Abstract:
:O6-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 O6-benzylguanine (O6-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.
journal_name
Int J Mol Scijournal_title
International journal of molecular sciencesauthors
Xiao W,Sun G,Fan T,Liu J,Zhang N,Zhao L,Zhong Rdoi
10.3390/ijms20246308subject
Has Abstractpub_date
2019-12-13 00:00:00issue
24issn
1422-0067pii
ijms20246308journal_volume
20pub_type
杂志文章abstract::Colon cancer constitutes 33% of all cancer cases in humans and the majority of patients with metastatic colon cancer still have poor prognosis. An important role in cancer development is the communication between cancer and normal cells. This may occur, among others, through extracellular vesicles (including microvesi...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21051826
更新日期:2020-03-06 00:00:00
abstract::Osteochondrosis is a failure of the endochondral ossification that affects developing joints in humans and several animal species. It is a localized idiopathic joint disorder characterized by focal chondronecrosis and growing cartilage retention, which can lead to the formation of fissures, subchondral bone cysts, or ...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms20246179
更新日期:2019-12-07 00:00:00
abstract::Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to i...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms19051308
更新日期:2018-04-27 00:00:00
abstract::Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulation...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms22010274
更新日期:2020-12-29 00:00:00
abstract::The Asian cycads are mostly allopatric, distributed in small population sizes. Hybridization between allopatric species provides clues in determining the mechanism of species divergence. Horticultural introduction provides the chance of interspecific gene flow between allopatric species. Two allopatrically eastern Asi...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms14048228
更新日期:2013-04-15 00:00:00
abstract::The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains th...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21041539
更新日期:2020-02-24 00:00:00
abstract::Cell adhesion ability is one of the components to establish cell organization and shows a great contribution to human body construction consisting of various types of cells mixture to orchestrate tissue specific function. The cell adhesion molecule 1 (CADM1) is a molecule of cell adhesion with multiple functions and h...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21249732
更新日期:2020-12-20 00:00:00
abstract::MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pa...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms15011418
更新日期:2014-01-20 00:00:00
abstract::MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro, whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of other oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this study, we analyzed the role of HER rece...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms22010082
更新日期:2020-12-23 00:00:00
abstract::McArdle disease, also known as glycogen storage disease type V (GSDV), is characterized by exercise intolerance, the second wind phenomenon, and high serum creatine kinase activity. Here, we recapitulate PYGM mutations in the population responsible for this disease. Traditionally, McArdle disease has been considered a...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms20235919
更新日期:2019-11-25 00:00:00
abstract::Breakthroughs in the development of programmable site-specific nucleases, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases (MNs), and most recently, the clustered regularly interspaced short palindromic repeats (CRISPR) associated proteins (including Cas9)...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms18122565
更新日期:2017-11-29 00:00:00
abstract::In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, s...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms18071381
更新日期:2017-06-28 00:00:00
abstract::n/a. ...
journal_title:International journal of molecular sciences
pub_type: 评论,杂志文章
doi:10.3390/ijms18050994
更新日期:2017-05-05 00:00:00
abstract::Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions throu...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21041194
更新日期:2020-02-11 00:00:00
abstract::Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21228435
更新日期:2020-11-10 00:00:00
abstract::Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) sign...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms19010026
更新日期:2017-12-22 00:00:00
abstract::Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70-80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diag...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21165629
更新日期:2020-08-06 00:00:00
abstract::Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21186687
更新日期:2020-09-12 00:00:00
abstract::The paper studies the combined effects of beta-emitting radionuclide tritium and Humic Substances (HS) on the marine unicellular microorganism-luminous bacteria-under conditions of low-dose radiation exposures (<0.04 Gy). Tritium was used as a component of tritiated water. Bacterial luminescence intensity was consider...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21186783
更新日期:2020-09-16 00:00:00
abstract::Adiponectin is the adipokine associated with insulin sensitization, reducing liver gluconeogenesis, and increasing fatty acid oxidation and glucose uptake. Adiponectin is present in the kidneys, mainly in the arterial endothelium and smooth muscle cells, as well as in the capillary endothelium, and might be considered...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21249375
更新日期:2020-12-09 00:00:00
abstract::The excellent biocompatibility and biological effects of fullerenol and its derivatives make their biomedical application promising. The potential effects of fullerenol in mammals have been extensively studied, but little is known about its effects on female reproduction. Using canonical oocyte-granulosa cell complexe...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms19030699
更新日期:2018-03-01 00:00:00
abstract::The circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-associated factor X, MAX, plays a repressive role in this network and operates through a MYC-independent bind...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21072294
更新日期:2020-03-26 00:00:00
abstract::Photodynamic inactivation (PDI) is a non-antibiotic option for the treatment of infectious diseases. Although Gram-positive bacteria have been shown to be highly susceptible to PDI, the inactivation of Gram-negative bacteria has been more challenging due to the impermeability properties of the outer membrane. In the p...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms20010134
更新日期:2019-01-01 00:00:00
abstract::The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of th...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms21249608
更新日期:2020-12-17 00:00:00
abstract::Mucin1 (MUC1) is aberrantly glycosylated and overexpressed in various cancers, and it plays a crucial role in cancerogenesis. MUC1 is a type I membranous protein composed of α and β subunits. MUC1-α can be cleaved in cancers, exposing MUC1-β (MUC1-C). MUC1-C is involved with multiple cancer cellular functions, which m...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21093258
更新日期:2020-05-05 00:00:00
abstract::Perillafrutescen is used as traditional food and medicine in East Asia. Its seeds contain high levels of α-linolenic acid (ALA), which is important for health, but is scarce in our daily meals. Previous reports on RNA-seq of perilla seed had identified fatty acid (FA) and triacylglycerol (TAG) synthesis genes, but the...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms18112433
更新日期:2017-11-16 00:00:00
abstract::Microalgae are unicellular photosynthetic organisms considered as potential alternative sources for biomass, biofuels or high value products. However, limited biomass productivity is commonly experienced in their cultivating system despite their high potential. One of the reasons for this limitation is the high therma...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms19010155
更新日期:2018-01-05 00:00:00
abstract::Bacteria generate membrane vesicles, which are structures known as extracellular vesicles (EVs), reported to be involved in different pathogenic mechanisms, as it has been demonstrated that EVs participate in biofilm formation, cell-to-cell communication, bacteria-host interactions, and nutrients supply. EVs deliver n...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms20215307
更新日期:2019-10-25 00:00:00
abstract::Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, sig...
journal_title:International journal of molecular sciences
pub_type: 杂志文章,评审
doi:10.3390/ijms19061803
更新日期:2018-06-19 00:00:00
abstract::Various sulfonamide derivatives are intensively studied as anticancer agents owing to their inhibitory activity against human tumor-associated carbonic anhydrase isoforms. In this work, different synthetic procedures for the series of 1,3,5-triazinyl-aminobenzenesulfonamide conjugates with amino acids, possessing pola...
journal_title:International journal of molecular sciences
pub_type: 杂志文章
doi:10.3390/ijms21103661
更新日期:2020-05-22 00:00:00