期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024年146(9):6307-6316 ISSN：0002-7863
通讯作者：
Chen, FE;Zhou, H
作者机构：
[Zhao, Fei; Dong, Jianghu; Wang, Wei; Chen, Fen-Er; Yan, Qiongjiao; Xuan, Liangming; Chen, Qinlin; Fan, Rundong; Wang, Haifeng] Wuhan Inst Technol, Pharmaceut Res Inst, Sch Chem Engn & Pharm, Wuhan 430205, Peoples R China.;[Zhou, Hui] Cent China Normal Univ, Coll Chem, Wuhan 430079, Hubei, Peoples R China.;[Chen, Fen-Er] Fudan Univ, Engn Ctr Catalysis & Synth Chiral Mol, Dept Chem, Shanghai 200433, Peoples R China.;[Chen, Fen-Er] Shanghai Engn Ctr Ind Catalysis Chiral Drugs, Shanghai 200433, Peoples R China.
通讯机构：
[Zhou, H ] C;[Chen, FE ] W;Wuhan Inst Technol, Pharmaceut Res Inst, Sch Chem Engn & Pharm, Wuhan 430205, Peoples R China.;Cent China Normal Univ, Coll Chem, Wuhan 430079, Hubei, Peoples R China.;Fudan Univ, Engn Ctr Catalysis & Synth Chiral Mol, Dept Chem, Shanghai 200433, Peoples R China.
摘要：
Saturated hydrocarbon bonds are ubiquitous in organic molecules; to date, the selective functionalization of C(sp(3))-H bonds continues to pose a notorious difficulty, thereby garnering significant attention from the synthetic chemistry community. During the past several decades, a wide array of powerful new methodologies has been developed to enantioselectively modify C(sp(3))-H bonds that is successfully applied in asymmetric formation of diverse bonds, including C-C, C-N, and C-O bonds; nevertheless, the asymmetric C(sp(3))-H alkylation is elusive and, therefore, far less explored. In this work, we report a direct and robust strategy to construct highly valuable enantioenriched unnatural α-amino acid (α-AA) cognates and peptides by a copper-catalyzed enantioselective remote C(sp(3))-H alkylation of N-fluorocarboxamides and readily accessible glycine esters under ambient conditions. The key to success lies in the optically active Cu catalyst generated through the coordination of glycine derivatives to enantiopure bisphosphine/Cu(I) species, which is beneficial to the single electronic reduction of N-fluorocarboxamides and the subsequent stereodetermining alkylation. More importantly, all types (primary, secondary, tertiary, and even α-oxy) of δ-C(sp(3))-H bonds could be site- and stereospecifically activated by the kinetically favored 1,5-hydrogen atom transfer (1,5-HAT) step.
摘要：
Cancer cells need a greater supply of glucose mainly due to their aerobic glycolysis, known as the Warburg effect. Glucose transport by glucose transporter 1 (GLUT1) is the rate-limiting step for glucose uptake, making it a potential cancer therapeutic target. However, GLUT1 is widely expressed and performs crucial functions in a variety of cells, and its indiscriminate inhibition will cause serious side effects. In this study, we designed and synthesized a photocaged GLUT1 inhibitor WZB117-PPG to suppress the growth of cancer cells in a spatiotemporally controllable manner. WZB117-PPG exhibited remarkable photolysis efficiency and substantial cytotoxicity toward cancer cells under visible light illumination with minimal side effects, ensuring its safety as a potential cancer therapy. Furthermore, our quantitative proteomics data delineated a comprehensive portrait of responses in cancer cells under glucose deprivation, underlining the mechanism of cell death via necrosis rather than apoptosis. We reason that our study provides a potentially reliable cancer treatment strategy and can be used as a spatiotemporally controllable trigger for studying nutrient deprivation-related stress responses.
作者机构：
[Guan, Rui; Sun, Yao; Li, Junrong; Liu, Guorong] Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensor Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Yan, Mingzhe] Huazhong Univ Sci & Technol, Wuhan Jinyintan Hosp, Tongji Med Coll, Wuhan 430023, Peoples R China.;[Cheng, Jing] Wuhan Univ Sci & Technol, Sch Publ Hlth, Wuhan 430072, Peoples R China.;[Zhan, Jianbo] Hubei Prov Ctr Dis Control & Prevent, Inst Hlth Inspect & Testing, Wuhan 430072, Peoples R China.;[Wuethrich, Alain; Trau, Matt; Wuethrich, A] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Ctr Personalized Nanomed, Brisbane, Qld 4072, Australia.
通讯机构：
[Wuethrich, A ] U;[Sun, Y ] C;Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensor Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;Univ Queensland, Australian Inst Bioengn & Nanotechnol, Ctr Personalized Nanomed, Brisbane, Qld 4072, Australia.
摘要：
The molecular detection of multiple respiratory viruses provides evidence for the rational use of drugs and effective health management. Herein, we developed and tested the clinical performance of an electrohydrodynamic-driven nanobox-on-mirror platform (E-NoM) for the parallel, accurate, and sensitive detection of four respiratory viral antigens. The E-NoM platform uses gold-silver alloy nanoboxes as the core material with the deposition of a silver layer as a shell on the core surfaces to amplify and enable a reproducible Raman signal readout that facilitates accurate detection. Additionally, the E-NoM platform employs gold microelectrode arrays as the mirror with electrohydrodynamics to manipulate the fluid flow and enhance molecular interactions for an improved biosensing response. The presence of viral antigens binds the nanobox-based core-shell nanostructure on the gold microelectrode and creates the nanocavity with extremely strong "hot spots" to benefit sensitive analysis. Significantly, in a large clinical cohort with 227 patients, the designed E-NoM platform demonstrates the capability of screening respiratory infection with achieved clinical specificity, sensitivity, and accuracy of 100.0, 96.48, and 96.91%, respectively. It is anticipated that the E-NoM platform can find a position in clinical usage for respiratory disease diagnosis.
作者机构：
[Li, Qian; Yan, Qiang; Yan, Q; Li, Yuntao] Zhejiang Univ, Huzhou Cent Hosp, Affiliated Huzhou Hosp, Dept Gen Surg,Sch Med, Huzhou 313000, Peoples R China.;[Li, Qian; Sun, Yao; Zhao, Fang] Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Ye, Huan] Guangxi Univ, Sch Light Ind & Food Engn, Nanning 530004, Peoples R China.;[Zhang, ZP; Zhang, Zhipeng] Hubei Univ Sci & Technol, Xianning Med Coll, Coll Pharm, Xianning 437100, Peoples R China.
通讯机构：
[Zhang, ZP ] H;[Sun, Y ] C;[Yan, Q ] Z;Zhejiang Univ, Huzhou Cent Hosp, Affiliated Huzhou Hosp, Dept Gen Surg,Sch Med, Huzhou 313000, Peoples R China.;Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.
摘要：
Bacterial infections can lead to the development of large-scale outbreaks of diseases that pose a serious threat to human life and health. Also, conventional antibiotics are prone to producing resistance and allergic reactions, and their therapeutic effect is dramatically diminished when bacterial communities form biofilms. Fortunately, well-designed supramolecular coordination complexes (SCCs) have been used as antibacterials or anti-biofilms in recent years. SCCs can kill bacteria by directly engaging with the bacterial surface through electrostatic interactions or by penetrating the bacterial membrane through the auxiliary effect of cell-penetrating peptides. Furthermore, scientists have engineered fluorescent SCCs that can produce reactive oxygen species (ROS) to eliminate bacteria when exposed to laser irradiation, and they also demonstrate outstanding performance in in vivo imaging, enabling integrated diagnosis and treatment. In this review, we summarize the design strategy and applications of SCCs in antibacterials or anti-biofilms and provide an outlook on future research.
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY,2024年72(8):3884-3893 ISSN：0021-8561
通讯作者：
Lin, Hong-Yan;Wang, DW
作者机构：
[Ye, Bao-Qing; Yang, Guang-Fu; Cai, Zhuo-Mei; Chen, Li-Jun; Wang, Da-Wei; Dong, Jin; Huang, Guang-Yi; Lin, Hong-Yan; Lin, HY] Cent China Normal Univ, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Ye, Bao-Qing; Yang, Guang-Fu; Cai, Zhuo-Mei; Chen, Li-Jun; Wang, Da-Wei; Dong, Jin; Huang, Guang-Yi; Lin, Hong-Yan; Lin, HY] Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensor Technol &, Wuhan 430079, Peoples R China.
通讯机构：
[Wang, DW ; Lin, HY] C;Cent China Normal Univ, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensor Technol &, Wuhan 430079, Peoples R China.
摘要：
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is one of the most valuable herbicide targets due to its unique biological functions. In search of HPPD inhibitors with promising biological performance, we designed and synthesized a series of novel tetrazolamide-benzimidazol-2-ones using a structure-based drug design strategy. Among the synthesized compounds, 1-(2-chlorobenzyl)-3-methyl-N-(1-methyl-1H-tetrazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide, <bold>25</bold>, IC50 = 10 nM, was identified to be the most outstanding HPPD inhibitor, which showed more than 36-fold increased Arabidopsis thaliana HPPD (AtHPPD) inhibition potency than mesotrione (IC50 = 363 nM). Our AtHPPD-<bold>25</bold> complex indicated that one nitrogen atom on the tetrazole ring and the oxygen atom on the amide group formed a classical bidentate chelation interaction with the metal ion, the benzimidazol-2-one ring created a tight pi-pi stacking interaction with Phe381 and Phe424, and some hydrophobic interactions were also found between the ortho-Cl-benzyl group and surrounding residues. Compound <bold>32</bold> showed more than 80% inhibition against all four tested weeds at 150 g ai/ha by the postemergence application. Our results indicated that the tetrazolamide-benzimidazol-2-one scaffold may be a new lead structure for herbicide discovery.
摘要：
Engineering isolated metal sites resembling the primary coordination sphere of metallocofactors enables atomically dispersed materials as promising nanozymes. However, most existing nanozymes primarily focus on replicating specific metallocofactors while neglecting other supporting cofactors within active pockets, leading to reduced electron transfer (ET) efficiency and thus inferior catalytic performances. Herein, we report a metal–organic framework UiO-67 nanozyme with atomically dispersed iron sites, which involves multiple tailored enzyme-like nanocofactors that synergistically drive the ET process for enhanced peroxidase-like catalysis. Among them, the linker-coupled atomic iron site plays a critical role in substrate activation, while bare linkers and zirconia nodes facilitate the ET efficiency of intermediates. The synergy of three nanocofactors results in a 4.29-fold enhancement compared with the single effort of isolated metal site-based nanocofactor, holding promise in immunoassay for sensitive detection of chlorpyrifos. This finding opens a new way for designing high-performance nanozymes by harmonizing various nanocofactors at the atomic and molecular scale.
作者机构：
[Li, Guang; Xu, Weiwei; Hameed, Muhammad Salman; Yang, Qinglin; Li, Haibing; Qu, Haonan] Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Quan, Jiaxin; Quan, JX] Hanjiang Normal Univ, Dept Chem Biol & Environm Engn, Shiyan 442000, Peoples R China.;[Zhang, J; Zhang, Jin] Yunnan Normal Univ, Coll Chem & Chem Engn, Kunming 650092, Peoples R China.;[Sun, Zhongyue] Hubei Univ Chinese Med, Sch Lab Med, Wuhan 430065, Peoples R China.
通讯机构：
[Quan, JX ; Sun, ZY ] H;[Li, HB ] C;[Zhang, J ] Y;Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;Hanjiang Normal Univ, Dept Chem Biol & Environm Engn, Shiyan 442000, Peoples R China.
关键词：
arginine;biomimetic;mimic Cyt C transport;nanochannel;pH
摘要：
Proteins are vital components in cells, biological tissues, and organs, playing a pivotal role in growth and developmental processes in living organisms. Cytochrome C (Cyt C) is a class of heme proteins found in almost all life and is involved in cellular energy metabolic processes such as respiration, mainly as electron carriers or terminal reductases. It binds cardiolipin in the inner mitochondrial membrane, leading to apoptosis. It is a challenge to design a simple and effective artificial system to mimic the complex Cyt C biological transport process. In this paper, an asymmetric biomimetic pH-driven protein gate is described by introducing arginine (Arg) at one end of an hourglass-shaped nanochannel. The nanochannel shows a sensitive protonation-driven protein gate that can be "off" at pH = 7 and "on" at pH = 2. Further studies show that differences in the binding of Arg and Cyt C at different levels of protonation lead to different switching behaviors within the nanochannels, which in turn lead to different surface charges within the nanochannels. It can be used for detecting Cyt C and as an excellent and robust gate for developing integrated circuits and nanoelectronic logic devices.
作者机构：
[Qiu, Xiaofeng; Zheng, Juan; Zhu, Xiaoxiao; Zhang, Qian; Guo, Yanbing; Zhu, Yuhua; Chen, Wei; Zhang, Baojian; Guo, YB; Luo, Zhu; Li, Weihao; Pan, Chuanqi; Fang, Yarong; Wang, Jinlong] Cent China Normal Univ, Inst Environm & Appl Chem, Engn Res Ctr Photoenergy Utilizat Pollut Control &, Minist Educ,Coll Chem,Key Lab Pesticide & Chem Bio, Wuhan 430079, Peoples R China.;[Guo, Yanbing; Guo, YB; Luo, Zhu; Wang, Jinlong] Wuhan Inst Photochem & Technol, Wuhan 430082, Peoples R China.;[Wu, Jinsong; Wang, Yutao] Wuhan Univ Technol, Nanostruct Res Ctr, State Key Lab Adv Technol Mat Synth & Proc, Wuhan 430070, Peoples R China.;[Hu, Jinpeng; Wang, Sibo] Fujian Longxin 3D Array Technol Co Ltd, Longyan 364000, Peoples R China.;[Cui, Shuang] SINOPEC Beijing Res Inst Chem Ind Co Ltd, Div Anal, Beijing 100013, Peoples R China.
通讯机构：
[Guo, YB ; Luo, Z] C;Cent China Normal Univ, Inst Environm & Appl Chem, Engn Res Ctr Photoenergy Utilizat Pollut Control &, Minist Educ,Coll Chem,Key Lab Pesticide & Chem Bio, Wuhan 430079, Peoples R China.;Wuhan Inst Photochem & Technol, Wuhan 430082, Peoples R China.
关键词：
(Pt−S−O)-Ti active structure;C3H8 catalytic oxidation;C−H bond activation;Pt-based catalysts;SO2 promotion
摘要：
Typically, SO(2) unavoidably deactivates catalysts in most heterogeneous catalytic oxidations. However, for Pt-based catalysts, SO(2) exhibits an extraordinary boosting effect in propane catalytic oxidation, but the promotive mechanism remains contentious. In this study, an in situ-formed tactful (Pt-S-O)-Ti structure was concluded to be a key factor for Pt/TiO(2) catalysts with a substantial SO(2) tolerance ability. The experiments and theoretical calculations confirm that the high degree of hybridization and orbital coupling between Pt 5d and S 3p orbitals enable more charge transfer from Pt to S species, thus forming the (Pt-S-O)-Ti structure with the oxygen atom dissociated from the chemisorbed O(2) adsorbed on oxygen vacancies. The active oxygen atom in the (Pt-S-O)-Ti active structure is a robust site for C(3)H(8) adsorption, leading to a better C(3)H(8) combustion performance. This work can provide insights into the rational design of chemical bonds for high SO(2) tolerance catalysts, thereby improving economic and environmental benefits.
期刊：
CHEMICAL SOCIETY REVIEWS,2024年53(1):137-162 ISSN：0306-0012
通讯作者：
Zhu, CZ;Lin, YH
作者机构：
[Xu, Weiqing; Zhu, Chengzhou; Wu, Yu; Zhu, CZ; Gu, Wenling] Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensing Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Lin, YH; Du, Dan; Lin, Yuehe] Washington State Univ, Sch Mech & Mat Engn, Pullman, WA 99164 USA.
通讯机构：
[Lin, YH ] W;[Zhu, CZ ] C;Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensing Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;Washington State Univ, Sch Mech & Mat Engn, Pullman, WA 99164 USA.
摘要：
Natural metalloenzymes with astonishing reaction activity and specificity underpin essential life transformations. Nevertheless, enzymes only operate under mild conditions to keep sophisticated structures active, limiting their potential applications. Artificial metalloenzymes that recapitulate the catalytic activity of enzymes can not only circumvent the enzymatic fragility but also bring versatile functions into practice. Among them, metal-organic frameworks (MOFs) featuring diverse and site-isolated metal sites and supramolecular structures have emerged as promising candidates for metalloenzymes to move toward unparalleled properties and behaviour of enzymes. In this review, we systematically summarize the significant advances in MOF-based metalloenzyme mimics with a special emphasis on active pocket engineering at the atomic level, including primary catalytic sites and secondary coordination spheres. Then, the deep understanding of catalytic mechanisms and their advanced applications are discussed. Finally, a perspective on this emerging frontier research is provided to advance bioinspired catalysis. This review systematically summarizes the significant advances in MOF-based metalloenzyme mimics for bioinspired catalysis with a special emphasis on active pocket engineering at the atomic level.
摘要：
The contamination of drinking water by microbes is a critical health concern, underscoring the need for safe, reliable, and efficient methods to treat pathogenic microorganisms. While most sterilization materials are available in powder form, this presents safety risks and challenges in recycling. Herein, this study reports the preparation of an innovative copper oxide supported silver monolithic nanoarray mesh with abundant oxygen vacancies (Ag/CuO-V(O)) by laser ablation. The instantaneous high temperature caused by laser ablation preserves the material's original structure while generating oxygen vacancies on the CuO surface. The Ag/CuO-V(O) mesh demonstrated a remarkable ability to inactivate over 99% of Escherichia coli (E. Coli) within 20min. The oxygen vacancies in the Ag/CuO-V(O) enhance interactions between oxygen species and the Ag/CuO-V(O), leading to the accumulation of large amounts of reactive oxygen species (ROS). The generated ROS effectively disrupt both layers of the bacterial cell wall - the peptidoglycan and the phospholipid - as confirmed by Fourier Transform Infrared (FTIR) spectroscopy, culminating in cell death. This research presents a monolithic material capable of inactivating pathogenic microorganisms efficiently, offering a significant advancement in water sterilization technology.
作者机构：
[Zhu, Chengzhou; Gu, Wenling; Li, Jingshuai; Xi, Mengzhen] Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensing Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Hu, Liuyong] Wuhan Inst Technol, Hubei Engn Technol Res Ctr Optoelect & New Energy, Hubei Key Lab Plasma Chem & Adv Mat, Wuhan 430205, Peoples R China.;[Sun, Hongcheng] Hangzhou Normal Univ, Coll Mat Chem & Chem Engn, Key Lab Organosilicon Chem & Mat Technol, Minist Educ, Hangzhou 311121, Peoples R China.;[Gu, Wenling] Key Lab Opt Elect Sensing & Analyt Chem Life Sci, MOE, Qingdao 266042, Peoples R China.
通讯机构：
[Gu, WL ] C;Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensing Technol &, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;Key Lab Opt Elect Sensing & Analyt Chem Life Sci, MOE, Qingdao 266042, Peoples R China.
摘要：
Improving the sensitivity in electrochemiluminescence (ECL) detection systems necessitates the integration of robust ECL luminophores and efficient signal transduction. In this study, we report a novel ECL nanoprobe (Zr-MOF) that exhibits strong and stable emission by incorporating aggregation-induced emission ligands into Zr-based metal-organic frameworks (MOFs). Meanwhile, we designed a high-performance signal modulator through the implementation of a well-designed controlled release system with a self-on/off function. ZnS quantum dots (QDs) encapsulated within the cavities of aminated mesoporous silica nanoparticles (NH(2)-SiO(2)) serve as the ECL quenchers, while adenosine triphosphate (ATP) aptamers adsorbed on the surface of NH(2)-SiO(2) through electrostatic interaction act as "gatekeepers." Based on the target-triggered ECL resonance energy transfer between Zr-MOF and ZnS QDs, we establish a coreactant-free ECL aptasensor for the sensitive detection of ATP, achieving an impressive low detection limit of 0.033 nM. This study not only demonstrates the successful combination of ECL with controlled release strategies but also opens new avenues for developing highly efficient MOFs-based ECL systems.
摘要：
Picolinamide fungicides, structurally related to UK-2A and antimycin-A, bind into the Qi-site in the bc(1) complex. However, the detailed binding mode of picolinamide fungicides remains unknown. In the present study, antimycin-A and UK-2A were selected to study the binding mode of picolinamide inhibitors with four protonation states in the Qi-site by integrating molecular dynamics simulation, molecular docking, and molecular mechanics Generalized Born surface area (MM/GBSA) calculations. Subsequently, a series of new picolinamide derivatives were designed and synthesized to further understand the effects of substituents on the tail phenyl ring. The computational results indicated that the substituted aromatic rings in antimycin-A and UK-2A were the pharmacophore fragments and made the primary contribution when bound to a protein. Compound 9g-hydrolysis formed H-bonds with Hie201 and Ash228 and showed an IC(50) value of 6.05 ± 0.24 μM against the porcine bc(1) complex. Compound 9c, with a simpler chemical structure, showed higher control effects than florylpicoxamid against cucumber downy mildew and expanded the fungicidal spectrum of picolinamide fungicides. The structural and mechanistic insights obtained from the present study will provide a valuable clue for the future designing of new promising Qi-site inhibitors.
摘要：
Ten previously unreported [11]-chaetoglobosins, chaepseubakerins A-J (1-10), were characterized from the solid rice-based culture of Pseudeurotium bakeri P1-1-1, an endophyte harbored in the roots of Macrocoma tenue subsp. sullivantii Vitt. (Orthotrichaceae). Their structures were determined by spectroscopic analysis, single -crystal X-ray diffraction (Cu K alpha radiation), and chemical methods. Chaepseubakerin A (1) exhibited signifi-cant cytotoxic effects against seven human cancer cell lines, A549, A427, HCT116, HT-29, HeLa, HepG2, and MCF-7, with IC50 values of 2.9, 3.0, 4.0, 4.4, 7.1, 6.7, and 8.9 mu M, respectively. Mechanistically, 1 induced G2/M cell cycle arrest and apoptosis in A549, Hela, and HCT116 cells in a dose dependent manner.
作者机构：
[Chen, Shuibing; Pan, Fong Cheng; Feng, Lingling; Evans, Todd; Pan, FC; Duan, Xiaohua; de Silva, Neranjan; Greenspun, Benjamin; Chandwani, Rohit] Weill Cornell Med, Dept Surg, 1300 York Ave, New York, NY 10065 USA.;[Chen, Shuibing; Evans, Todd; Duan, Xiaohua; Greenspun, Benjamin] Weill Cornell Med, Ctr Genom Hlth, 1300 York Ave, New York, NY 10065 USA.;[Zhang, Tuo] Weill Cornell Med, Genom Resources Core Facil, New York, NY 10065 USA.;[Feng, Lingling] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol CCNU, Minist Educ, Wuhan 430079, Hubei, Peoples R China.;[Wang, Xing; Moyer, Jenna; Elemento, Olivier; Martin, M. Laura] Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY USA.
通讯机构：
[Evans, T; Chen, SB; Chen, SB ; Pan, FC ] W;Weill Cornell Med, Dept Surg, 1300 York Ave, New York, NY 10065 USA.;Weill Cornell Med, Ctr Genom Hlth, 1300 York Ave, New York, NY 10065 USA.
关键词：
KRAS;SREBP2;cholesterol biosynthesis;colon cancer organoids;lung cancer organoids;orthotopic transplantation;pancreatic organoid;perhexiline maleate;targeted therapy
摘要：
KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRAS(G12C) suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the Kras(G12D) mutation both invitro and invivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.
作者机构：
[Zhang, Xiangqian; Chen, Yu; Deng, GZ; Feng, Huili; Deng, Ganzhen; Zhou, Qingqing] Huazhong Agr Univ, Coll Vet Med, State Key Lab Agr Microbiol, Wuhan 430070, Peoples R China.;[Liu, Shuang] Wuhan Univ Technol, Sch Mat Sci & Engn, 122 Luoshi Rd, Wuhan 430070, Peoples R China.;[Li, JR; Li, Junrong; Li, Chonglu] Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticides, Wuhan 430079, Peoples R China.;[Guan, Xiaofang] Wuhan Univ Sci & Technol, Hubei Prov Key Lab Occupat Hazard Identificat & C, Wuhan 430081, Peoples R China.;[Deng, Yun; Fu, Cheng] Jianghan Univ, Key Lab Optoelect Chem Mat & Devices, Minist Educ, Wuhan 430056, Peoples R China.
通讯机构：
[Liu, S ] W;[Li, JR ] C;[Deng, GZ ] H;Huazhong Agr Univ, Coll Vet Med, State Key Lab Agr Microbiol, Wuhan 430070, Peoples R China.;Wuhan Univ Technol, Sch Mat Sci & Engn, 122 Luoshi Rd, Wuhan 430070, Peoples R China.
摘要：
High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy. High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy.
摘要：
The role of AXL in various oncogenic processes has made it an attractive target for cancer therapy. Currently, kinase selectivity profiles, especially circumventing MET inhibition, remain a scientific issue of great interest in the discovery of selective type II AXL inhibitors. Starting from a dual MET/AXL-targeted lead structure from our previous work, we optimized a 1,6-naphthyridinone series using molecular modeling-assisted compound design to improve AXL potency and selectivity over MET, resulting in the potent and selective type II AXL-targeted compound 25c. This showed excellent AXL inhibitory activity (IC(50)=1.1nM) and 343-fold selectivity over the highly homologous kinase MET in biochemical assays. Moreover, compound 25c significantly inhibited AXL-driven cell proliferation, dose-dependently suppressed 4T1 cell migration and invasion, and induced apoptosis. Compound 25c also showed noticeable antitumor efficacy in a BaF3/TEL-AXL xenograft model at well-tolerated doses. Overall, this study presented a potent and selective type II AXL-targeted lead compound for further drug discovery.
期刊：
JOURNAL OF NATURAL PRODUCTS,2024年87(1):141-151 ISSN：0163-3864
通讯作者：
Ruan, HL
作者机构：
[Ruan, Han-Li; Hu, Jia-Yun; Qin, Chun-Lun; Chang, Jin-Ling; Pei, Jiao; Ouyang, Qian-Xi; Ruan, HL; Zhou, Yin-Hui] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China.;[Meng, Xiang-Gao] Cent China Normal Univ, Coll Chem, Wuhan 430079, Peoples R China.
通讯机构：
[Ruan, HL ] H;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Peoples R China.
摘要：
Twelve new austalide meroterpenoids (1-12) were isolated from the endophytic fungus Diaporthe sp. XC1211. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1, 3, 4, and 6 were established by single-crystal X-ray diffraction, whereas those for the others were established by experimental electronic circular dichroism (ECD) data analysis. Compounds 1-12 represent a rare class of austalides with a 24α-CH(3). Compounds 2 and 5 demonstrated potent proliferation inhibitory effects against LPS-induced B cells with IC(50) values of 6.7 (SI = 3.6) and 3.8 (SI > 13) μM, respectively. Compounds 2 and 5 decreased the secretion of IL-6 in LPS-induced B cells in a dose-dependent manner.
作者机构：
[Wang, SW; Wang, Shaowei; Liu, Shuang] Chinese Acad Sci, Shanghai Inst Tech Phys, State Key Lab Infrared Phys, 420 Zhongshan Rd, Shanghai 200434, Peoples R China.;[Zhang, Qiuxin] Brandeis Univ, Dept Chem, 415 South St, Waltham, MA 02454 USA.;[Peng, Xingrao; Sun, Yao] Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.;[Hu, Cong] Guilin Univ Elect Technol, Guangxi Key Lab Automat Detecting Technol & Instru, Guilin 541004, Peoples R China.
通讯机构：
[Wang, SW ; Sun, Y ; Liu, S] C;Chinese Acad Sci, Shanghai Inst Tech Phys, State Key Lab Infrared Phys, 420 Zhongshan Rd, Shanghai 200434, Peoples R China.;Cent China Normal Univ, Coll Chem, Natl Key Lab Green Pesticide, Wuhan 430079, Peoples R China.
摘要：
Herein, we show a pair of leucine-rich l- and d-phosphopeptides which self-assemble into twisting nanofibers, whose secondary structures contain a strong beta-sheet component after being dephosphorylated by alkaline phosphatase (ALP). While being incubated with ALP overexpressing osteosarcoma cells, both of the peptides self-assemble in the nuclei and induce cell death. The cell death involves multiple cell death modalities and occurs along with the disruption of cell membranes. Enzyme-instructed self-assembly (EISA) inhibits osteosarcoma cells and shows no side effect to other cells. In addition, the cancer cells hardly gain drug resistance after repeated treatment. This work reports a pair of EISA-based nanofibers to target cell nuclei, and also provides a novel chemotherapeutic agent to inhibit osteosarcoma cells without side effects and drug resistance. Dephosphorylated by the highly expressed alkaline phosphatase, phosphopeptides self-assemble into twisted nanofibers in nuclei to selectively induce the death of osteosarcoma cells.
