59(P1-7) 有用な制癌剤を指向したアンスラサイクリン抗生物質の化学誘導(ポスター発表の部)  [in Japanese] 59(P1-7) CHEMICAL MODIFICATIONS OF ANTITUMOR ANTHRACYCLINES FOR USEFUL CHEMOTHERAPEUTICS  [in Japanese]

A semi-synthetic anthracycline antibiotic, pirarubicin (1), namely 4'-O-((R)-tetrahydropyranyl)adriamycin prepared by H. Umezawa et al. as a less cardiotoxic analogue of doxorubicin (2), is widely used for treatments of leukemia and other tumors. In the search for clinically useful and orally absorbable analogues, we found that N-salicylidene derivatives of 1 were therapeutically superior to 2 in murine models. Some of them showed the possibility of being orally absorbable agents in vivo tests. Preparation and biological evaluation of N-salicylidene derivatives of 1 are studied. Daunorubicin (3) was treated with benzoylhydrazone of acrolein dimer (7) to give 8 having a unique structure, and with o-phthaladehyde to give isoindolinone 9. Both of them reduced the antitumor effect in vivo. Reaction of 1 with salicylaldehyde gave 3'-N-salicylidenepirarubicin (10), which showed marked prolongation of the survival period in experimental tumor-bearing mice by the oral administration. Among N-salicylidene analogues (15〜22) substituted with electron-donating group(s) on the aryl ring, 15 exhibited good therapeutic effects. N-Salicylidene analogues (23〜35) having electron-withdrawing group(s) were also prepared. Compound 28 showed a significant antitumor activity by oral and intraperitoneal administrations. Derivatives of forphenicine (36) which was a structural homologue of salicylaldehyde were coupled with 1 to give interesting compounds 39〜41. Compound 39 had the broadest effective dose range. Furthermore, 40 showed remarkable antitumor effect by oral administration against murine tumor. The parameters on gastrointestinal absorption among compounds synthesized are also discussed.