The production of skeletal muscle atrophy and mammary tumors in rats by feeding 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide

Chronic toxicity and carcinogenicity of a food additive, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) was examined by its oral administration to Wistar rats for 18 months. Male rats given 0.4% AF-2 diet developed ataxia of the hind foot around 4 months of feeding, and severe atrophy of skeletal muscles of the whole body was seen in 31 of 43 rats after 12 months. In female rats, mammary tumors developed in 78% of the animals given 0.4% AF-2 diet. Multiple papillomas were observed in the forestomach.     

2-羟甲基-青霉烯-3-羧酸对硝基苄酯的制备

目的研究(5R,6S)-2-羟甲基-6-[(1R)-1-叔丁基-2-二甲基硅氧乙基]-青霉烯-3-羧酸对硝基苄酯的合成方法.方法以商品化的小四环为原料,经噻酸亲核取代、与对硝基苄基草酰氯反应、与亚磷酸三乙酯反应、加热环合、脱去保护基生成目标化合物1.结果与结论设计的合成路线经4步反应,总收率为23%,合成路线简便易行,适宜大规模生产.所合成的中间体及目标产物经核磁共振氢谱确证.     

Deacetylation of 4-(5-acetylamino-2-furyl)thiazole and formation of 1-(4-thiazolyl)-3-cyano-1-propanone by rat liver tissues

The reductive metabolism of the rat carcinogen 4-(5-nitro-2furyl)thiazole (NFT) to 1-4-thiazolyl)-3-cyano-1-propanone (TCP) is reported. Formation of TCP from NFT involved furan ring fission. This could have occurred through involvement of either aminofuran or N-hydroxylaminofuran as precursors. To examine if 4-(5-amino-2-furyl)thiazole is a precursor for TCP, a stable model compound, 4-(5-acetylamino-2-furyl)thiazole (AAFT), was prepared and subjected to enzymatic deacetylation, using rat liver tissue homogenates. AAFT was synthesized by catalytic hydrogenation of NFT with 5% palladium on activated carbon, followed by acetylation with acetic anhydride. AAFT, a white crystalline powder, melted at 168–170°, had an extinction coefficient of 17.9 mM^?1 cm^?1 at 293 nm in ethyl acetate, and exhibited spectroscopic and mass spectral characteristics consistent with the assigned structure. Incubation with rat liver 10,000 g supernatant preparations resulted in the biotransformation of AAFT as evidenced by a decrease in absorption at 290 nm. Incubation of ¹⁴C-labeled AAFT followed by extraction with chloroform-diethyl ether (1:1) resulted in the recovery of a major portion (56%) of the radioactivity in the organic phase when the label was at the 2-position of the thiazole ring, while the major amount (82%) of radioactivity was recovered in the aqueous phase when the 1-¹⁴C-acetyl group was labeled. The radioactivity from the aqueous phase was extractable into the organic phase following acidification to pH 1, an observation consistent with deacetylation. Furthermore, the deacetylation product exhibited a mass spectrum, and retention times in gas and high pressure liquid chromatography, similar to those of synthetic TCP. These data establish 4-(5-amino-2-furyl)thiazole, derived from AAFT by deacetylation, as a precursor for TCP.     

Metabolic fate of 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone), a new antidepressant agent, in man.

1. In man, the antidepressant agent 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone) on oral dosing was mainly eliminated in urine (80% dose in 12 h). 2. Plasma concn. of total radioactivity was max (5.8 micrograms equiv./ml) at 30 min to 1 h after administration and declined rapidly (t1/2, 1.25 h). Unchanged drug accounted for 48, 32 and 13% of plasma radioactivity at 15 min, 1 h and 6 h, respectively. 3. The drug was extensively metabolized. The major urinary metabolites were 3-(3-carboxyphenyl)-5-hydroxymethyl-2-oxazolidinone and a glucuronide of toloxatone. A minor urinary metabolite, characterized as a phenolic derivative, was also excreted conjugated.     

1-(m-chlorophenyl)-biguanide, a potent high affinity 5-HT3 receptor agonist

1-(m-Chlorophenyl)-biguanide (mCPBG) was examined and compared with three 5-HT3 receptor agonists in three 5-HT3 receptor models. mCPBG inhibited [3H]GR67330 binding to 5-HT3 receptors with high affinity (IC50 1.5 nM). mCPBG depolarized the rat vagus nerve with an EC50 one tenth of that for 5-HT (0.05 vs. 0.46 microM); the maximum depolarization was approximately half that for 5-HT. The mCPBG depolarization was potently blocked by the selective 5-HT3 antagonist, ondansetron (pKB 8.6 +/- 0.1). In anaesthetised cats, mCPBG potently evoked the Bezold-Jarisch reflex which was blocked by low doses of ondansetron (10 micrograms/kg i.v.). It is concluded that mCPBG is a potent, high affinity 5-HT3 receptor agonist.     

Synthesis of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate, a hypolipidemic agent, and related compounds

A series of 2-aryl and 2-alkyl derivatives of 5-furyl-4-oxazoleacetic acid and their homologues having alkyl groups at the alpha-position of the acids were synthesized and evaluated for their hypolipidemic activities in Sprague-Dawley rats. On the basis of the structure-activity relationships and subacute toxicities, ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate (35) was selected as a candidate compound for development. Compound 35 reduced serum cholesterol and triglyceride levels by 23% and 35%, respectively, at a dose of 0.05% in a diet in normal rats, and it was about 10 times more active in hereditary hyperlipidemic rats (THLR/1) than in normal rats. Compound 35 inhibited platelet aggregation in vitro and also normalized hyperaggregability of hyperlipidemic plasma platelet ex vivo.     

2R-羟甲基-5S-(5′-氟胞嘧啶-1′-)-1,3-氧硫杂环戊烷的合成

报道2R-羟甲基-5S-（5′-氟胞嘧啶-1′-）-1,3-氧硫杂环戊烷（FTC）及其关键中间体 5R-乙酰氧基-1,3-氧硫杂环戊烷-2-羧酸（1′R，2′S，5′R）-薄荷酯的合成，并对文献报道的路线进行了改进，特别是避免使用昂贵而敏感的三甲基碘硅烷，易于工业化生产。     

Reductive metabolism of the carcinogen 4-(5-nitro-2-furyl)thiazole to 1-(4-thiazolyl)-3-cyano-1-propanone by rat liver subcellular fractions

The reductive metabolism of 4-(5-nitro-2-furyl)thiazole (NFT), a rat mammary gland and forestomach carcinogen, was examined in vitro using rat liver tissues. NFT was reduced by rat liver cytosol or microsomes on anaerobic incubation with NADPH. The stoichiometry of microsomal reduction revealed that about 3 moles of NADPH were used per mole of NFT. Gas chromatographic analysis of the reaction mixture showed a major peak with a retention time of about 4.0 min in contrast to NFT with a retention time of about 6.5 min. Catalytic hydrogenation of NFT with palladium and activated carbon yielded a product with a retention time of 4.0 min. The component corresponding with the above metabolite was isolated from chemically reduced NFT and identified as 1-(4-thiazolyl)-3-cyano-l-propanone. The metabolite derived from enzymatic reduction had chromatographic and spectral properties and a mass spectral fragmentation pattern similar to those obtained chemically. These data establish that the enzymatically derived product is identical to that obtained by chemical reduction and that it corresponds to 1(4thiazolyl)3cyano1propanone.     

Synthesis of 11-phenyl-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a)indoles and 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles as 5-hydroxytryptamine antagonists

A series of novel 11-phenyl-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a) indoles (5a-f) and 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles (6a-f) are reported. The compounds (5a-f) were prepared by the lithium aluminum hydride (LAH) reduction of corresponding 11-phenyl-1H-1-oxo-2,3,4,5-tetrahydro(1,4)diazepino(1,2-a)indoles (4a-f). The precursors (4a-f) were, in turn, prepared by the catalytic reduction of 1-(2-cyanoethyl)-3-phenylindole-2-carboxylates (2a-f) and cyclization of the resulting 1-(3-aminopropyl)-3-phenylindole-2-carboxylates (3a-f) with sodium hydride in xylene. The LAH reduction of 2a-f gave exclusively 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles (6a-f) and not the diazepinoindoles (5a-f) which were expected. The title compounds and the intermediates have been screened for their anti-5-hydroxytryptamine (anti-5-HT) activity. The most potent anti-5-HT compounds of this series, 6a and 6e, were found to be weak compared with cyproheptadiene, a standard anti-5-HT drug.