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Molecules 2018, 23(8), 2041; https://doi.org/10.3390/molecules23082041

Evaluation of Nitrobenzyl Derivatives of Camptothecin as Anti-Cancer Agents and Potential Hypoxia Targeting Prodrugs

1
College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
2
Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: William Robert Wilson
Received: 30 June 2018 / Revised: 14 August 2018 / Accepted: 14 August 2018 / Published: 15 August 2018
(This article belongs to the Special Issue Targeted Prodrugs 2018)
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Abstract

As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive) properties. All three derivatives were found to possess reduced toxicity towards human leukemia K562 cells compared to SN-38, validating a condition for prodrug action. Using an MTS assay, IC50’s were found to be 3.0, 25.9, 12.2 and 58.0 nM for SN-38, 2-nitro-, 3-nitro- and 4-nitrobenzyl-C10-substituted-SN-38, respectively, representing an 8-, 4- and 19-fold decrease in cytotoxicity. Using a topoisomerase I assay, one of the analogs (4-nitrobenzyl) was shown to inhibit the ability of this enzyme to relax supercoiled pBR322 DNA, at a similar concentration to the clinically-approved active metabolite SN-38. Cyclic voltammetry detailed the reductive nature of the analogs, and was used to infer the potential of these compounds to serve as hypoxia-targeting prodrugs. The electrochemical results also validated the quasi-reversible nature of the first reduction step, and served as a proof-of-principle that hypoxia-targeting prodrugs of SN-38 can participate in a redox-futile cycle, the proposed mechanism of activation and targeting. Chemical reduction of the 4-nitrobenzyl analog led to the formation/release of SN-38 and validated the prodrug ability of the C-10 substituted derivative. View Full-Text
Keywords: camptothecin; hypoxia-activated prodrug; topoisomerase I inhibitor; K562 cells; anti-cancer agents; SN-38 camptothecin; hypoxia-activated prodrug; topoisomerase I inhibitor; K562 cells; anti-cancer agents; SN-38
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Liang, D.; Wu, X.; Hasinoff, B.B.; Herbert, D.E.; Tranmer, G.K. Evaluation of Nitrobenzyl Derivatives of Camptothecin as Anti-Cancer Agents and Potential Hypoxia Targeting Prodrugs. Molecules 2018, 23, 2041.

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