Discovery of the Hypoxia-Activated Prodrug SN30000

Hay, Michael P.; Hicks, Kevin O.; Wilson, William R.

doi:10.1016/b978-0-12-409547-2.12450-3

Cited by 5 publications

(5 citation statements)

References 214 publications

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“…Chlorambucil was obtained from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany) while SN30000 ( 2 ) and its 1 N -oxide [28] and TPZ ( 3 ) [77] were prepared as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…SN30000 is a second generation benzotriazine di-oxide that undergoes selective activation to a DNA-reactive radical species under hypoxia [24]. It was designed to be a more potent, selective analogue of the clinically evaluated tirapazamine (TPZ, 3 ) [25,26,27], and to have improved extravascular transport properties [28]. SN30000 displays increased killing of hypoxic cells both in vitro and in vivo when compared to TPZ [29,30].…”

Section: Introductionmentioning

confidence: 99%

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Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

et al. 2019

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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.

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“…Chlorambucil was obtained from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany) while SN30000 ( 2 ) and its 1 N -oxide [28] and TPZ ( 3 ) [77] were prepared as previously described.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

et al. 2019

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“…Therefore, a strong interest in the development of novel, less toxic compounds exist. These include new derivatives of TPZ (for example SN30000, a TPZ analogue that demonstrated superior activity in preclinical studies [ 193 , 194 ]) or compounds with chemical moieties (nitro-compounds and quinones) that are only activated under severe hypoxia.…”

Section: Radiotherapy and Tumor Hypoxiamentioning

confidence: 99%

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Telarovic

Wenger

Pruschy

2021

J Exp Clin Cancer Res

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Hypoxia in solid tumors is an important predictor of treatment resistance and poor clinical outcome. The significance of hypoxia in the development of resistance to radiotherapy has been recognized for decades and the search for hypoxia-targeting, radiosensitizing agents continues. This review summarizes the main hypoxia-related processes relevant for radiotherapy on the subcellular, cellular and tissue level and discusses the significance of hypoxia in radiation oncology, especially with regard to the current shift towards hypofractionated treatment regimens. Furthermore, we discuss the strategies to interfere with hypoxia for radiotherapy optimization, and we highlight novel insights into the molecular pathways involved in hypoxia that might be utilized to increase the efficacy of radiotherapy.

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“…The benzotriazine di-N-oxide SN30000 (CEN-209) is an analog of the well-studied HAP tirapazamine, with superior extravascular diffusion properties and activity against hypoxic cells in xenograft models. 24,25 Free radical metabolites of SN30000 are responsible for its cytotoxicity in hypoxic cells, 26 but these are too reactive to diffuse out of hypoxic zones. 27 This localization of killing to the cells that metabolically activate SN30000 (i.e.…”

Section: Introductionmentioning

confidence: 99%

Schedule-dependent potentiation of chemotherapy drugs by the hypoxia-activated prodrug SN30000

Mao

McManaway

Jaiswal

et al. 2019

Cancer Biology & Therapy

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Hypoxia-activated prodrugs (HAPs) are hypothesized to improve the therapeutic index of chemotherapy drugs that are ineffective against tumor cells in hypoxic microenvironments. SN30000 (CEN-209) is a benzotriazine di-N-oxide HAP that potentiates radiotherapy in preclinical models, but its combination with chemotherapy has not been explored. Here we apply multiple models (monolayers, multicellular spheroids and tumor xenografts) to identify promising SN30000/chemotherapy combinations (with chemotherapy drugs before, during or after SN30000 exposure). SN30000, unlike doxorubicin, cisplatin, gemcitabine or paclitaxel, was more active against cells in spheroids than monolayers by clonogenic assay. Combinations of SN30000 and chemotherapy drugs in HCT116/GFP and SiHa spheroids demonstrated hypoxia-and schedule-dependent potentiation of gemcitabine or doxorubicin in growth inhibition and clonogenic assays. Co-administration with SN30000 suppressed clearance of gemcitabine in NIH-III mice, likely due to SN30000-induced hypothermia which also modulated extravascular transport of gemcitabine in tumor tissue as assessed from its diffusion through HCT116 multicellular layer cultures. Despite these systemic effects, the same schedules that gave therapeutic synergy in spheroids (SN30000 3 h before or during gemcitabine, but not gemcitabine 3 h before SN30000) enhanced growth delay of HCT116 xenografts without increasing host toxicity. Identification of hypoxic and S-phase cells by immunohistochemistry and flow cytometry established that hypoxic cells initially spared by gemcitabine subsequently reoxygenate and re-enter the cell cycle, and that this repopulation is prevented by SN30000 only when administered with or before gemcitabine. This illustrates the value of spheroids in modeling tumor microenvironment-dependent drug interactions, and the potential of HAPs for overcoming hypoxia-mediated drug resistance.

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Discovery of the Hypoxia-Activated Prodrug SN30000

Cited by 5 publications

References 214 publications

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors

Interfering with Tumor Hypoxia for Radiotherapy Optimization

Schedule-dependent potentiation of chemotherapy drugs by the hypoxia-activated prodrug SN30000

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