Synthesis and structure–activity relationships of nitrobenzyl phosphoramide mustards as nitroreductase-activated prodrugs

Hu, Longqin; Wu, Xinghua; Han, Junqiang; Chen, Lin; Vass, Simon O.; Browne, Patrick; Hall, Belinda S.; Bot, Christopher; Gobalakrishnapillai, Vithurshaa; Searle, Peter F.; Knox, Richard J.; Wilkinson, Shane R.

doi:10.1016/j.bmcl.2011.05.009

Cited by 37 publications

(28 citation statements)

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“…It has been reported that nitrophenylacetic acid compounds can be used as triggers for producing bioreductive prodrugs [10, 12, 28–29]. In the present research, we synthesized a novel bioreductive PTX product NPPA-PTX.…”

Section: Discussionmentioning

confidence: 96%

“…Its derivatives tend to be nontoxic or only weakly toxic in normal tissues but become activated in hypoxic tumor tissues [11–12]. Introduction of nitrophenylalkanoic acid to form conjugate with conventional chemotherapeutic drug is relatively simple and the produced prodrug tends to exhibit specific selectivity for hypoxic tumor tissues [13–14].…”

Section: Introductionmentioning

confidence: 99%

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The anti-tumor efficacy of 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX): a novel paclitaxel bioreductive prodrug

et al. 2016

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Hypoxia is an important microenvironmental pressure present in the majority of solid tumors and, so, tumor hypoxia might be considered an attractive target for tumor therapy. One strategy for targeting hypoxia is to develop bioreductive prodrugs. In the present research, we synthesized a bioreductive paclitaxel prodrug, 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX). The stability of NPPA-PTX in PBS and rat plasma was investigated. The anti-tumor activity of NPPA-PTX was also evaluated in vitro and in vivo. The results of our stability study indicated that NPPA-PTX was stable in PBS and rat plasma as well as in the blood circulation. The in vitro and in vivo anti-tumor activity of NPPA-PTX was confirmed in both KB cells and MDA-MB-231 cells. Our results also indicated that NPPA-PTX could completely convert to active PTX in tumor tissues and produced the anti-tumor activity in both KB and MDA-MB-231 tumor-bearing nude mice. We suggest that the dissociated PTX which converted from NPPA-PTX in tumor tissues played a key role in producing anti-tumor activity. Considering all our results, we suggest that NPPA-PTX is a novel bioreductive PTX prodrug which could undergo further evaluation.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

The anti-tumor efficacy of 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX): a novel paclitaxel bioreductive prodrug

et al. 2016

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“…This enzyme mediates a series of two-electron reduction reactions that result in the fragmentation of the heterocyclic ring and production of toxic metabolites [11]. The fact that the activation of nitroheterocyclic prodrugs can be catalyzed by a type I NTR specific to trypanosomatids has led to a renewed interest in the use of such compounds as antiparasitic agents [12–17]. …”

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confidence: 99%

Novel 3-Nitro-1 H -1,2,4-Triazole-Based Compounds as Potential Anti-Chagasic Drugs: In Vivo Studies

et al. 2013

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Background Chagas disease is caused by the parasite Trypanosoma cruzi, is endemic in Latin America and leads to an estimated 14,000 deaths per year and around 100 million people at risk of infection. Drugs currently used in the treatment of Chagas are old, partially effective and have numerous side effects. Methodology We have previously reported that 3-nitro-1H-1,2,4-triazole-based compounds demonstrate significant and selective activity against T. cruzi amastigotes in infected L6 cells via activation of a type I nitroreductase, specific to trypanosomatids. In the present work we evaluated in vivo 13 of these compounds based on their high in vitro potency against T. cruzi (IC50 < 1 µM) and selectivity (SI: toxicity to L6 cells/toxicity against T. cruzi amastigotes > 200). Representative compounds of different chemical classes were included. A fast luminescence assay with transgenic parasites that express luciferase, and live imaging techniques were used. A total of 11 out of 13 compounds demonstrated significant antichagasic activity when administered intraperitoneally for 5–10 days at relatively small doses. The best in vivo activity was demonstrated by amides and sulfonamide derivatives. ADMET studies were performed for specific compounds. Conclusion At least three compounds were identified as effective, non-toxic antichagasic agents suitable for further development.

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“…The aziridinyl dinitrobenzamidine CB1954 and the two nitrobenzyl phosphoramide mustards LH7 and LH37 were more readily metabolized by TbNTR than by TcNTR. In the case of the mustards, this property has been shown to extend to trypanocidal activity: LH37 displays considerable growth-inhibitory activity against BSF T. brucei, yielding an IC 50 of 7 nM, whereas in studies of its activity against intracellular T. cruzi, an IC 50 140-fold higher (0.99 M) has been reported (28,32).…”

Section: Trypanosomal Type I Nitroreductases Are Fmn Binding Proteinsmentioning

confidence: 99%

Targeting the Substrate Preference of a Type I Nitroreductase To Develop Antitrypanosomal Quinone-Based Prodrugs

Hall

Meredith

Wilkinson

2012

Antimicrob Agents Chemother

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Nitroheterocyclic prodrugs are used to treat infections caused by Trypanosoma cruzi and Trypanosoma brucei. A key component in selectivity involves a specific activation step mediated by a protein homologous with type I nitroreductases, enzymes found predominantly in prokaryotes. Using data from determinations based on flavin cofactor, oxygen-insensitive activity, substrate range, and inhibition profiles, we demonstrate that NTRs from T. cruzi and T. brucei display many characteristics of their bacterial counterparts. Intriguingly, both enzymes preferentially use NADH and quinones as the electron donor and acceptor, respectively, suggesting that they may function as NADH:ubiquinone oxidoreductases in the parasite mitochondrion. We exploited this preference to determine the trypanocidal activity of a library of aziridinyl benzoquinones against bloodstream-form T. brucei. Biochemical screens using recombinant NTR demonstrated that several quinones were effective substrates for the parasite enzyme, having K cat /K m values 2 orders of magnitude greater than those of nifurtimox and benznidazole. In tests against T. brucei, antiparasitic activity mirrored the biochemical data, with the most potent compounds generally being preferred enzyme substrates. Trypanocidal activity was shown to be NTR dependent, as parasites with elevated levels of this enzyme were hypersensitive to the aziridinyl agent. By unraveling the biochemical characteristics exhibited by the trypanosomal NTRs, we have shown that quinone-based compounds represent a class of trypanocidal compound.

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Synthesis and structure–activity relationships of nitrobenzyl phosphoramide mustards as nitroreductase-activated prodrugs

Cited by 37 publications

References 20 publications

The anti-tumor efficacy of 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX): a novel paclitaxel bioreductive prodrug

The anti-tumor efficacy of 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX): a novel paclitaxel bioreductive prodrug

Novel 3-Nitro-1 H -1,2,4-Triazole-Based Compounds as Potential Anti-Chagasic Drugs: In Vivo Studies

Targeting the Substrate Preference of a Type I Nitroreductase To Develop Antitrypanosomal Quinone-Based Prodrugs

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