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

Dinghua Liang,David E Herbert,Geoffrey K Tranmer,Xing Wu,Brian B Hasinoff

doi:10.3390/molecules23082041

Dinghua Liang, David E Herbert + Show 3 more

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https://doi.org/10.3390/molecules23082041

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Journal: Molecules (Basel, Switzerland)	Publication Date: Aug 15, 2018
Citations: 8	License type: CC BY 4.0

Affiliation: University of Manitoba

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.

Highlights

Camptothecins are a family of compounds that are structurally related to the natural product camptothecin (CPT), which was initially extracted from a tree native to southern China, Camptotheca acuminata
We first needed to establish whether this class of compounds can serve as stand-alone anti-cancer agents, followed by their evaluation as inhibitors of topoisomerase I, and evaluation of the electrochemical reduction potentials of the compounds will allow us to ascertain their potential to serve as hypoxia-activated prodrugs
A cell viability assay using human leukemia K562 cells indicated that the analogs of SN-38 possessed anticancer properties with measured IC50 ’s between

Summary

Introduction

Camptothecins are a family of compounds that are structurally related to the natural product camptothecin (CPT), which was initially extracted from a tree native to southern China, Camptotheca acuminata Several of these compounds have entered into clinical trials for their anti-cancer properties and their ability to inhibit topoisomerase I, with both topotecan and irinotecan receiving. Following the synthesis of a series of nitrobenzyl derivatives of camptothecin, we evaluated their ability to serve as anti-cancer agents using K562 cells and as inhibitors of topoisomerase I using an enzymatic. The oxygenation state of tumors has been shown to be the strongest independent prognostic factor, at least for cervical cancer [6] Due to these drawbacks, there is an urgent need to develop therapeutic strategies that target hypoxia in tumors.

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