Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with potent cytotoxic activity against cisplatin-resistant tumor cells.
Novel 1- and 1,4-substituted chloroethylaminoanthraquinones with DNA binding and alkylating properties along with their respective hydroxyethylaminoanthraquinone intermediates were synthesized. Selected chloroethylaminoanthraquinones were shown to cross-link DNA and alkylate guanines (at low nM concentration) with a preference for reaction sites containing 5'-PyG. A compound (Alchemix) with the bis-chloroethyl functionality confined to one side chain alkylated but did not cross-link DNA. All the 1,4-disubstituted chloroethylaminoanthraquinones were potently cytotoxic (nM IC(50)s) against cisplatin-resistant ovarian cancer cell lines.
Pors
Klaus
K
Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, 29-39 Brunswick Square, University of London, London WC1N 1AX, UK.
Paniwnyk
Zennia
Z
Ruparelia
Ketan C
KC
Teesdale-Spittle
Paul H
PH
Hartley
John A
JA
Kelland
Lloyd R
LR
Patterson
Laurence H
LH
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013329:Structure-Activity Relationship
C484869:1-((2-(bis(2-chloroethyl)amino)ethyl)amino)-4-((2-(dimethylamino)ethyl)amino)-5,8-dihydroxyanthracene-9,10-dione; D000880:Anthraquinones; D018906:Antineoplastic Agents, Alkylating; D004247:DNA; D002945:Cisplatin