Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b
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- 作者：Andrey E. Shchekotikhin ; Valeria A. Glazunova ; Lyubov G. Dezhenkova ; Yuri N. Luzikov ; Yuri B. Sinkevich ; Leonid V. Kovalenko ; Vladimir N. Buyanov ; Jan Balzarini ; Fong-Chun Huang ; Jing-Jer Lin ; Hsu-Sha
- 关键词：Anthra[2 ; 3-b]thiophene-5 ; 10-diones ; Topoisomerase I ; Telomerase ; Cytotoxicity ; Drug resistance ; Tumor cells
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2009
- 出版时间：1 March 2009
- 年：2009
- 卷：17
- 期：5
- 页码：1861-1869
- 全文大小：932 K
文摘
We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53−/− cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.