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.
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.
Shchekotikhin
Andrey E
AE
Gause Institute of New Antibiotics, Moscow, Russian Federation. shchekotikhin@mail.ru
Glazunova
Valeria A
VA
Dezhenkova
Lyubov G
LG
Luzikov
Yuri N
YN
Sinkevich
Yuri B
YB
Kovalenko
Leonid V
LV
Buyanov
Vladimir N
VN
Balzarini
Jan
J
Huang
Fong-Chun
FC
Lin
Jing-Jer
JJ
Huang
Hsu-Shan
HS
Shtil
Alexander A
AA
Preobrazhenskaya
Maria N
MN
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D008942:Mitoxantrone; D004264:DNA Topoisomerases, Type I; C020182:ametantrone