Correlation of the in vitro cytotoxic and in vivo antitumor activities of gold(I) coordination complexes.

A series of gold(I) coordination complexes including analogues of the antiarthritic agent auranofin 1 were evaluated for in vitro cytotoxic potency against both B16 melanoma cells and P388 leukemia cells and in vivo antitumor activity against P388 leukemia in mice. A number of the complexes showed potent cytotoxic activity in vitro and antitumor activity in vivo, with the phosphine-coordinated gold(I) thiosugar complexes demonstrating the greatest in vitro and in vivo activity. The data compiled for 63 complexes of the general structural formula LAuX provide the basis for the following observations: potent in vitro cytotoxic activity is observed for substituted (phosphine) gold complexes, lack of potency in vitro correlates well with lack of antitumor activity, potent cytotoxicity in vitro is not necessarily predictive of activity in vivo, in vivo antitumor activity is generally optimized by ligation of Au(I) with a substituted phosphine and a thiosugar.

Dopaminergic activity of substituted 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.

6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were synthesized and evaluated as agonists of central and peripheral dopamine receptors. These benzazepines were prepared by cyclization of certain amino alcohols followed by demethylation of the 7,8-dimethoxy groups of the precursors to the 7,8-catecholic moiety. Preliminary evidence of dopaminergic activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained an hydroxyl group on the 1-phenyl group or were substituted at the 3' position with a chloro, methyl, or trifluoromethyl group. Evidence for central dopaminergic activity was obtained by measuring rotational effects in rats lesioned in the substantia nigra and also in an in vitro assay which measured stimulation of rat striatal adenylate cyclase. The compounds with the best central dopaminergic activity were generally the benzazepines which were the most lipophilic, were substituted on the 3' position of th 1-phenyl group, and contained either a 3-N-methyl or 3-N-allyl group.

Identification of ibopamine metabolites in rat and dog urine.

Metabolism of ibopamine (N-methyldopamine-O,O'-diisobutyryl ester) was studied in rats and dogs. The compound was well absorbed in both species when given orally. Most of the administered radiolabel (74-94%) was excreted within 24 hr in urine of both species. The major metabolite in rat urine was 4-glucuronylepinine (63% of the total administered dose). Minor metabolites identified were 4-O-glucuronyl-3-O-methylepinine, 3,4-dihydroxyphenylacetic acid (DOPAC), DOPAC-glucuronide, homovanillic acid (HVA), and HVA-glucuronide. Free epinine and epinine sulfate were detected in the range of less than 1% of the total administered dose. Metabolite patterns in dog urine were different from those of rat urine. The major metabolite was epinine-3-O-sulfate (62% of the total administered dose). Minor metabolites identified in dog urine were DOPAC-sulfate, HVA-sulfate, and free HVA. Free epinine was detected but in the range of less than 1% of the total administered dose. These results showed that ibopamine underwent extensive hydrolysis in vivo to epinine, which was subsequently conjugated and excreted as major metabolites in urine. In addition, side chain degradation of epinine led to minor metabolites, which were excreted in urine as free and conjugated forms. The route of conjugation of ibopamine metabolites is species dependent.

Metabolism of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, a phenylethanolamine N-methyltransferase inhibitor. II. Species difference in metabolism and synthesis of its metabolites.

1. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (DCTQ), a potent reversible inhibitor of phenylethanolamine N-methyltransferase, was well absorbed, readily metabolized and excreted mainly in urine. 2. Its pathways of metabolism in rats and dogs were markedly different. In the dog, N-methylation was followed by N-oxidation to give the corresponding N-methyl-N-oxide as the final metabolic product. This was not observed in the rat. 3. In the rat, major pathways are aromatization of DCTQ to the corresponding isoquinoline and subsequent hydroxylation in the hetero ring to all three possible isomeric hydroxy-isoquinolines. 4. Authentic metabolites were synthesized for comparison with metabolites isolated from urine.

In vivo metabolism of the leukotriene receptor antagonist, 5-(2-dodecylphenyl)-4,6-dithianonanedioic acid (SK&F 102,081) in the guinea pig.

Both leukotrienes and their receptor antagonists possess substantial pharmacologic activity in in vitro systems, but their duration of action in vivo is extremely short. The exact mechanism of rapid inactivation of these lipids is unknown, but is likely due to metabolism. Therefore, the metabolic fate of a model antagonist 5-(2-dodecylphenyl)-4,6-dithianonanedioic acid (SK&F 102,081) was elucidated in anesthetized guinea pigs. Following iv administration of [14C]SK&F 102,081 (5 mg/kg), 85% of injected radioactivity was excreted in bile in 1 hr. Approximately 6% of the radioactivity in bile was associated with parent. At least 14 metabolites were present in bile, 2 of which accounted for almost 60% of the excreted radioactivity. Identification of biliary metabolites revealed that metabolism occurred by two major routes, omega-oxidation with subsequent beta-oxidation and acyl glucuronidation at approximately a 4:1 ratio. Since current structure-activity relationships suggest that omega-oxidation results in the loss of pharmacologic activity of SK&F 102,081, the rapid loss in pharmacologic activity observed in vivo may be due to rapid metabolism.