Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells.
A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkylamino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropylamino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.
Pors
Klaus
K
Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London.
Plumb
Jane A
JA
Brown
Robert
R
Teesdale-Spittle
Paul
P
Searcey
Mark
M
Smith
Paul J
PJ
Patterson
Laurence H
LH
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
C505980:1-((2-dimethylamino)ethylamino)-4-(2-(3-hydroxymethylpiperidin-1-yl)ethylamino)-5,8-dihydroxyanthracene-9,10-dione; D000880:Anthraquinones; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin