Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells
Teesdale-Spittle, P.H. Pors, Klaus Brown, R. Patterson, Laurence H. Plumb, J.A.
Teesdale-Spittle, P.H.
Pors, Klaus
Brown, R.
Patterson, Laurence H.
Plumb, J.A.
Publication Date
2005
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Keywords
Treatment resistance, Transition metal Complexes, Divalent metal Complexes, Platinum II Complexes, Malignant tumour, Alkylating agent, Vertebrata, Mammalia, Rodentia, Cell line, Chlorine Organic compounds, Animal, Ovary, Tumour cell, Human, Alcohol, Antineoplastic agent, Mechanism of action, Antimitotic, Intraperitoneal administration, Chemotherapy, Cytotoxicity, In vivo, Pyrrolidine derivatives, Piperidine derivatives, Tricyclic compound, Condensed benzenic compound, Structure activity relation, Diphenols, Aromatic amine, Ovarian cancer, In vitro, Chemical synthesis, Cisplatin
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Abstract
A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino 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.
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Pors, K., Plumb, J.A., Brown, R., Teesdale-Spittle, P., Searcey, M., Smith, P.J. and Patterson, L.H. (2005). Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells. Journal of Medicinal Chemistry. Vol. 48, No. 21, pp. 6690-6695.
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