Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

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• 作者：Qasem M.A. Abdallah^a ; ¹ ; Roger M. Phillips^a ; Fredrik Johansson^b ; ^c ; Thomas Helleday^c ; Laura Cosentino^a ; Hamdy Abdel-Rahman^a ; ² ; Jasarat Etzad^a ; Richard T. Wheelhouse^a ; Konstantinos Kiakos^d ; John P. Bingham^d ; John A. Hartley^d ; Laurence H. Patterson^a ; Klaus Pors^a ; ^{k.pors1@bradford.ac.uk}
• 关键词：CHO ; Chinese hamster ovary ; CT DNA ; calf thymus DNA ; DMSO ; dimethyl sulphoxide ; DSB ; double strand break ; H2AX ; histone-2AX ; MDR ; multidrug resistance ; MTT ; (3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide ; TdT ; terminal deoxynucleotidyl tran
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 June, 2012
• 卷：83
• 期：11
• 页码：1514-1522
• 文件大小：572 K

摘要

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.