Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU

Wang, Yameng; Lai, Xinxin; Sun, Guizhi; Zhao, Lu; Zhang, Na; Zhong, Rugang

doi:10.1021/acsmedchemlett.6b00358

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…The reduction products took the correct orientation as the crystal structure of AGT-DNA complex with PDB entry 1T38 ( Figure S18), and several hydrogen bonds were formed between the ligands and the amino acid residuals in the active pocket (Table 3). Four hydrogen bonds were formed between O 6 -BG and Tyr114, Cys145, Val148, and Ser159, which was consistent with the results of previous studies [52][53][54]. Five hydrogen bonds were observed between ABG or AMBG and AGT.…”

Section: Docking Resultssupporting

confidence: 91%

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: Docking Resultssupporting

confidence: 91%

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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“…The retention time of NBGNU was 12.2 min. As shown in Figure 3, the half-life of NBGNU in MEM-EBSS was 18 min, which was slightly longer than the 15 and 12 min half-lives of BCNU (in plasma) and ACNU (in plasma), respectively and was similar to those reported for combi-nitrosoureas (in cell culture media) in our previous studies [29,45,50,51].…”

Section: Stability Of Nbgnusupporting

confidence: 87%

“…Cell viability assay was determined by the Cell Counting Kit-8 (CCK-8, Dojindo China CO., Ltd, Shanghai, China) assay. Before treatment with drugs, human glioma SF763 cells with high AGT expression (119 fmol/10 6 cells) [43,44] were seeded as previous described [45]. Then the cells were incubated in fresh medium containing drugs with proposed concentrations for 24 h. The combination-treated groups were pretreated by O 6 -BG (20 μM) for 2 h before exposure to ACNU for 24 h. Subsequently, cells were treated with 10% CCK-8 reagent in fresh medium for 4 h, followed by measuring the absorbance at 450 nm.…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…The negative control groups were incubated without drugs under the same conditions as the treated groups. Then the obtained cellular pellets were used for DNA isolation and enzymatic hydrolysis according previous studies [29,[45][46][47][48], which was described in the Supplementary Materials.…”

Section: Determination Of Dguo-dcyd Crosslinks In Cellsmentioning

confidence: 99%

“…The dGuo-dCyd crosslinks in DNA enzymatic hydrolysis was quantified by HPLC-ESI-MS/MS as previously described with minor modification [29,45,46]. Briefly, the analytes were separated using a reverse phase column (ZORBAX SB C18, column size 2.1 × 150 mm 2 ; particle size 5 μm; Agilent Technologies, CA, USA).…”

Section: Hplc-ms Analysis Of Dguo-dcyd Crosslinksmentioning

confidence: 99%

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

Lai

et al. 2018

Future Med. Chem.

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A hypoxia-activated combi-nitrosourea prodrug, N-(2-chloroethyl)-N -2-(2-(4-nitrobenzylcarbamate)-O 6 -benzyl-9-guanine)ethyl-N-nitrosourea (NBGNU), was synthesized and evaluated for its hypoxic selectivity and anticancer activity in vitro. Results: The prodrug was designed as a tripartite molecule consisting of a chloroethylnitrosourea pharmacophore to induce DNA interstrand crosslinks (ICLs) and an O 6 -benzylguanine analog moiety masked by a 4-nitrobenzylcarbamate group to induce hypoxia-activated inhibition of O 6 -alkylguanine-DNA alkyltransferase. NBGNU was tested for hypoxic selectivity, cytotoxicity and DNA ICLs ability. The reduction product amounts, cell death rates and DNA ICL levels induced by NBGNU under hypoxic conditions were all significantly higher than those induced by NBGNU under normoxic conditions. Conclusion: The tripartite combi-nitrosourea prodrug exhibits desirable tumor-hypoxia targeting ability and abolished chemoresistance compared with the conventional chloroethylnitrosoureas.

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Triazines, Tetrazines, and Fused Ring Polyaza Systems

Audebert

Allain

2018

Progress in Heterocyclic Chemistry

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Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU

Cited by 11 publications

References 30 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

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

Triazines, Tetrazines, and Fused Ring Polyaza Systems

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