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Chinese Journal of Chemistry 2023年第11期41卷 1327-1332页

作者： Miaomiao Tian Lingyun Yang Bingxian Liu Junbiao Chang NMPA Key Laboratory for Research and Evaluation of Innovative Drug School of Chemistry and Chemical EngineeringHenan Normal UniversityPingyuan LaboratoryXinxiangHenan453007 China

A Rh(III)-catalyzed,transmetalation triggered C—H activation/annulation of 2-biphenylboronic acids with diazo compounds fromβ-keto esters or 1,3-dicarboxylates has been developed,leading to the synthesis of two kinds of 9,10-phenanthrenes.Notably,a rhodacyle was synthesized by treating the rhodium catalyst with stoichiometric amounts of 2-biphenylboronic acids and pyridine,which was further verified to be active for the catalytic system.The reactions proceeded under redox-neutral and air-tolerant conditions to produce a series of all-carbon six-membered rings with high efficiency.

关键词： 9,10-Phenanthrenes Rh(Il)-catalyzed Diazo reagent Transmetallation Annulation Carbocycles C-Hactivation

Small molecule-based immunomodulators for cancer therapy

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4287-4308页

作者： Yinrong Wu Zichao Yang Kui Cheng Huichang Bi Jianjun Chen Guangdong Provincial key laboratory of New drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Immunotherapy has led to a paradigm shift in the treatment of cancer.Current cancer immunotherapies are mostly antibody-based,thus possessing advantages in regard to pharmacodynamics(e.g.,specificity and efficacy).However,they have limitations in terms of pharmacokinetics including long half-lives,poor tissue/tumor penetration,and little/no oral bioavailability.In addition,therapeutic antibodies are immunogenic,thus may cause unwanted adverse effects.Therefore,researchers have shifted their efforts towards the development of small molecule-based cancer immunotherapy,as small molecules may overcome the above disadvantages associated with antibodies.Further,small molecule-based immunomodulators and therapeutic antibodies are complementary modalities for cancer treatment,and may be combined to elicit synergistic effects.Recent years have witnessed the rapid development of small molecule-based cancer immunotherapy.In this review,we describe the current progress in small molecule-based immunomodulators(inhibitors/agonists/degraders)for cancer therapy,including those targeting PD-1/PD-L1,chemokine receptors,stimulator of interferon genes(STING),Toll-like receptor(TLR),etc.The tumorigenesis mechanism of various targets and their respective modulators that have entered clinical trials are also summarized.

关键词： Cancer immunotherapy Small molecules Immunomodulators Inhibitors Agonists

Synthesis of spirocyclopropylpyrazole derivatives via the cascade reaction of alkylidenecyclopropanes with pyrazolidinones and trifluoroethanol

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Organic Chemistry Frontiers 2022年第5期9卷 1410-1416页

作者： Mengyang Shen Yuanshuang Xu Xinying Zhang Xuesen Fan NMPA Key Laboratory for Research and Evaluation of Innovative Drug Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine ChemicalsKey Laboratory of Green Chemical Media and ReactionsMinistry of EducationSchool of Chemistry and Chemical EngineeringHenan Normal UniversityXinxiangHenan 453007China

A novel synthesis of spirocyclopropylpyrazole derivatives tethered with a trifluoromethyl unit through an unprecedented cascade reaction of alkylidenecyclopropanes with pyrazolidinones and trifluoroethanol(TFE)has bee... 详细信息

关键词： alkyl ethanol spiro

2,11-Dimethoxyldipyridopurinone as an efficientreducing visible-light photocatalyst for organic transformations

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Organic Chemistry Frontiers 2022年第6期9卷 1634-1641页

作者： Yameng Wan Qingfeng Liu Hao Wu Zhiguo Zhang Guisheng Zhang key laboratory of Green Chemical Media and Reactions Ministry of EducationCollaborative Innovation Center of Henan Province for Green Manufacturing of Fine ChemicalsHenan Key Laboratory of Organic Functional Molecules and Drug InnovationNMPA Key Laboratory for Research and Evaluation of Innovative DrugSchool of Chemistry and Chemical EngineeringHenan Normal University46 East of Construction RoadXinxiangHenan 453007China

We report for the first time 2,11-dimethoxyldipyridopurinone (DP4) as a potent reducing visible-lightphotocatalyst toward three prototypic organic transformations: redox-neutral intramolecular aryltrifluoromethylations of acrylamides and the direct C–H arylation of heteroarenes with aryl diazonium salts, netoxidative hydroxylations of arylboronic acids using molecular oxygen as a green oxidant, and the netreductive dehalogenation/deuteration of α-bromocarbonyl compounds. This work reveals a bright futurefor dipyridopurinone derivatives as a new class of metal-free visible-light photocatalysts for a wide rangeof organic transformations.

关键词： visible catalyst boron

Palladium-catalyzed multi components oxy-aminofluorination and aminofluorination of gem-difluoroalkenes

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Chinese Chemical Letters 2024年第2期35卷 420-425页

作者： Fen Wu Xin Li Junbiao Chang Dachang Bai State key laboratory of Antiviral drugs NMPA Key Laboratory for Research and Evaluation of Innovative DrugKey Laboratory of Green Chemical Media and ReactionsMinistry of EducationSchool of Chemistry and Chemical EngineeringPingyuan LaboratoryHenan Normal UniversityXinxiang 453007China State key laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Organofluorine compounds are widely used in the realm of drug discovery and material science.Herein,we developed palladium catalyzed intermolecular aminofluorination and oxy-aminofluorination of gem‑difluoroalkenes with N-fluorobenzenesulfonimide(NFSI),in which NFSI was used as the nitrogen source and oxidant.The reaction provides an efficient and straightforward synthesis route of a series ofα-trifluoromethyl benzylic amines.Notably,three/four components oxy-aminofluorination processes were realized to giveα-trifluoromethyl benzylic ether with a terminal amino group,which proceed through C(sp^(3))-O bond cleavage of easily available ether and simultaneous introduced a fluorine,an amino and an oxy substituent in one pot with excellent regioselectivity.The divergent reactivity not only included the incorporation of one ether molecular,but also much more challenged two ether insertion with excellent selectivity through succession C(sp^(3))-O bonds cleavage.This protocol allows for concise synthesis of high value amines with fluoroalkyl-substituents and selectively transformation of easily available ethers by high-valent palladium catalysis.

关键词： Palladium Multi components Aminofluorination Oxy-aminofluorination C(sp^(3))-O bond cleavage

Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator

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药学学报:英文版 2023年第7期13卷 3106-3120页

作者： Jingwen Dong Chenfei Zhu Ying Huang Quanhao Li Jing Li Zheng Wang Yixin Wang Zhanwei Zhou Minjie Sun nmpa key laboratory for research and evaluation of Pharmaceutical Preparations and Excipients State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors.Although degradation of fiber is a promising strategy,its application was still bottlenecked by the side effects of causing metastasis,resulting in the failure of immunotherapy.Here,we developed an antimetastatic polymer(HPA)for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator.Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis,and further promoted the sustained infiltration and activation of T cells for killing tumor cells.Moreover,metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs.The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+T cells to 52.5%in tumor tissues,inhibiting nearly 90%metastasis by HPA in distant organs.The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

关键词： Immune exclusion PAI-1 Fibrosis Deep penetration AMD3100 CXCR4/CXCL12 Metastasis Immunotherapy

Rh(Ⅲ)-Catalyzed Diverse C-H Functionalization of Iminopyridinium Ylides

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Chinese Journal of Chemistry 2021年第9期39卷 2489-2494页

作者： Zhenzhen Dong Pengfei Li Xingwei Li Bingxian Liu NMPA Key Laboratory for Research and Evaluation of Innovative Drug Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine ChemicalsSchool of Chemistry and Chemical EngineeringHenan Normal UniversityXinxiangHenan 453007China

Divergent synthesis of useful skeletons has been realized via rhodium(Ⅲ)-catalyzed C-H activation of iminopyridinium ylides and coupling with various unsaturated coupling reagents.Isocoumarins and isoquinolones were obtained via cleavage of the C-N or N-N bond in the ylidic di recti ng group,while fluorinated alkenes were delivered with the di recti ng group in tact.The reactions occurred with wide substrate scopes and good efficiency under redox-neutral and air-tolerant conditions.Representative products exhibit solid-state fluoresce nt property and bioactivity of in hibiti on toward huma n cancer cells.

关键词： C-H functionalization Iminopyridinium ylide Diverse transformation Redox-neutral Ylidic directing group

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1740-1754页

作者： Xiaoqing Liu Shuang Liang Xiao Sang Lili Chang Shunli Fu Han Yang Huizhen Yang Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

关键词： Nano-engager Cold tumors Increased DNA damage Augmented immunogenic cell death Dual immune checkpoint inhibition BRD4 inhibition Differ-targeting delivery MMP-2 sensitive

Design Strategy of Infrared 4-Hydroxybenzylidene-imidazolinone-Type Chromophores based on Intramolecular Charge Transfer:a Theoretical Perspective

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化学物理学报(英文) 2023年第5期36卷 582-592,I0002页

作者： Jian Song WenLong Liang Shouning Yang Huayan Yang School of Physics Henan Normal UniversityXinxiang 453007China NMPA Key Laboratory for Research and Evaluation of Innovative Drug Henan Key Laboratory of Organic Functional Molecule and Drug InnovationCollaborative Innovation Center of Henan Province for Green Manufacturing of Fine ChemicalsSchool of Chemistry and Chemical EngineeringHenan Normal UniversityXinxiang 453007China

Partial genetically encoded 4-hy-droxybenzylidene-imidazolinone(HBI)-type chromophores are new promising fluorescent probes,which are suitable for imaging and detection of living cells.How-ever,the lack of infrared chro-mophores hinders the develop-ment seriously.Here more than 30 HBI-type chromophores with reg-ular structure modifications were employed and typical spectral redshift change laws and mechanisms were investigated by quantum methods.Results show that both one-photon spectrum(OPS,absorption/emission)and two-photon absorption(TPA)can achieve large redshift via either extending conjugated lengths of frag-3 or enlarging conjugated areas of frag-1 of HBI skeleton.Spectral redshifts of all chromophores are highly related to intramolecular charge transfer(ICT),but neutral ones are closely related to the total ICT or electron-accept-ing-numbers of frag-3,and the high correlative factor of anions is the aromaticity of frag-2 bridge.The frag-2 bridge with high aromaticity can open a reverse charge transfer channel in anion relative to neutral,obtaining significant redshift.Based on analysis,a new 6-hydroxyl-naphthalene-imidazolinone(HNI)series,which have larger conjugated area in frag-1,are pre-dicted.The OPS and TPA of anionic HNI ones acquire about 76−96 nm and 119−146 nm red-shift relative to traditional HBI series respectively as a whole.The longest emission of anionic HNI-4 realizes more 244 nm redshift relative to HBI-1.Our work clarifies worthy spectral reg-ularities and redshift mechanisms of HBI-type chromophores and provides valuable design strategy for infrared chromophores synthesis in experiment.

关键词： Intramolecular charge transfer Near-infrared fluorescent chromophore 4-Hy-droxybenzylidene-imidazolinone One-photon spectrum Two-photon absorption

YAP regulates the liver size during the fasting-refeeding transition in mice

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1588-1599页

作者： Xuan Li Shicheng Fan Chenghui Cai Yue Gao Xinhui Wang Yifei Zhang Hangfei Liang Huilin Li Jie Yang Min Huang Huichang Bi Guangdong Provincial key laboratory of New drug Design and evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China nmpa key laboratory for research and evaluation of drug Metabolism&Guangdong Provincial key laboratory of New drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518000China

Liver is the central hub regulating energy metabolism during feeding-fasting transition.Evidence suggests that fasting and refeeding induce dynamic changes in liver size,but the underlying mechanisms remain unclear.Yes-associated protein(YAP)is a key regulator of organ size.This study aims to explore the role of YAP in fasting-and refeeding-induced changes in liver size.Here,fasting significantly reduced liver size,which was recovered to the normal level after refeeding.Moreover,hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting.Conversely,refeeding promoted hepatocyte enlargement and proliferation compared to fasted state.Mechanistically,fasting or refeeding regulated the expression of YAP and its downstream targets,as well as the proliferation-related protein cyclin D1(CCND1).Furthermore,fasting significantly reduced the liver size in AAV-control mice,which was mitigated in AAV Yap(5SA)mice.Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation.Besides,the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice.Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation.In summary,this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition,which provides new evidence for YAP in regulating liver size under energy stress.

关键词： Liver Fasting Refeeding Yes-associated protein Hepatocyte size Hepatocyte proliferation β-Catenin Cyclin D1