Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
17
Journal Issue
5
Pages
1861-1869
Date Issued
2009
Author(s)
Shchekotikhin A.E.
Glazunova V.A.
Dezhenkova L.G.
Luzikov Y.N.
Sinkevich Y.B.
Kovalenko L.V.
Buyanov V.N.
Balzarini J.
Huang F.-C.
Huang H.-S.
Shtil A.A.
Preobrazhenskaya M.N.
Abstract
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.
Type
journal article