Synthesis of the acridone alkaloids glyfoline and congeners. Structure-activity relationship studies of cytotoxic acridones.
Glyfoline (4, 1,6-dihydroxy-10-methyl-2,3,4,5-tetramethoxyacridin-9-one) and its congeners were synthesized for evaluation of their cytotoxicity. A detailed structure-activity relationships (SAR) of these acridone derivatives were also studied. To study the SAR of glyfoline analogues, substituent(s) at C-1 and C-6 and at the heterocyclic nitrogen of glyfoline nucleus were modified. Nitro- and amino-substituted glyfoline analogues were also synthesized to study the effects of substituent(s) (electron-withdrawing vs electron-donating) on their cytotoxicity. These compounds were synthesized via the Ullmann condensation of anthranilic acids with iodobenzenes or 2-chlorobenzoic acids with aniline derivatives. The SAR studies showed that 1-hydroxy-9-acridones were more active than their 1-OMe derivatives against cell growth of human leukemic HL-60 cells in culture. Replacement of NMe of glyfoline with NH or N(CH2)2NEt2 resulted in either total loss or dramatic reduction of cytotoxicity. Glyfoline congeners with nitro function at the A-ring were inactive, while compounds with amino substituent were shown to be cytotoxic in vitro.
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Laboratory of Organic Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Köhler
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Chou
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Chun
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Watanabe
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D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054831:Acridones; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000166:Acridines; D054831:Acridones; D000970:Antineoplastic Agents; C041300:acridone; C075802:glyfoline