10-Acetyl-10-hydroxyxantho[2,3-f]tetralin 8-glycosides as angular chromophore analogues of anthracyclines: synthesis, redox properties, microsomal oxygen consumption, and antileukemic evaluation.
10-Acetyl-7,8-dihydroxyxantho[2,3-f]tetralin is obtained by photo-Fries rearrangement of an acylated and double ketal protected tetralin followed by sodium thiocresylate catalyzed rearrangement of the resulting benzoyltetralin. Introduction of the 10-hydroxy function with base, triethyl phosphite, and molecular oxygen affords six products. These include the desired epimeric 10-acetyl-7,8,10-trihydroxyxantho[2,3-f]tetralins in addition to products resulting from novel valence tautomerism and cycloreversion reactions in the oxidation reaction. Glycosidic coupling to the fully functionalized cis-8,10-dihydroxy epimer of the aglycon to protected chlorodaunosamine by a modified Koenigs-Knorr method proceeded satisfactorily. By contrast the epimeric trans-8,10-dihydroxy compound failed to undergo coupling under these conditions. This is attributed to facile competing intramolecular hemiketal formation in the latter case. The new angular glycosides are very resistant to electrochemical reduction and display very low (3-10%) augmentation of hepatic microsomal oxygen consumption relative to doxorubicin. The observed, albeit low, cytotoxicity against leukemia L1210 in cell culture provides an additional example where the presence of the quinone moiety in the parent anthracyclines, which is implicated in the clinical cardiotoxicity, may not be necessary for the expression of anticancer properties.
Lown
J W
JW
Sondhi
S M
SM
Plambeck
J A
JA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D002863:Chromogenic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D008862:Microsomes, Liver / Q000378:metabolism; D009279:Naphthacenes / Q000138:chemical synthesis / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014966:Xanthenes / Q000138:chemical synthesis* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002863:Chromogenic Compounds; D006027:Glycosides; D009279:Naphthacenes; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D014966:Xanthenes