title: Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates.
abstract: Two series of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates (BACs), ametantrone (AT)-amino acid conjugates (AACs) and mitoxantrone (MX)-amino acid conjugates (MACs), were designed and synthesized. The DNA binding of BACs was evaluated by DNA thermal denaturation experiment. In the series, the methionine-substituted BACs had the weakest DNA binding, while the lysine-substituted BACs had the highest T(m) values. The abilities of BACs to inhibit the growth of MCF-7, NCI-H460, SF-268, and PC-3 cell lines were determined. l-Met-MAC 16 and l-Lys-MAC 20 were the most potent growth inhibitors. MAC 16 was more cytotoxic than MX, whereas the T(m) of MAC 16 was much lower than that of MX. In contrast to MAC 16, l-Lys-MAC 20 demonstrated higher T(m) than MX. These data suggested that Met-BACs possessed a different pharmacological profile, in which the ability to stabilize DNA is not parallel to the ability to kill cancer cells, from that of AT and MX. The primary mechanism of cytotoxicity for MAC 16 was most likely through TOP2 poisoning. Therefore, MAC 16 may provide a lead for the development of novel generations of anthraquinone-type antitumor agents.
authors.affiliation: Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Room 1336, Taipei 10018, Taiwan, ROC. lwhsin@ntu.edu.tw
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hsin
authors.forename: Hui-Po
authors.initials: HP
authors.lastname: Wang
authors.forename: Pi-Hung
authors.initials: PH
authors.lastname: Kao
authors.forename: On
authors.initials: O
authors.lastname: Lee
authors.forename: Wan-Ru
authors.initials: WR
authors.lastname: Chen
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chan
authors.forename: Chin-Ping
authors.initials: CP
authors.lastname: His
authors.forename: Ming-Show
authors.initials: MS
authors.lastname: Yang
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Chieh-Hua
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA