22 results on '"Shipeng He"'
Search Results
2. Strategies for designing proteolysis targeting chimaeras (PROTACs)
- Author
-
Shipeng, He, Guoqiang, Dong, Junfei, Cheng, Ying, Wu, and Chunquan, Sheng
- Subjects
Pharmacology ,Proteolysis ,Drug Discovery ,Humans ,Molecular Medicine - Abstract
Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the molecular design and drug development of PROTACs is efficient identification of potent and drug-like degraders. This review aims to comprehensively summarize and analyse state-of-the-art methods and strategies in the design of PROTACs. We provide a detailed illustration of the general principles and tactics for designing potent PROTACs, highlight representative case studies, and discuss the advantages and limitations of these strategies. Particularly, structure-based rational PROTAC design and emerging new types of PROTACs (e.g., homo-PROTACs, multitargeting PROTACs, photo-control PROTACs and PROTAC-based conjugates) will be focused on. more...
- Published
- 2022
- Full Text
- View/download PDF
Catalog
3. Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer
- Author
-
Kaijian Bi, Junfei Cheng, Shipeng He, Yuxin Fang, Min Huang, Chunquan Sheng, and Guoqiang Dong
- Subjects
Drug Discovery ,Molecular Medicine - Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader ( more...
- Published
- 2022
4. Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation
- Author
-
Donghuan Sun, Jing Zhang, Guoqiang Dong, Shipeng He, and Chunquan Sheng
- Subjects
Drug Discovery ,Proteolysis ,Ubiquitination ,Molecular Medicine ,Humans ,Proteins ,Signal Transduction - Abstract
The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions. more...
- Published
- 2022
5. Nucleic-Acid-Based Targeted Degradation in Drug Discovery
- Author
-
Wei Wang, Shipeng He, Guoqiang Dong, and Chunquan Sheng
- Subjects
Nucleic Acids ,Drug Discovery ,Proteolysis ,Molecular Medicine ,Proteins ,RNA - Abstract
Targeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the application of conventional PROTACs is limited to protein targets containing cytosolic domains with ligandable sites. Recently, nucleic-acid-based modalities, such as modified oligonucleotide mimics and aptamers, opened new avenues to degrade protein targets and greatly expanded the scope of TPD. Beyond constructing protein-degrading chimeras, nucleic acid motifs can also serve as substrates for targeted degradation. Particularly, the new type of chimeric RNA degrader termed ribonuclease-targeting chimera (RIBOTAC) has shown promising features in drug discovery. Here, we provide an overview of the newly emerging TPD strategies based on nucleic acids as well as new strategies for targeted degradation of nucleic acid (RNA) targets. The design strategies, case studies, potential applications, and challenges are focused on. more...
- Published
- 2022
6. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery
- Author
-
Chunquan Sheng, Guoqiang Dong, Shipeng He, and Yu Ding
- Subjects
Molecular Structure ,Serendipity ,Chemistry ,Drug discovery ,Proteins ,Computational biology ,Isoindoles ,Protein degradation ,Proteins metabolism ,Acetamides ,Proteolysis ,Drug Discovery ,otorhinolaryngologic diseases ,Humans ,Molecular Medicine ,Piperidones - Abstract
Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, and favorable physicochemical properties. Classical molecular glue degraders have been identified serendipitously, but rational discovery and design strategies are emerging rapidly. In this review, we aim to highlight the recent advances in molecular glues for targeted protein degradation and discuss the challenges in developing molecular glues into therapeutic agents. In particular, discovery strategies, action mechanisms, and representative case studies will be addressed. more...
- Published
- 2021
- Full Text
- View/download PDF
7. Front Cover Image, Volume 42, Issue 3
- Author
-
Shipeng He, Guoqiang Dong, Junfei Cheng, Ying Wu, and Chunquan Sheng
- Subjects
Pharmacology ,Drug Discovery ,Molecular Medicine - Published
- 2022
- Full Text
- View/download PDF
8. Optimization of clofibrate with O-desmethyl anetholtrithione lead to a novel hypolipidemia compound with hepatoprotective effect
- Author
-
Haitao Liu, Panpan Zhang, Xiaoxiao Ge, Qiong Wu, Chuchu Han, Linyang Zhang, Yuxin Hua, Yuxuan Zhang, Jiping Liu, Yongheng Shi, Bin Wang, Xiaoping Wang, Wei Wang, Yi Jiang, Huawei Zhang, Chong Deng, Yundong Xie, Ying Liu, and Shipeng He more...
- Subjects
Anethole Trithione ,NF-E2-Related Factor 2 ,Liver Diseases ,Organic Chemistry ,Clinical Biochemistry ,NF-kappa B ,Pharmaceutical Science ,Biochemistry ,Antioxidants ,Mice ,Oxidative Stress ,Liver ,Drug Discovery ,Molecular Medicine ,Animals ,Aspartate Aminotransferases ,Clofibrate ,Chemical and Drug Induced Liver Injury ,Molecular Biology - Abstract
Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339. In addition, CF-ATT has a significantly protective effect on the liver compared with CF. The liver weight and liver coefficient were reduced. The hepatic function indexes were also decreased, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Histopathological examination of the liver revealed that inflammatory cell infiltration, nuclear degeneration, cytoplasmic loosening and hepatocyte necrosis were ameliorated by administration with CF-ATT. The hepatoprotective mechanism showed that CF-ATT significantly up-regulated Nrf2 and HO-1 protein expression and down-regulated p-NF-κB P65 expression in the liver. CF-ATT has obviously antioxidant and anti-inflammatory activity. These findings suggested that CF-ATT has significant hypolipidemia activity and exact hepatoprotective effect possibly through the Nrf2/NF-κB-mediated signal pathway. more...
- Published
- 2022
9. Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells
- Author
-
Menglu Guo, Shipeng He, Junfei Cheng, Yu Li, Guoqiang Dong, and Chunquan Sheng
- Subjects
Organic Chemistry ,Drug Discovery ,Biochemistry - Abstract
[Image: see text] The development of KRAS–PDEδ protein–protein interaction (PPI) inhibitors is generally hampered by limited antitumor activity. Herein, the first hydrophobic tagging (HyT)-based PDEδ degraders were designed. Compound 17c efficiently bound to PDEδ and induced degradation of PDEδ in SW480 colon cancer cells. As compared with PDEδ inhibitor deltazinone, HyT-based degrader 17c exhibited improved antitumor activity toward KRAS mutant cancer cells. This study highlighted the potential of HyT as a valuable chemical tool for tumorigenic PDEδ knockdown, which could be developed into a promising strategy for antitumor drug discovery. more...
- Published
- 2021
10. Hydrocarbon stapling modification of peptide alyteserin-2a: Discovery of novel stapled peptide antitumor agents
- Author
-
Ziqiang Yu, Hua Tang, Wei Cong, Fei Gao, Huaqiang Li, Honggang Hu, Xiaoyan Wang, and Shipeng He
- Subjects
Pharmacology ,Organic Chemistry ,Antineoplastic Agents ,General Medicine ,Biochemistry ,Hydrocarbons ,Protein Structure, Secondary ,Structural Biology ,Drug Discovery ,Molecular Medicine ,Animals ,Anura ,Peptides ,Molecular Biology ,Antimicrobial Cationic Peptides - Abstract
Alyteserin-2a (ILGKLLSTAAGLLSNLNH
- Published
- 2021
11. Efficient synthesis of artificial pharmaceutical solid-phase modules for constructing aptamer-drug conjugates
- Author
-
Fei, Gao, Hongli, Huang, Chunquan, Sheng, and Shipeng, He
- Subjects
Drug Delivery Systems ,Pharmaceutical Preparations ,Organic Chemistry ,Drug Discovery ,Aptamers, Nucleotide ,Molecular Biology ,Biochemistry ,Solid-Phase Synthesis Techniques - Abstract
As a promising targeted drug delivery system, aptamer-drug conjugates (ApDCs) can specifically bind with cognate molecular targets for improving therapeutic efficacy and reducing drug toxicity. However, current ApDC strategies suffer from problems caused by the complicated synthesis, relatively high cost, low controllability of drug binding sites and loading ratio. To solve these difficulties, we have designed and synthesized an artificial pharmaceutical solid-phase module of Combretastatin A-4 (CA-4), in which an inactive ingredient was selected as bonding moiety to incorporate with solid phase functionalities. Through solid-phase synthesis technology, this module was automatically and efficiently conjugated with an aptamer at predesigned positions. Biological studies revealed that these ApDCs can not only maintain excellent specific recognition ability, but also possess definite cytotoxicity against tumor cells. more...
- Published
- 2022
- Full Text
- View/download PDF
12. Frontispiece: Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer
- Author
-
Yu Li, Shanchao Wu, Wei Wang, Shipeng He, Chunquan Sheng, and Guoqiang Dong
- Subjects
Chemistry ,Drug discovery ,Pancreatic cancer ,Cancer research ,medicine ,General Chemistry ,DUAL (cognitive architecture) ,medicine.disease ,Catalysis - Published
- 2020
- Full Text
- View/download PDF
13. Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents
- Author
-
Kun Fang, Guoqiang Dong, Wei Wang, Shanchao Wu, Zhenyuan Miao, Shipeng He, and Chunquan Sheng
- Subjects
0301 basic medicine ,Mice, Nude ,Antineoplastic Agents ,Histone Deacetylases ,Histones ,Rats, Sprague-Dawley ,Small Molecule Libraries ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Binding Sites ,biology ,Chemistry ,Drug discovery ,Acetylation ,Proto-Oncogene Proteins c-mdm2 ,Stereoisomerism ,Xenograft Model Antitumor Assays ,Small molecule ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Histone ,Drug development ,A549 Cells ,Drug Design ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Mdm2 ,Female ,Tumor Suppressor Protein p53 - Abstract
p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of-concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery. more...
- Published
- 2018
- Full Text
- View/download PDF
14. Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors
- Author
-
Shanchao Wu, Chunquan Sheng, Kun Fang, Wei Wang, Shipeng He, Guoqiang Dong, Yu Li, and Ying Wu
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Organic Chemistry ,Biochemistry ,HDAC1 ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Cancer immunotherapy ,chemistry ,In vivo ,030220 oncology & carcinogenesis ,Drug Discovery ,Cancer cell ,medicine ,Cancer research ,Histone deacetylase ,Epigenetics ,Indoleamine 2,3-dioxygenase ,Lead compound - Abstract
[Image: see text] In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC(50) = 69.0 nM) and HDAC1 (IC(50) = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics. more...
- Published
- 2018
- Full Text
- View/download PDF
15. Structural simplification and bioisostere principle lead to Bis-benzodioxole-fibrate derivatives as potential hypolipidemic and hepatoprotective agents
- Author
-
Lifei Cheng, Jiping Liu, Yundong Xie, Xinya Xu, Bin Wang, Wei Wang, Xiao-Ping Wang, Yongheng Shi, Shipeng He, and Meng Sun
- Subjects
Male ,medicine.drug_class ,Administration, Oral ,Hyperlipidemias ,Mice, Inbred Strains ,Fibrate ,Pharmacology ,Protective Agents ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Sesamin ,Drug Discovery ,Hyperlipidemia ,medicine ,Animals ,PPAR alpha ,Benzodioxoles ,Hepatoprotective Agent ,Molecular Biology ,Hypolipidemic Agents ,Fenofibrate ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Fibric Acids ,Lipid Metabolism ,medicine.disease ,Molecular Docking Simulation ,Liver ,chemistry ,Hepatoprotection ,Low-density lipoprotein ,Bioisostere ,medicine.drug - Abstract
The bis-benzodioxole-fibrate hybrids were designed by structural simplification and bioisostere principle. Lipids lowering activity was preliminarily screened by Triton WR 1339 induced hyperlipidemia mice model, in which T3 showed the best hypolipidemia, decreasing plasma triglyceride (TG) and total cholesterol (TC), which were better than sesamin and fenofibrate (FF). T3 was also found to significantly reduce TG, TC and low density lipoprotein cholesterin (LDL-C) both in plasma and liver tissue of high fat diet (HFD) induced hyperlipidemic mice. In addition, T3 showed hepatoprotective activity, which the noteworthy amelioration in liver aminotransferases (AST and ALT) was evaluated and the histopathological observation exhibited that T3 inhibited lipids accumulation in the hepatic and alleviated liver damage. The expression of PPAR-α receptor involved lipids metabolism in liver tissue significantly increased after T3 supplementation. Other potent activity, such as antioxidation and anti-inflammation, was also observed. The molecular docking study revealed that T3 has good affinity activity toward to the active site of PPAR-α receptor. Based on these findings, T3 may serve as an effective hypolipidemic agent with hepatoprotection. more...
- Published
- 2021
- Full Text
- View/download PDF
16. Improving the Potency of Cancer Immunotherapy by Dual Targeting of IDO1 and DNA
- Author
-
Chunquan Sheng, Shipeng He, Wei Wang, Shanchao Wu, Kun Fang, Hongyu Wang, and Guoqiang Dong
- Subjects
Male ,0301 basic medicine ,Drug ,Dual targeting ,media_common.quotation_subject ,medicine.medical_treatment ,Mice, Nude ,Apoptosis ,Molecular Dynamics Simulation ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cancer immunotherapy ,Cell Line, Tumor ,Neoplasms ,Oximes ,Drug Discovery ,medicine ,Animals ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Potency ,Enzyme Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,Antineoplastic Agents, Alkylating ,media_common ,Pharmacology ,Antitumor activity ,Mice, Inbred BALB C ,Sulfonamides ,Binding Sites ,Low toxicity ,Organic Chemistry ,DNA ,Immunotherapy ,030104 developmental biology ,chemistry ,Drug Design ,030220 oncology & carcinogenesis ,Nitrogen Mustard Compounds ,Cancer research ,Molecular Medicine - Abstract
Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers. more...
- Published
- 2017
- Full Text
- View/download PDF
17. Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran–oxindole derivatives as potent p53-MDM2 inhibitors
- Author
-
Shuqiang Chen, Chunquan Sheng, Yan Jiang, Shipeng He, Changjin Ji, Shengzheng Wang, Jian Li, and Zhenyuan Miao
- Subjects
Indoles ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Fluorescence Polarization ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Spiro Compounds ,Oxindole ,Molecular Biology ,Cell Proliferation ,Pyrans ,Antitumor activity ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Enantioselective synthesis ,Proto-Oncogene Proteins c-mdm2 ,Combinatorial chemistry ,Oxindoles ,0104 chemical sciences ,chemistry ,Drug development ,Drug Design ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Molecular Medicine ,Mdm2 ,Drug Screening Assays, Antitumor ,Tumor Suppressor Protein p53 ,Lead compound - Abstract
p53–MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran–oxindole p53–MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships. Among them, compound B14 bearing a novel spiroindole–thiopyranopyridone scaffold exhibited potent MDM2 inhibitory activity as well as antitumor activity, which could effectively induce the apoptosis of A549 cancer cells. It represents a promising lead compound for the development of novel antitumor agents. more...
- Published
- 2017
- Full Text
- View/download PDF
18. Design, synthesis and biological evaluation of novel antitumor spirodihydrothiopyran-oxindole derivatives
- Author
-
Shipeng He, Chunquan Sheng, Shengzheng Wang, Wei Liu, Fan Zhang, and Shuqiang Chen
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Humans ,Oxindole ,Spiro Compounds ,Molecular Biology ,Biological evaluation ,Antitumor activity ,biology ,010405 organic chemistry ,Drug discovery ,Chemistry ,Organic Chemistry ,Cell cycle ,In vitro ,0104 chemical sciences ,Oxindoles ,010404 medicinal & biomolecular chemistry ,biology.protein ,Molecular Medicine ,Mdm2 ,Lead compound - Abstract
Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships. Among the derivatives, compounds 4b, 4i, 4m, 4n and 4q displayed superior or comparable antitumor activity than nutlin-3. Molecular mechanism study revealed this scaffold displayed moderate MDM2 inhibitory activity, significantly induced cancer cell apoptosis and arrested cell cycle at G0/G1 phase, which represented a good lead compound for antitumor drug discovery. more...
- Published
- 2019
19. Synthesis of spiro-tetrahydrothiopyran-oxindoles by Michael-aldol cascade reactions: discovery of potential P53-MDM2 inhibitors with good antitumor activity
- Author
-
Shengzheng Wang, Chunquan Sheng, Shengyong Zhang, Xueying Liu, Fan Zhang, Zhongjie Guo, Shipeng He, Shuqiang Chen, and Weiping Chen
- Subjects
Proline ,Stereoisomerism ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Biochemistry ,P53 mdm2 ,Catalysis ,Cascade reaction ,Aldol reaction ,Cell Line, Tumor ,Humans ,Spiro Compounds ,Physical and Theoretical Chemistry ,Enzyme Inhibitors ,Antitumor activity ,Binding Sites ,010405 organic chemistry ,Chemistry ,Drug discovery ,Organic Chemistry ,Proto-Oncogene Proteins c-mdm2 ,Combinatorial chemistry ,0104 chemical sciences ,Oxindoles ,Molecular Docking Simulation ,Tumor Suppressor Protein p53 - Abstract
Using proline as the catalyst, an organocatalytic Michael–aldol cascade reaction was developed for the synthesis of spiro-tetrahydrothiopyran oxindoles. The highly functionalized scaffold was assembled in moderate to good yields (51–78%) and excellent diastereoselectivities (>20 : 1 dr). Interestingly, the oxindoles displayed moderate to good in vitro antitumor activities and were validated as p53-MDM2 inhibitors, which represented promising lead compounds for antitumor drug discovery. more...
- Published
- 2018
20. Identification of benzothiophene amides as potent inhibitors of human nicotinamide phosphoribosyltransferase
- Author
-
Wei Chen, Tian-Ying Xu, Chunquan Sheng, Na Liu, Guoqiang Dong, Chao-Yu Miao, Shipeng He, Wannian Zhang, and Xia Wang
- Subjects
0301 basic medicine ,High-throughput screening ,Clinical Biochemistry ,Nicotinamide phosphoribosyltransferase ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Thiophenes ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,medicine ,Structure–activity relationship ,Humans ,Enzyme Inhibitors ,Nicotinamide Phosphoribosyltransferase ,Molecular Biology ,IC50 ,Binding Sites ,Organic Chemistry ,Benzothiophene ,Cancer ,Hep G2 Cells ,medicine.disease ,Amides ,In vitro ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Molecular Medicine - Abstract
Nicotinamide phosphoribosyltransferase (Nampt) is an attractive therapeutic target for cancer. A Nampt inhibitor with novel benzothiophene scaffold was discovered by high throughput screening. Herein the structure-activity relationship of the benzothiophene Nampt inhibitor was investigated. Several new inhibitors demonstrated potent activity in both biochemical and cell-based assays. In particular, compound 16b showed good Nampt inhibitory activity (IC50=0.17 μM) and in vitro antitumor activity (IC50=3.9 μM, HepG2 cancer cell line). Further investigation indicated that compound 16b could efficiently induce cancer cell apoptosis. Our findings provided a good starting point for the discovery of novel antitumor agents. more...
- Published
- 2015
21. Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors
- Author
-
Zhenyuan Miao, Shipeng He, Zhibin Wang, Yahui Huang, Jianzhong Yao, Wannian Zhang, Wei Chen, Guoqiang Dong, Yan Jiang, Na Liu, Sheng Chunquan, and Li Zhengang
- Subjects
biology ,Apoptosis ,Chemistry ,Drug discovery ,Topoisomerase ,Organic Chemistry ,Drug Discovery ,biology.protein ,Histone deacetylase ,Pharmacology ,Biochemistry - Abstract
Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents. more...
- Published
- 2014
22. Scaffold hopping of sampangine: discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformans
- Author
-
Shipeng He, Zhenyuan Miao, Xiaomeng He, Jianzhong Yao, Guoqiang Dong, Wannian Zhang, Yan Jiang, Li Zhengang, Jiang Zhigan, Yang Liu, Wei Chen, Chunquan Sheng, Yahui Huang, and Na Liu
- Subjects
Antifungal ,Antifungal Agents ,medicine.drug_class ,Clinical Biochemistry ,Sampangine ,Antifungal drug ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Scaffold hopping ,Biochemistry ,Heterocyclic Compounds, 4 or More Rings ,Aspergillus fumigatus ,Microbiology ,chemistry.chemical_compound ,Structure-Activity Relationship ,Alkaloids ,Drug Discovery ,medicine ,Naphthyridines ,Molecular Biology ,Cryptococcus neoformans ,Natural product ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,biology.organism_classification ,Molecular Medicine ,Lead compound - Abstract
Discovery of novel antifungal agents against Aspergillus fumigatus and Cryptococcus neoformans remains a significant challenge in current antifungal therapy. Herein the antifungal natural product sampangine was used as the lead compound for novel antifungal drug discovery. A series of D-ring scaffold hopping derivatives were designed and synthesized to improve antifungal activity and water solubility. Among them, the thiophene derivative S2 showed broad-spectrum antifungal activity, particularly for Aspergillus fumigatus and Cryptococcus neoformans. Moreover, compound S2 also revealed better water solubility than sampangine, which represents a promising antifungal lead compound for further structural optimization. more...
- Published
- 2014
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.