Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates.
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.
Hsin
Ling-Wei
LW
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
Wang
Hui-Po
HP
Kao
Pi-Hung
PH
Lee
On
O
Chen
Wan-Ru
WR
Chen
Hung-Wei
HW
Guh
Jih-Hwa
JH
Chan
Ya-Ling
YL
His
Chin-Ping
CP
Yang
Ming-Show
MS
Li
Tsai-Kun
TK
Lee
Chieh-Hua
CH
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
D000596:Amino Acids; D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA