title: Synthesis and antitumor evaluation of symmetrical 1,5-diamidoanthraquinone derivatives as compared to their disubstituted homologues.
abstract: A series of symmetrical 1,5-diamidoanthraquinone derivatives with potentially bioreducible groups has been synthesized and their cytostatic activity against the panel of various cancer cell lines in vitro has been studied. Preliminary structure-activity relationships were established. The results indicated that compounds 5 and 18 exhibited significant potent cytotoxicity at 1.24-1.75 microM for Hepa G2 cell line; compounds 5, 16, and 18 exhibited cytotoxicity at 0.14-1.82 microM for 2.2.15 cell line as determined by XTT colorimetric assay. Two structurally related compounds, mitoxantrone and adriamycin, were tested in parallel as positive controls. In addition, it was found that compounds 5 and 18 were a more potent and specific human hepatoma cell line than mitoxantrone and showed comparable activity to adriamycin. Among them, compound 18 was the most potent for 2.2.15 cells. We have demonstrated that the anthraquinone moiety is essential for activity and that less sterically hindered substituents contribute to enhanced in vitro efficacy. Implications for amidoanthraquinone cytotoxicity as potential anticancer agents are discussed. We further delineate the nature of the pharmacophore for this class of compounds, which provides a rational basis for the structure-activity relationships.
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. huanghs@ndmctsgh.edu.tw
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Chiu
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Tao
authors.forename: In-Been
authors.initials: IB
authors.lastname: Chen
mesh_terms: D000880:Anthraquinones / Q000819:agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008942:Mitoxantrone / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C511007:1,5-diamidoanthraquinone; D000880:Anthraquinones; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011799:Quinazolines; D004317:Doxorubicin; D008942:Mitoxantrone