Synthesis, DNA binding, and cytotoxicity of 1,4-bis(2-amino-ethylamino)anthraquinone-amino acid conjugates
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
16
Journal Issue
2
Pages
1006-1014
Date Issued
2008
Author(s)
Wang H.-P.
Kao P.-H.
Lee O.
Chen W.-R.
Chen H.-W.
Chan Y.-L.
His C.-P.
Yang M.-S.
Lee C.-H.
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 Tm 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 Tm of MAC 16 was much lower than that of MX. In contrast to MAC 16, l-Lys-MAC 20 demonstrated higher Tm 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. ? 2007 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
1,4 bis[2 (2 amino 3 hydroxy propionylamino)ethylamino] 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 (2 amino 3 tert butoxypropionylamino)ethylamino] 9,10 anthracenedione; 1,4 bis[2 (2 amino 4 methylsulfanyl butyrylamino)ethylamino] 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 (2 amino 4 methylsulfanylbutyrylamino)ethylamino] 5,8 dihydroxy 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 (2 amino 4 methylsulfanylbutyrylamino)ethylamino] 5,8 dihyroxy 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 (2 amino 6 tert butoxycarbonylamino hexanoylamino) ethylamino] 9,10 anthracenedione; 1,4 bis[2 (2 tert butoxycarbonylamino 4 methylsulfanyl butyrylamino)ethylamino] 9,10 anthracenedione; 1,4 bis[2 (2 tert butoxycarbonylamino 4 methylsulfanylbutyrylamino)ethylamino] 5,8 dihydroxy 9,10 anthracenedione; 1,4 bis[2 (2,6 diamino hexanoylamino)ethylamino] 5,8 dihydroxy 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 (2,6 diamino hexanoylamino)ethylamino] 9,10 anthracenedione; 1,4 bis[2 (2,6 diaminohexanoyl carbamoyl)ethylamino] 9,10 anthracenedione; 1,4 bis[2 [2 amino 3 (4 hydroxyphenyl)propionylamino]ethylamino] 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 [2 amino 3 (4 tert butoxyphenyl)propionylamino]ethylamino] 9,10 anthracenedione trifluoroacetate; 1,4 bis[2 [2,6 bis(tert butoxycarbonylamino)hexanoylamino]ethylamino] 5,8 dihydroxy 9,10 anthracenedione; 1,4 bis[2 [2,6 bis(tert butoxycarbonylamino)hexanoylamino]ethylamino] 9,10 anthracenedione; 1,4 bis[2 [3 tert butoxy 2 (9h fluoren 9 yl methoxycarbonylamino) propionylamino]ethylamino] 9,10 anthracenedione; 1,4 bis[2 [6 tert butoxycarbonylamino 2 (9h fluoren 9 ylmethoxycarbonylamino)hexanoylamino]ethylamino] 9,10 anthracenedione; ametantrone; antineoplastic agent; DNA; lysine; methionine; mitoxantrone; unclassified drug; article; cancer cell; cancer growth; cancer inhibition; cell killing; cytotoxicity; DNA binding; DNA denaturation; drug design; drug potency; drug synthesis; human; human cell; Amino Acid Sequence; Amino Acids; Anthraquinones; Antineoplastic Agents; Combinatorial Chemistry Techniques; DNA; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Stereoisomerism; Structure-Activity Relationship
Type
journal article