Masuo Koizumi

Toxicological and Tumoricidal Evaluations of a New Platinum Complex, (–)‐(R)‐2‐Aminomethy lpyrrolidine (1,1‐cyclobutanedicarboxylato) platinum (II) Monohydrate, in Rats

The toxicities and antitumor activity of a new anticancer platinum compound, (‐)‐(R)‐2‐amino‐methylpyrrolidine(l,l‐cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis‐diammine(1,1‐cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight <10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub‐LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35–43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.

The lipid-lowering profile in rodents AZ-1355, A New Dibenzoxazepine Derivative

The lipid-lowering profile of ethyl 10,11-dihydro-4-methoxydibenz[b,f]-(1,4)oxazepine-8-carboxylate (AZ-1355) has been evaluated using clofibrate as a reference compound. This compound is structurally unrelated to any other hypolipidemic agent. AZ-1355 was selected not only for its effect in reducing serum lipids, but also because it inhibits platelet aggregation in vivo and elevates the prostaglandin I2/thromboxane A2 ratio in vitro. It lowers serum total cholesterol in Triton-treated hyperlipidemic mice, and also lowers serum total cholesterol and triglyceride in dietary hyperlipidemic rats. In golden hamsters chosen for further evaluation, AZ-1355 reduced serum, liver and cardiac lipids, improved the beta/alpha-lipoprotein ratio and increased the HDL cholesterol. Thus, it is apparent that the lipid-lowering profile of AZ-1355 differs from that of clofibrate.

Chapter 4 Phenethylisoquinoline Alkaloids

Publisher Summary This chapter provides an overview of the structural elucidation, chemical reaction, and stereochemistry, biosynthesis, synthesis, and pharmacology of phenethylisoquinoline alkaloids. Phenethylisoquinoline alkaloids are classified into seven major alkaloid groups based on structural differences—simple 1-phenethylisoquinolines, homomorphinanedienones, bisphenethylisoquinolines, homoproaporphines, homoaporphines, homoerythrines, and dibenz[ d,f ]azecines, which are related to benzylisoquinoline alkaloids. Of the simple phenethylisoquinoline alkaloids dysoxyline, (S)-(+)-homolaudanosine, and (–)-isoautumnaline, dysoxyline and (S)-(+)-homolaudanosine are isolated from Dysoxyfum lenticeflare Gillespie. Three alkaloids—namely alkaloids CC-10, CC-20, and collutine, are isolated from Colchicum cornigerum and Colchicum luteum, respectively. Extensive tracer experiments show that tropolone alkaloids of the species Colchicum are derived from the 1-phenethylisoquinoline system by means of the dienone O-methylandrocymbine. One-electron withdrawing inorganic reagents are used to perform biomimetic syntheses of phenolic phenethylisoquinoline alkaloids.