Photodegradation of the Benzotriazine 1,4-Di-N-Oxide Hypoxia-Activated Prodrug SN30000 in Aqueous Solution

Gu, Yongchuan; Jaiswal, Jagdish K.; Wang, Jingli; Hicks, Kevin O.; Hay, Michael P.; Wilson, William R.

doi:10.1002/jps.24099

Cited by 9 publications

(12 citation statements)

References 41 publications

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“…Metabolites were investigated in plasma, liver and HT29 tumors following i.p. dosing of female NIH-III mice with SN30000 at 186 mg/kg, which represents its previously determined MTD for this route and mouse strain ( Gu et al, 2014 ). Representative chromatograms are shown in Supplementary Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…SN30000 and metabolites M14 and M13 ( Hicks et al, 2010 ) and photodegradation product M15 ( Gu et al, 2014 ) were synthesized and formulated as the hydrochloride salts, as were octadeuterated stable isotope internal standards of SN30000, M14 and M13 ( Wang et al, 2012 ). The synthesis and characterization of metabolite M18 is provided in Supplementary Data.…”

Section: Methodsmentioning

confidence: 99%

“…These studies demonstrated that SN30000 induces an acute toxicity in mice, characterized by immobility and coldness to touch, as well as later histological changes ( Hicks et al, 2010 ; Gu et al, 2014 ). The rapidity of onset of the acute signs (within minutes) would seem inconsistent with DNA damage as the cause, leading to the hypothesis that there is a second mechanism of normal tissue toxicity.…”

Section: Introductionmentioning

confidence: 90%

“…The 1-oxide and nor-oxide species were also identified as major metabolites of SN30000 in liver and HCT116 tumor xenografts in NIH-III mice ( Wang et al, 2012 ), suggesting the major biotransformation route in mice is reduction of the N -oxide moieties as is the case for TPZ ( Walton and Workman, 1993 ). A further study demonstrated photodegradation of SN30000 in solution via transfer of the 4- N -oxygen to the side chain to generate a morpholino- N -oxide with low toxicity both in cell culture and in mice ( Gu et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice

Chang

Wang

et al. 2017

Front. Pharmacol.

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3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (SN30- 000), an analog of the well-studied bioreductive prodrug tirapazamine (TPZ), has improved activity against hypoxic cells in tumor xenografts. However, little is known about its biotransformation in normal tissues. Here, we evaluate implications of biotransformation of SN30000 for its toxicokinetics in NIH-III mice. The metabolite profile demonstrated reduction to the 1-N-oxide (M14), oxidation of the morpholine side-chain (predominantly to the alkanoic acid M18) and chromophore, and subsequent glucuronidation. Plasma pharmacokinetics of SN30000 and its reduced metabolites was unaffected by the presence of HT29 tumor xenografts, indicating extensive reduction in normal tissues. This bioreductive metabolism, as modeled by hepatic S9 preparations, was strongly inhibited by oxygen indicating that it proceeds via the one-electron (radical) intermediate previously implicated in induction of DNA double strand breaks and cytotoxicity by SN30000. Plasma pharmacokinetics of SN30000 and M14 (but not M18) corresponded closely to the timing of reversible acute clinical signs (reduced mobility) and marked hypothermia (rectal temperature drop of ∼8°C at nadir following the maximum tolerated dose). Similar acute toxicity was elicited by dosing with TPZ or M14, although M14 did not induce the kidney and lung histopathology caused by SN30000. M14 also lacked antiproliferative potency in hypoxic cell cultures. In addition M14 showed much slower redox cycling than SN30000 in oxic cultures. Thus a non-bioreductive mechanism, mediated through M14, appears to be responsible for the acute toxicity of SN30000 while late toxicities are consistent with DNA damage resulting from its one-electron reduction. A two-compartment pharmacokinetic model, in which clearance of SN30000 is determined by temperature-dependent bioreductive metabolism to M14, was shown to describe the non-linear PK of SN30000 in mice. This study demonstrates the importance of non-tumor bioreductive metabolism in the toxicology and pharmacokinetics of benzotriazine di-oxides designed to target tumor hypoxia.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice

Chang

Wang

et al. 2017

Front. Pharmacol.

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“…The results of the stability test may be helpful and have important implications for formulation development, quality control, and clinical uses. 18,19) Correlation between stability and cellular efficacy of β-lapachone was investigated subsequent to the stability tests. Collagen synthesis assay in HDF cells and in vitro cytotoxicity study were performed to evaluate the biological safety and efficacy of an active ingredient, with individual impurity or degradation products.…”

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confidence: 99%

Stability of β-Lapachone upon Exposure to Various Stress Conditions: Resultant Efficacy and Cytotoxicity

et al. 2016

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Even though β-lapachone is a promising compound with antitumor, antiinflammatory, antineoplastic, and wound-healing effects, there are still issues concerning its chemical stability and degradation mechanisms. The objective of this study was to obtain degradation profiles of β-lapachone and evaluate its chemical stability under various stress conditions. Moreover, the correlation between stability and efficacy was evaluated. The degradation study of β-lapachone was performed using heat, acid, base, oxidation, and light conditions. Kinetics and degradation profiles were investigated with HPLC and LC-MS. The stability indicated in the LC method was validated according to the International Conference on Harmonization guidelines. Human dermal fibroblast (HDF) cells were cultured with the standard and its degraded samples in the cellular activity and cytotoxicity test. β-Lapachone was relatively unstable upon exposure to light, and its photodegradation was accelerated with high relative humidity. Three degradants were identified, and their degradation followed zero-order kinetics. It was shown to degrade to phthalic acid under oxidative conditions, and the degradation kinetics were dependent on the concentration of hydrogen peroxide. Two degradation products were identified upon exposure to basic conditions, which followed first-order kinetics. β-Lapachone was relatively stable under acidic and thermal conditions. It increased the synthesis of collagen compared with the control. However, as the contents decreased, the synthesis of collagen also decreased in the photodegraded samples. β-Lapachone did not exert cytotoxic effects at the effective concentration in the cytotoxicity test. Therefore, in order to ensure efficacy and safety, the chemical stability of β-lapachone needs to be controlled carefully while considering instability mechanisms.

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Discovery of the Hypoxia-Activated Prodrug SN30000

Hay

Hicks

Wilson

2017

Comprehensive Medicinal Chemistry III

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Photodegradation of the Benzotriazine 1,4-Di-N-Oxide Hypoxia-Activated Prodrug SN30000 in Aqueous Solution

Cited by 9 publications

References 41 publications

Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice

Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice

Stability of β-Lapachone upon Exposure to Various Stress Conditions: Resultant Efficacy and Cytotoxicity

Discovery of the Hypoxia-Activated Prodrug SN30000

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