Development of Nonsymmetrical 1,4-Disubstituted Anthraquinones That Are Potently Active against Cisplatin-Resistant Ovarian Cancer Cells

• Published in: Journal of medicinal chemistry Vol. 48; no. 21; pp. 6690 - 6695
• Main Authors: Pors, Klaus, Plumb, Jane A, Brown, Robert, Teesdale-Spittle, Paul, Searcey, Mark, Smith, Paul J, Patterson, Laurence H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.10.2005; Amer Chemical Soc
• Subjects: Animals; Anthraquinones - chemical synthesis; Anthraquinones - chemistry; Anthraquinones - pharmacology; Antigens, Neoplasm; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Cisplatin - pharmacology; DNA Topoisomerases, Type II; DNA-Binding Proteins - antagonists & inhibitors; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Nude; Ovarian Neoplasms; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; Topoisomerase II Inhibitors; Transplantation, Heterologous; TETRACHLOROMETHANE; MITOXANTRONE; HMLH1 EXPRESSION; DRUG-RESISTANCE; UNSYMMETRICALLY SUBSTITUTED 1,4-BIS<(AMINOALKYL)AMINO>ANTHRACENE-9,10-DIONES; Antineoplastic agent; Divalent metal Complexes; Intraperitoneal administration; Ovary cancer; Alcohol; Cytotoxicity; Diphenols; Pyrrolidine derivatives; Ovary; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Mechanism of action; Chemical synthesis; Antimitotic; Tumor cell; Platinum II Complexes; Human; Treatment resistance; Rodentia; Transition metal Complexes; Malignant tumor; Tricyclic compound; Condensed benzenic compound; In vitro; Cisplatin; In vivo; Alkylating agent; Vertebrata; Chemotherapy; Mammalia; Cell line; Treatment; Mouse; Animal; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050438f

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.