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Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines


Citation

Stanslas, Johnson and Hagan, Damien J. and Ellis, Michael J. and Turner, Claire and Carmichael, James and Ward, Wynne and Hammonds, Timothy R. and Stevens, Malcolm F. G. (2000) Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines. Journal of Medicinal Chemistry, 43 (8). pp. 1563-1572. ISSN 0022-2623; eISSN: 0022-2623

Abstract

New synthetic routes to a series of tetra- and pentacyclic acridines related in structure to marine natural products are reported. The novel water-soluble agent dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exceeding that of m-AMSA. The salt inhibited the release of minicircle products of kDNA confirming that disorganization of topoisomerase II partly underlies the activity of the compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the GI50 level corroborates this conclusion with Pearson correlation coefficients (> 0.6) to clinical agents of the topoisomerase II class: however, this correlation was not seen at the LC50 level. The inhibitory action of 14 on Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed a 3-fold selectivity against the IIα isoform over the IIβ isoform. Unlike m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains activity in lung cells with derived resistance to the topoisomerase II inhibitor etoposide.


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Official URL or Download Paper: https://pubs.acs.org/doi/10.1021/jm9909490

Additional Metadata

Item Type: Article
Divisions: Faculty of Medicine and Health Science
DOI Number: https://doi.org/10.1021/jm9909490
Publisher: American Chemical Society
Keywords: Antitumor agents; Acridines; Anthranilic acid; Cancer; Chemistry; DNA topoisomerase ii; Drug design; Drug evaluation; Drug resistance; Lung neoplasms; Marine toxins; Saccharomyces cerevisiae
Depositing User: Ms. Zaimah Saiful Yazan
Date Deposited: 15 Jan 2025 02:32
Last Modified: 15 Jan 2025 02:32
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1021/jm9909490
URI: http://psasir.upm.edu.my/id/eprint/114416
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