JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Yang Liuxin,Cheng Yiyu,Qin Si,Jiang Jun,Zhong Shiyi,Bi Xinyue,Xu Jiali,Wang Kai,Qiu Shuang,Li Xiang
Cellular resilience to therapy often arises from adaptive
mechanisms
that safeguard iron–sulfur (Fe–S) proteins. Here, we
present a rational strategy to overcome such resilience by integrating
two synergistic vulnerabilities, copper toxicity and Fe–S cluster
homeostasis, into a single molecular scaffold. Inspired by a bacterial
sulfur mobilization (SUF) inhibitor, we hybridized its core structure
with a copper-transporting 8-hydroxyquinoline moiety to generate HDQ , HDQ-S , HDQ-Ph , and HDQ-Me . They coordinate copper via hydroxyquinoline and efficiently transport
copper into cancer cells, with HDQ-Me achieving an efficacy
comparable to that of the clinical copper ionophore elesclomol ( ES ). Strikingly, HDQ alone suppresses Fe–S
proteins across multiple functions, including respiration, iron homeostasis,
and DNA replication. HDQ -mediated copper loading triggers
cuproptosis hallmarks, DNA damage, and ATP collapse, generating a
synergistic lethality. This work establishes HDQs as
bifunctional tools that cotarget copper and Fe–S protein homeostasis,
validating a convergent therapeutic strategy against resilient cells.
✓ 已验证
产品关联
DOI
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2023
·
IF 11.4
Guangrong Sun,Pei Guo,Han Yeong Kaw,Meijiao Zhou,Wei Wang
Constant efforts have been devoted to exploring new disinfection byproducts in drinking water causally related to adverse health outcomes. In this study, five halogenated nucleobases were identified as emerging disinfection byproducts in drinking water, including 5-chlorouracil, 6-chlorouracil, 2-chloroadenine, 6-chloroguanine, and 5-bromouracil. We developed a solid phase extraction–ultraperformance liquid chromatography–tandem mass spectrometry method with the limits of detection (LOD) and recoveries ranging between 0.04–0.86 ng/L and 54–93%, respectively. The detection frequency of the five halogenated nucleobases ranged from 73 to 100% with a maximum concentration of up to 65.3 ng/L in the representative drinking water samples. The cytotoxicity of the five identified halogenated nucleobases in Chinese hamster ovary (CHO-K1) cells varied with great disparity, in which the cytotoxicity of 2-chloroadenine (IC50 = 9.4 μM) is appropriately three times higher than emerging DBP 2,6-dichloro-1,4-benzoquinone (IC50 = 42.4 μM), indicating the significant toxicological risk of halogenated nucleobase-DBPs. To the best of our knowledge, this study reports the analytical method, occurrence, and toxicity of halogenated nucleobase-DBPs for the first time. These findings will provide a theoretical basis for further research on probing the relationship between its mutagenicity and human health risk.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
APPLIED SURFACE SCIENCE
·
2019
·
IF 5.155
Meng Tian,Zhenhua Li,Ruihong Song,Yingxian Li,Chengang Guo,Yujie Sha,Wanling Cui,Shicai Xu,Guodong Hu,Jihua Wang
Guanine riboswitch (GR) is located in the untranslated region of mRNA that performs important biological functions by interactions with specific ligand molecules. The present standard methods for detecting mRNA has been widely used, but suffer from extra labeling steps, high cost, low throughput, low sensitivities and limited dynamic ranges. The field effect transistor (FET) biosensors showed high performance in detecting a large number of biological analytes. However, the detection of analytes with low charge and small molecule still remains a challenge. In this paper, a label-free graphene field effect transistor (G-FET) biosensor has been developed to detect the binding interactions between GR and four purine analog ligand molecules (GUA, 6GU, 2BP, XAN). We demonstrated that the G-FET biosensor were highly sensitive in detecting the electric-neutral and low molecular weight ligands by using GR as probe. The sensing mechanisms for electric-neutral molecule is revealed by molecular dynamics simulation. The equilibrium dissociation constants K D and binding free energy Δ G of GR-GUA, GR-6GU, GR-2BP and GR-XAN were obtained by the G-FET biosensor, and the results are comparable with the calculated by molecular dynamics simulation and previous reports. We demonstrated that the G-FET biosensor can be used as affinity biosensors to quantify biomolecular interactions.
✓ 已验证
产品关联
DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2018
·Vol. 42
·期 16
·13375-13381
·
IF 3.201
Haobo Han,Wenqi Chen,Jiebing Yang,Jiayuan Zhang,Quanshun Li,Yan Yang
The modification of 2-amino-6-chloropurine on polyamidoamine was performed to synthesize a derivative, AP-PAMAM, which was then employed as a carrier for p53 gene delivery to achieve anti-tumor efficacy. Using a human prostate tumor cell line PC-3 as a model, enhanced expression level of p53 gene could be detected by RT-PCR, qPCR and western blotting. Based on the successful p53 gene transfection, an obvious anti-proliferative effect could be obtained, which was identified to be associated with the simultaneous induction of cell apoptosis and cell cycle arrest at the G1 phase. The cell apoptosis was elucidated to be triggered by the activation of the mitochondria-dependent apoptotic signaling pathway. In addition, AP-PAMAM/p53 transfection could restrain the migration of tumor cells as demonstrated by wound healing and Transwell migration assays. Notably, AP-PAMAM-mediated p53 delivery exhibited a stronger inhibitory effect on both cell proliferation and migration than the PAMAM/p53 group. In summary, AP-PAMAM/p53 transfection provided a promising route to achieve the p53-based gene therapy.
✓ 已验证
产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2015
·
IF 4.152
Hui Wang,Haifeng Wei,Quan Huang,Hongmei Liu,Jingjing Hu,Yiyun Cheng,Jianru Xiao
Cationic dendrimers are associated with relatively low transfection efficacy and high toxicity in gene delivery. Surface modification of these dendrimers with functional ligands may resolve these issues. Here, we proposed a novel strategy to prepare surface-engineered dendrimers with high transfection efficacy and low toxicity on transfected cells. Several nucleobase analogues were modified on cationic dendrimers by a facile method. These nucleobase-modified dendrimers show improved transfection efficacy and reduced cytotoxicity compared to unmodified dendrimers on HEK293 and HeLa cells. Efficacy of the most efficient polymer is comparable to that of commercial transfection reagents such as SuperFect, PolyFect, and Lipofectamine 2000. The improved transfection efficacy of dendrimers after nucleobase modification is probably attributed to easier intracellular DNA unpacking and lower cytotoxicity. The results provide a valuable insight to guide the design of efficient and low cytotoxic gene vectors.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-11
·
IF 5.228
Liu Hongmei,Chang Hong,Lv Jia,Jiang Cong,Li Zhenxi,Wang Fei,Wang Hui,Wang Mingming,Liu Chongyi,Wang Xinyu,Shao Naimin,He Bingwei,Shen Wanwan,Zhang Qiang,Cheng Yiyun
Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2017
·Vol. 5
·期 11
·2268-2275
·
IF 4.21
Haobo Han,Jiebing Yang,Yudi Wang,Wenqi Chen,Jiawen Chen,Yan Yang,Quanshun Li
The nucleobase analogue 2-amino-6-chloropurine was modified on the surface of polyamidoamine (PAMAM) to construct a derivative AP-PAMAM, and then it was used as a gene carrier for miR-23b delivery to achieve the anti-tumor effects. The carrier AP-PAMAM could condense miR-23b into stable nanoparticles with a particle size of 97.3 nm (N/P ratio of 50), which was favorable for the cellular uptake of nanoparticles. Compared with PAMAM, AP-PAMAM exhibited an obviously enhanced transfection efficiency through the transfection assay of plasmids pEGFP-N3 and pGL-3. Using the human lung adenocarcinoma cell line A549 as a model, AP-PAMAM-mediated miR-23b delivery could achieve a stronger anti-proliferative effect than PAMAM/miR-23b. The inhibition of cell proliferation was elucidated to be associated with the apoptotic induction (apoptotic ratio of 23.2%) and S phase arrest owing to the decreased expression level of cyclin D1. Meanwhile, the AP-PAMAM-mediated miR-23b delivery could suppress the cell migration and invasion of cancer cells through wound healing and Transwell migration assays. In summary, the PAMAM derivative-mediated miR-23b delivery could be a promising strategy for achieving tumor gene therapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）