A 5'-(trifluoromethyl)anthracycline glycoside: synthesis of antitumor-active 7-O-(2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl) adriamycinone.
7-O-(2,6-Dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl)adriam ycinone (3), whose substituent at C-5' is a lipophilic trifluoromethyl group, has been prepared by coupling of 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyran osyl bromide (20) with 14-O-(tert-butyldimethylsilyl)adriamycinone under the Koenigs-Knorr conditions. The key step in this synthesis was the C-trifluoromethylation of 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-aldehydo-L-erythro-pentose (10), derived from D-lyxose in 10 steps, with (trifluoromethyl)trimethylsilane in the presence of tetrabutylammonium fluoride, whereupon 1,1,1-trifluoro-L-arabino-hexitol (11) was obtained along with its 2-epimer. The synthetic product 3 showed remarkable antitumor activity in vivo in a low dose range compared to the analogs including doxorubicin. The fact may be ascribed to the presence of a trifluoromethyl group at C-5', suggesting the importance of the group in view of biological activity.
Takagi
Y
Y
Institute of Bioorganic Chemistry, Kawasaki, Japan.
Nakai
K
K
Tsuchiya
T
T
Takeuchi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006027:Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C098900:7-O-(2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl)adriamycinone; D000970:Antineoplastic Agents; D006027:Glycosides; D004317:Doxorubicin