Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells

Pors, Klaus, Plumb, Jane A., Brown, Robert, Teesdale-Spittle, Paul, Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949, Smith, Paul J. and Patterson, Laurence H. (2005) Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells. Journal of Medicinal Chemistry, 48 (21). pp. 6690-6695. ISSN 0022-2623

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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 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.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Depositing User:	Rachel Smith
Date Deposited:	13 Jun 2011 11:53
Last Modified:	24 Sep 2024 09:59
URI:	https://ueaeprints.uea.ac.uk/id/eprint/32142
DOI:	10.1021/jm050438f

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