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

Qasem M A Abdallah, Roger M. Phillips, Fredrik Johansson, Thomas Helleday, Laura Cosentino, Hamdy Abdel-Rahman, Jasarat Etzad, Richard T. Wheelhouse, Konstantinos Kiakos, John P. Bingham, John A. Hartley, Laurence H. Patterson, Klaus Pors

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

LanguageEnglish
Pages1514-1522
Number of pages9
JournalBiochemical Pharmacology
Volume83
Issue number11
Early online date29 Feb 2012
DOIs
Publication statusPublished - 1 Jun 2012
Externally publishedYes

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Molecular Mechanisms of Pharmacological Action
Anthraquinones
DNA
MCF-7 Cells
Chromophores
Bearings (structural)
HCT116 Cells
Type II DNA Topoisomerase
Chemotherapy
CHO Cells
Alkylation
DNA Repair
Toxicity
Alchemix
Tumors
Neoplasms
Repair
Cells
Drug Therapy
Cell Line

Cite this

Abdallah, Q. M. A., Phillips, R. M., Johansson, F., Helleday, T., Cosentino, L., Abdel-Rahman, H., ... Pors, K. (2012). Minor structural modifications to alchemix influence mechanism of action and pharmacological activity. Biochemical Pharmacology, 83(11), 1514-1522. https://doi.org/10.1016/j.bcp.2012.02.017
Abdallah, Qasem M A ; Phillips, Roger M. ; Johansson, Fredrik ; Helleday, Thomas ; Cosentino, Laura ; Abdel-Rahman, Hamdy ; Etzad, Jasarat ; Wheelhouse, Richard T. ; Kiakos, Konstantinos ; Bingham, John P. ; Hartley, John A. ; Patterson, Laurence H. ; Pors, Klaus. / Minor structural modifications to alchemix influence mechanism of action and pharmacological activity. In: Biochemical Pharmacology. 2012 ; Vol. 83, No. 11. pp. 1514-1522.
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Abdallah, QMA, Phillips, RM, Johansson, F, Helleday, T, Cosentino, L, Abdel-Rahman, H, Etzad, J, Wheelhouse, RT, Kiakos, K, Bingham, JP, Hartley, JA, Patterson, LH & Pors, K 2012, 'Minor structural modifications to alchemix influence mechanism of action and pharmacological activity', Biochemical Pharmacology, vol. 83, no. 11, pp. 1514-1522. https://doi.org/10.1016/j.bcp.2012.02.017

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity. / Abdallah, Qasem M A; Phillips, Roger M.; Johansson, Fredrik; Helleday, Thomas; Cosentino, Laura; Abdel-Rahman, Hamdy; Etzad, Jasarat; Wheelhouse, Richard T.; Kiakos, Konstantinos; Bingham, John P.; Hartley, John A.; Patterson, Laurence H.; Pors, Klaus.

In: Biochemical Pharmacology, Vol. 83, No. 11, 01.06.2012, p. 1514-1522.

Research output: Contribution to journalArticle

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T1 - Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

AU - Abdallah, Qasem M A

AU - Phillips, Roger M.

AU - Johansson, Fredrik

AU - Helleday, Thomas

AU - Cosentino, Laura

AU - Abdel-Rahman, Hamdy

AU - Etzad, Jasarat

AU - Wheelhouse, Richard T.

AU - Kiakos, Konstantinos

AU - Bingham, John P.

AU - Hartley, John A.

AU - Patterson, Laurence H.

AU - Pors, Klaus

PY - 2012/6/1

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N2 - 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.

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