intramolecular Knoevenagel reaction of beta-ketoester generated by condensation of an acid imidazolide with an ester enolate, followed by dehydration assisted with silica gel, and (3) stereoselective reduction of an allyl alcohol in 75% yield with zinc under acidic conditions. This synthesis enabled us to provide hundreds of grams of without chromatographic purification.

Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859.

Objective To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-105859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to conFIrm the potential of this compound as an ETA antagonist. Methods Vehicle and J-105859 were administered to saltloaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-105859. Results The Ki values of J-105859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-105859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-105859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-105859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. Conclusion J-105859 is a selective, potent, orally active ETA-selective antagonist. ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

Stereocontrolled total synthesis of (+)-tutin and (+)-asteromurin a, toxic picrotoxane sesquiterpenes

Abstract The first total synthesis of (+)-tutin ( 1 ), a toxic principle of the plants of the Coriaria species and (+)-asteromurin A ( 2 ), a bitter principle of the scale insect Asterococcus muratae KUWANA in the stereocontrolled manner is described, utilizing the epoxy olefin 10 as the common intermediate.

Structure–Activity relationships of 2-substituted 5,7-Diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids as a novel class of endothelin receptor antagonists

Synthesis and structure-activity relationships of 2-substituted-5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids, a novel class of endothelin receptor antagonists, were described. Derivatization of a lead structure 1 (IC(50)=2.4nM, 170-fold selectivity) by incorporating a substituent such as an alkyl, alkoxy, alkylthio, or alkylamino group into the 2-position of the cyclopenteno[1,2-b]pyridine skeleton was achieved via the key intermediate 8. Introduction of an alkyl group led to the identification of potent ET(A)/ET(B) mixed receptor antagonists, a butyl (2d: IC(50)=0.21nM, 52-fold selectivity) and an isobutyl (2f: IC(50)=0.32nM, 26-fold selectivity) analogue. In contrast, installment of a primary amino group resulted in ET(A) selective antagonists, a propylamino 2p (IC(50)=0.12nM, 520-fold selectivity) and an isopropylamino 2q (IC(50)=0.10nM, 420-fold selectivity) analogue. These results suggested that a substituent at the 2-position of the 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids played a key role in the binding affinity for both ET(A) and ET(B) receptors.

Novel 4-substituted pyridine derivatives: Practical derivatization and biological profiles of reversible H+K+-ATPase inhibitors

Abstract An easy method to prepare novel 4-alkoxy-, 4-alkylthio- or 4-aryloxy-5-methyl-2-[1-(hydroxymethyl)-2-(1-naphthyl)-ethyl (or -ethenyl)]pyridine derivatives having reversible inhibitory activity against H + K + -ATPase is described. Use of a methylsulfinyl- or methylsulfonyl group as a leaving group makes it possible to effectively introduce various alkoxy or alkylthio groups into the 4-position of the pyridine ring at the final stages of synthesis. Biological profiles of the prepared compounds are briefly mentioned.

Linear peptide ETA antagonists: rational design and practical derivatization of N-terminal amino- and imino-carbonylated tripeptide derivatives☆

Abstract Novel linear tripeptides possessing high endothelin antagonist activity were derived from endothelin antagonistic cyclic pentapeptides represented by BQ-123. The N-terminal urea moiety of the linear tripeptide derivatives was essential to show the strong antagonist activity. An easy method to prepare these peptides by treatment of the corresponding N-phenoxycarbonylated tripeptide esters with primary or secondary amines is described.

Application of tetrabutylammonium salt of N-(9-fluorenylmethoxycarbonyl)cysteic acid for solid phase peptide synthesis: Preparation of endothelin antagonistic cyclic pentapeptides

Abstract According to the Fmoc strategy, highly potent endothelin antagonistic cyclic pentapeptides possessing cysteic acid residue(s) were prepared in solid phase peptide synthesis. Use of a tetrabutylammonium salt overcame low solubility of N-(9-fluorenylmethoxycarbonyl)cysteic acid in a conventional solvent such as DMF.

Stereocontrolled total synthesis of (+)-tutin, a toxic sesquiterpene of picrotoxane-type

Abstract The first total synthesis of (+)-tutin (1), a toxic sesquiterpene of picrotoxane-type isolated from the poisonous plants of the Coriaria species is described.

Practical synthesis of a cyclic pentapeptide in solution: large-scale preparation of a representative ETA-selective antagonist, BQ-123Na

Abstract A 100-g scale preparation of a representative endothelin-A receptor (ET A ) selective antagonist, BQ-123Na (a sodium salt of BQ-123), is described. Application of a methyl ester as the side chain carboxy-protecting group for the d -Asp residue made it possible to use a benzyl ester as a carboxy-protecting group for the C-terminal Leu throughout the synthesis.