title: Minor structural modifications to alchemix influence mechanism of action and pharmacological activity.
abstract: Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, West Yorkshire, UK.
authors.forename: Qasem M A
authors.initials: QM
authors.lastname: Abdallah
authors.forename: Roger M
authors.initials: RM
authors.lastname: Phillips
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Laura
authors.initials: L
authors.lastname: Cosentino
authors.forename: Hamdy
authors.initials: H
authors.lastname: Abdel-Rahman
authors.forename: Jasarat
authors.initials: J
authors.lastname: Etzad
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wheelhouse
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: John P
authors.initials: JP
authors.lastname: Bingham
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects; D006224:Cricetinae; D018736:DNA Adducts; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C483940:Alchemix; D000880:Anthraquinones; D000970:Antineoplastic Agents; D018736:DNA Adducts; C468783:H2AX protein, human; D006657:Histones