Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors
Extracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acid...
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doaj-f817294cf9cf4d298cd9a829268a2ea32020-11-25T00:37:05ZengMDPI AGMolecules1420-30492019-07-012414252410.3390/molecules24142524molecules24142524Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in TumorsMichael P. Hay0Hong Nam Shin1Way Wua Wong2Wan Wan Sahimi3Aaron T.D. Vaz4Pooja Yadav5Robert F. Anderson6Kevin O. Hicks7William R. Wilson8Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandSchool of Chemical Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandAuckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New ZealandExtracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared eight bioreductive prodrugs based on the benzotriazine di-oxide (BTO) nucleus by appending alkanoic or aminoalkanoic acid sidechains. The BTO acids showed modest selectivity for both low pHe (pH 6.5 versus 7.4, ratios 2 to 5-fold) and anoxia (ratios 2 to 8-fold) in SiHa and FaDu cell cultures. Related neutral BTOs were not selective for acidosis, but had greater cytotoxic potency and hypoxic selectivity than the BTO acids. Investigation of the uptake and metabolism of representative BTO acids confirmed enhanced uptake at low pHe, but lower intracellular concentrations than expected for passive diffusion. Further, the modulation of intracellular reductase activity and competition by the cell-excluded electron acceptor WST-1 suggests that the majority of metabolic reductions of BTO acids occur at the cell surface, compromising the engagement of the resulting free radicals with intracellular targets. Thus, the present study provides support for designing bioreductive prodrugs that exploit pH-dependent partitioning, suggesting, however, that that the approach should be applied to prodrugs with obligate intracellular activation.https://www.mdpi.com/1420-3049/24/14/2524bioreductive prodrugsbenzotriazine di-oxidestumor acidosistumor hypoxiapH-dependent partitioningradical chemistrytirapazamineSN30000CEN-209chlorambucilWST-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael P. Hay Hong Nam Shin Way Wua Wong Wan Wan Sahimi Aaron T.D. Vaz Pooja Yadav Robert F. Anderson Kevin O. Hicks William R. Wilson |
spellingShingle |
Michael P. Hay Hong Nam Shin Way Wua Wong Wan Wan Sahimi Aaron T.D. Vaz Pooja Yadav Robert F. Anderson Kevin O. Hicks William R. Wilson Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors Molecules bioreductive prodrugs benzotriazine di-oxides tumor acidosis tumor hypoxia pH-dependent partitioning radical chemistry tirapazamine SN30000 CEN-209 chlorambucil WST-1 |
author_facet |
Michael P. Hay Hong Nam Shin Way Wua Wong Wan Wan Sahimi Aaron T.D. Vaz Pooja Yadav Robert F. Anderson Kevin O. Hicks William R. Wilson |
author_sort |
Michael P. Hay |
title |
Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors |
title_short |
Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors |
title_full |
Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors |
title_fullStr |
Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors |
title_full_unstemmed |
Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors |
title_sort |
benzotriazine di-oxide prodrugs for exploiting hypoxia and low extracellular ph in tumors |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2019-07-01 |
description |
Extracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared eight bioreductive prodrugs based on the benzotriazine di-oxide (BTO) nucleus by appending alkanoic or aminoalkanoic acid sidechains. The BTO acids showed modest selectivity for both low pHe (pH 6.5 versus 7.4, ratios 2 to 5-fold) and anoxia (ratios 2 to 8-fold) in SiHa and FaDu cell cultures. Related neutral BTOs were not selective for acidosis, but had greater cytotoxic potency and hypoxic selectivity than the BTO acids. Investigation of the uptake and metabolism of representative BTO acids confirmed enhanced uptake at low pHe, but lower intracellular concentrations than expected for passive diffusion. Further, the modulation of intracellular reductase activity and competition by the cell-excluded electron acceptor WST-1 suggests that the majority of metabolic reductions of BTO acids occur at the cell surface, compromising the engagement of the resulting free radicals with intracellular targets. Thus, the present study provides support for designing bioreductive prodrugs that exploit pH-dependent partitioning, suggesting, however, that that the approach should be applied to prodrugs with obligate intracellular activation. |
topic |
bioreductive prodrugs benzotriazine di-oxides tumor acidosis tumor hypoxia pH-dependent partitioning radical chemistry tirapazamine SN30000 CEN-209 chlorambucil WST-1 |
url |
https://www.mdpi.com/1420-3049/24/14/2524 |
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