NBGNU: a hypoxia-activated Tripartite combi-nitrosourea Prodrug Overcoming AGT-mediated Chemoresistance

Ge, Yao; Lai, Xinxin; Li, Jintao; Yu, Ran; Zhuang, Zhuochen; Sun, Guizhi; Cui, Xin; Zhang, Na; Zhao, Lu; Upadhyaya, Pramod; Zhong, Rugang

doi:10.4155/fmc-2018-0511

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…Therefore, inhibiting AGT activity in tumor cells is of great significance for improving the chemotherapeutic effects of treatment. Over the past few decades, a series of AGT inhibitors have been synthesized for combination chemotherapy with alkylating agents [3,[16][17][18][19][20][21][22][23]. Among them, O 6 -benzylguanine (O 6 -BG) was the first AGT inhibitor to enter clinical trials with superior AGT inhibitory activity [3,15,24].…”

Section: Introductionmentioning

confidence: 99%

Reductive Activity and Mechanism of Hypoxia- Targeted AGT Inhibitors: An Experimental and Theoretical Investigation

Xiao

Sun

Fan

et al. 2019

IJMS

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O 6 -alkylguanine-DNA alkyltransferase (AGT) is the main cause of tumor cell resistance to DNA-alkylating agents, so it is valuable to design tumor-targeted AGT inhibitors with hypoxia activation. Based on the existing benchmark inhibitor O 6 -benzylguanine (O 6 -BG), four derivatives with hypoxia-reduced potential and their corresponding reduction products were synthesized. A reductase system consisting of glucose/glucose oxidase, xanthine/xanthine oxidase, and catalase were constructed, and the reduction products of the hypoxia-activated prodrugs under normoxic and hypoxic conditions were determined by high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The results showed that the reduction products produced under hypoxic conditions were significantly higher than that under normoxic condition. The amount of the reduction product yielded from ANBP (2-nitro-6-(3-amino) benzyloxypurine) under hypoxic conditions was the highest, followed by AMNBP (2-nitro-6-(3-aminomethyl)benzyloxypurine), 2-NBP (2-nitro-6-benzyloxypurine), and 3-NBG (O6-(3-nitro)benzylguanine). It should be noted that although the levels of the reduction products of 2-NBP and 3-NBG were lower than those of ANBP and AMNBP, their maximal hypoxic/normoxic ratios were higher than those of the other two prodrugs. Meanwhile, we also investigated the single electron reduction mechanism of the hypoxia-activated prodrugs using density functional theory (DFT) calculations. As a result, the reduction of the nitro group to the nitroso was proven to be a rate-limiting step. Moreover, the 2-nitro group of purine ring was more ready to be reduced than the 3-nitro group of benzyl. The energy barriers of the rate-limiting steps were 34-37 kcal/mol. The interactions between these prodrugs and nitroreductase were explored via molecular docking study, and ANBP was observed to have the highest affinity to nitroreductase, followed by AMNBP, 2-NBP, and 3-NBG. Interestingly, the theoretical results were generally in a good agreement with the experimental results. Finally, molecular docking and molecular dynamics simulations were performed to predict the AGT-inhibitory activity of the four prodrugs and their reduction products. In summary, simultaneous consideration of reduction potential and hypoxic selectivity is necessary to ensure that such prodrugs have good hypoxic tumor targeting. This study provides insights into the hypoxia-activated mechanism of nitro-substituted prodrugs as AGT inhibitors, which may contribute to reasonable design and development of novel tumor-targeted AGT inhibitors. Figure 2. Typical selected reaction monitoring (SRM) ion chromatograms of ABG, AMBG, and O 6 -BG obtained from the four prodrugs (3-NBG, 2-NBP, ANBP, and AMNBP) and the internal standard D6-O 6 -BG. The prodrugs were reduced in normoxic or hypoxic condition. (A) Control sample without 3-NBG and ANBP. (B) Reduction of 3-NBG and ANBP under normoxic conditions. (C) Reduction of 3-NBG and ANBP under hypoxic conditions. (D) Control...

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Section: Introductionmentioning

confidence: 99%

Reductive Activity and Mechanism of Hypoxia- Targeted AGT Inhibitors: An Experimental and Theoretical Investigation

Xiao

Sun

Fan

et al. 2019

IJMS

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“…For example, the effective anticancer therapeutic outcome of the O 6 -benzylguanine (O 6 -BG) was overshadowed by toxicity to normal cells and chemoresistance. Ge et al constructed N -(2-chloroethyl)- N ′-2-(2-(4-nitrobenzylcarbamate)-O 6 -benzyl-9-guanine)ethyl- N -nitrosourea (NBGNU) by assembling a chloroethyl nitrosourea pharmacophore and an O 6 -benzylguanine analog moiety modified with a 4-nitrobenzylcarbamate group to inhibit O 6 -alkylguanine-DNA alkyltransferase . Under hypoxia, the reduction in product amounts and cell mortality rates stimulated by NBGNU were much higher than under normoxia.…”

Section: Utilizing Hypoxiamentioning

confidence: 99%

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

Pan,

Liu,

Mou

et al. 2023

ACS Nano

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Cancer with a complex pathological process is a major disease to human welfare. Due to the imbalance between oxygen (O 2 ) supply and consumption, hypoxia is a natural characteristic of most solid tumors and an important obstacle for cancer therapy, which is closely related to tumor proliferation, metastasis, and invasion. Various strategies to exploit the feature of tumor hypoxia have been developed in the past decade, which can be used to alleviate tumor hypoxia, or utilize the hypoxia for targeted delivery and diagnostic imaging. The strategies to alleviate tumor hypoxia include delivering O 2 , in situ O 2 generation, reprogramming the tumor vascular system, decreasing O 2 consumption, and inhibiting HIF-1 related pathways. On the other side, hypoxia can also be utilized for hypoxia-responsive chemical construction and hypoxia-active prodrug-based strategies. Taking advantage of hypoxia in the tumor region, a number of methods have been applied to identify and keep track of changes in tumor hypoxia. Herein, we thoroughly review the recent progress of nanomedicine strategies in both conquering and utilizing hypoxia to combat cancer and put forward the prospect of emerging nanomaterials for future clinical transformation, which hopes to provide perspectives in nanomaterials design.

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“…The most widely used nitrobenzyl trigger in prodrugs has been the 4-nitrosubstituted isomer, due partly to its overall higher one-electron reduction potentials (e.g., −356 mV for 4-nitroacetophenone (10) [23]. Ge et al [24] reported the 4-nitrobenzyl-triggered hypoxiaactivated nitrosourea prodrug NBGNU (11), which was designed to induce DNA interstrand crosslinks following reduction, by inhibiting O6-alkylguanine-DNA alkyltransferase, an enzyme which has the ability to suppress the chemotherapeutic effect of chloroethylnitrosoureas by removing drug-induced alkyl groups from the O6-site of guanine. In human glioma SF763 cells in culture, 11 was about 5-fold more potent under hypoxic compared to oxic cultures (IC 50 s 580 and 126 µM, respectively), with much higher levels of dG-dCd crosslinks in human brain glioma SF126 than cells treated with nimustine (12) under hypoxia (Figure 4).…”

Section: -Nitrobenzyl Triggersmentioning

confidence: 99%

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Denny

2022

Pharmaceuticals

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The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.

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NBGNU: a hypoxia-activated Tripartite combi-nitrosourea Prodrug Overcoming AGT-mediated Chemoresistance

Cited by 9 publications

References 47 publications

Reductive Activity and Mechanism of Hypoxia- Targeted AGT Inhibitors: An Experimental and Theoretical Investigation

Reductive Activity and Mechanism of Hypoxia- Targeted AGT Inhibitors: An Experimental and Theoretical Investigation

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

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