Synthesis and structure-activity correlations of the cytotoxic bifunctional 1,4-diamidoanthraquinone derivatives.
Anthraquinone-based compounds are attractive target for the design of new anticancer drugs. We have previously described a series of 1,5- and 1,4-difunctionalized anthraquinones, which exhibit different spectra of potency, together with human telomerase evaluation. The present study details the preparation of further, distinct series of regioisomeric difunctionalized amidoanthraquinone and examines their in vitro cytotoxicity in C6, Hepa G2, and 2.2.15 cell lines. Two structurally related compounds, mitoxantrone and adriamycin, were tested in parallel as positive controls. The structure-activity relationships indicated amido substitution may lead to a different mechanism of cytotoxicity. Compounds, which have -(CH2)n- side chains terminating in basic groups such as aminoalkyl-substituted, showed cytotoxic activity in several cell lines. The exact mode of intercalative binding may be dictated by the positional placement of substituent side chains. Implications for amidoanthraquinone cytotoxicity as potential anticancer agents are discussed. In addition, we further delineate the nature of the pharmacophore for this class of compounds, which provides a rational basis for the structure-activity relationships.
Huang
Hsu-Shan
HS
School of Pharmacy, National Defense Medical Center, PO Box 90048-508, Neihu 114 Taipei, Taiwan, ROC. huanghs@ndmctsgh.edu.tw
Chiu
Hui-Fen
HF
Lee
An-Long
AL
Guo
Ching-Long
CL
Yuan
Chun-Lung
CL
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship
D000577:Amides; D000880:Anthraquinones; D000970:Antineoplastic Agents; D007364:Intercalating Agents