Article
Biochemistry & Molecular Biology
Jianfang Fu, Jie Yu, Xiang Zhang, Yaoyao Chang, Hongze Fan, Mengzhen Dong, Mengjia Li, Yue Liu, Jinxing Hu
Summary: In this study, two series of EGFR kinase inhibitors were designed and synthesised. Compound B1 showed selective inhibition against EGFR (L858R/T790M) with an IC50 value of 13 nM and a 76-fold selectivity for EGFR (WT). In vitro experiments demonstrated that compound B1 effectively inhibited proliferation of H1975 cells with an IC50 value of 0.087 μM. Mechanistic studies confirmed the selective inhibition of EGFR (L858R/T790M) by compound B1 through cell migration and apoptosis assays.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Souad A. El-Metwally, Hazem Elkady, Mohamed Hagras, Eslam B. Elkaeed, Bshra A. Alsfouk, Ahmed S. Doghish, Ibrahim M. Ibrahim, Mohammed S. Taghour, Dalal Z. Husein, Ahmed M. Metwaly, Ibrahim H. Eissa
Summary: This study developed thieno[2,3-d]pyrimidine derivatives as potential anti-cancer agents targeting VEGFR-2. Compound 10d demonstrated strong anti-cancer potential by boosting apoptosis through VEGFR-2 inhibition. These compounds have good binding affinities to VEGFR-2 and may contribute to the development of new anticancer therapies.
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Tianshuai Wang, Fengxu Wu, Lun Luo, Yan Zhang, Junkai Ma, Yanggen Hu
Summary: The fused heterocyclic ring system of thienopyrimidine scaffold has been widely used in pharmaceuticals to enhance pharmacological and biological activities. In this study, polysubstituted thieno[2,3-d]pyrimidine derivatives were synthesized and tested for their cytotoxic activity against Hela and A549 cancer cell lines. Compound 8c showed promising activity similar to the lead drug Olmutinib, and its binding to EGFR kinase differed from Olmutinib. The preliminary structure-activity relationship suggested that introducing oxygen substituents favored antitumor activity.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemistry & Molecular Biology
Yan Sun, Rong Fu, Songwen Lin, Jingbo Zhang, Ming Ji, Yan Zhang, Deyu Wu, Kehui Zhang, Hua Tian, Mingyi Zhang, Li Sheng, Yan Li, Jing Jin, Xiaoguang Chen, Heng Xu
Summary: A new series of PI3K inhibitors were designed and synthesized, showing promising anti-cancer activity and in vivo efficacy. Among them, thiazolo [5,4-d]pyrimidine 7a demonstrated superior anti-cancer activity compared to other compounds, warranting further pre-clinical evaluation.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Rongcai Ding, Xiaoxia Wang, Jianfang Fu, Yaoyao Chang, Yingxue Li, Yajing Liu, Yue Liu, Jinlong Ma, Jinxing Hu
Summary: A series of novel pleuromutilin derivatives with substituted thienopyrimidines were designed, synthesized, and evaluated for their antibacterial activity. Most of the compounds exhibited moderate antibacterial activity against Staphylococcus aureus, Streptococcus agalactiae, and Escherichia coli. Compound A11 showed the most activity and displayed bacteriostatic activities against methicillin-resistant S. aureus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Eman A. Sobh, Mohammed A. Dahab, Eslam B. Elkaeed, Aisha A. Alsfouk, Ibrahim M. Ibrahim, Ahmed M. Metwaly, Ibrahim H. Eissa
Summary: A group of EGFR inhibitors derived from the thieno[2,3-d]pyrimidine nucleus were designed, synthesized, and evaluated as anti-proliferative lead compounds. The most active member, 5b, inhibited the growth of MCF-7 and A549 cell lines. It showed inhibitory selectivity of 37.19 and 204.10 nM against EGFR(WT) and EGFR(T790M), respectively. Compound 5b demonstrated potential for apoptosis induction and cell cycle arrest in A549 cells, as well as upregulation of BAX and downregulation of Bcl-2 genes.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Eman A. Sobh, Mohammed A. Dahab, Eslam B. Elkaeed, Aisha A. Alsfouk, Ibrahim M. Ibrahim, Ahmed M. Metwaly, Ibrahim H. Eissa
Summary: A new thieno[2,3-d]pyrimidine derivative was developed based on the pharmacophoric characteristics of EGFR inhibitors. Docking experiments showed its potential inhibitory effect against EGFR, with excellent binding energies of -98.44 and -88.00 kcal/mol against EGFR wild-type and mutant type, respectively. MD simulations studies confirmed the precise energetic, conformational, and dynamic alterations after binding to EGFR.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Zhangping Xiao, Angelina Osipyan, Shanshan Song, Deng Chen, Reinder A. Schut, Ronald van Merkerk, Petra E. van der Wouden, Robbert H. Cool, Wim J. Quax, Barbro N. Melgert, Gerrit J. Poelarends, Frank J. Dekker
Summary: This study discovered the importance of p38MAPK in maintaining the survival of T-ALL cells and revealed the potential therapeutic strategy of targeting aberrant phosphorylation of p38MAPK in leukemia.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Mahmoud S. Tolba, Ahmed M. Sayed, Mostafa Sayed, Mostafa Ahmed
Summary: A synthetic method for designing new thienopyrimidines was presented, with spectral analysis confirming the structures of all synthesized compounds. The compounds showed significant antibacterial and anti-inflammatory activity compared to standard drugs, and molecular docking was used to investigate their mechanisms. Drug-like properties were analyzed for potential oral drug candidates.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Chemistry, Medicinal
Ilyas Berhane, Niyada Hin, Ajit G. Thomas, Qian Huang, Chi Zhang, Vijayabhaskar Veeravalli, Ying Wu, Justin Ng, Jesse Alt, Camilo Rojas, Hiroe Hihara, Mika Aoki, Kyoko Yoshizawa, Tomoki Nishioka, Shuichi Suzuki, Shao-Qiu He, Qi Peng, Yun Guan, Xinzhong Dong, Srinivasa N. Raja, Barbara S. Slusher, Rana Rais, Takashi Tsukamoto
Summary: A orally available positive allosteric modulator of MRGPRX1 has been discovered, which shows potential in treating neuropathic pain.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Olga Riabova, Anna Egorova, Alexander Lepioshkin, Yan Li, Kerstin Voigt, Florian Kloss, Vadim Makarov
Summary: Thieno[2,3-d]pyrimidines represent a novel antibacterial prodrug scaffold with potential antibacterial effects against Gram-positive bacteria, particularly Staphylococci (MRSA). The two most promising hit compounds demonstrate good pharmacokinetic properties in vitro and acceptable toxicity, qualifying them as starting points for lead-generation campaigns.
Article
Biochemistry & Molecular Biology
Souad A. El-Metwally, Mohsen M. Abou-El-Regal, Ibrahim H. Eissa, Ahmed B. M. Mehany, Hazem A. Mahdy, Hazem Elkady, Alaa Elwan, Eslam B. Elkaeed
Summary: Novel thieno[2,3-d]pyrimidine derivatives with structural similarity to VEGFR-2 inhibitors were designed and synthesized, showing promising anticancer activities against human cancer cell lines. Compound 17f exhibited the highest cytotoxic activities against HCT-116 and HepG2 cell lines and displayed high inhibitory activity against VEGFR-2, comparable to the reference drug sorafenib. ADMET and toxicity assessments revealed that most compounds had low BBB penetration levels and were non-toxic, except for compounds 17b and 20b.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Menna Tallah M. Sayed, Peter A. Halim, Afaf K. El-Ansary, Rasha A. Hassan
Summary: A series of 20 thieno[2,3-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against 60 cancer cell lines. Compound 7b showed significant antineoplastic activity and inhibited the growth of 37 tested cancer cell lines at micromolar concentrations. It effectively inhibited EGFR and showed downregulation effects on total EGFR concentration and its phosphorylation. Compound 7b also increased apoptosis and arrested the cell cycle in the G1/S phase.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Chemistry, Medicinal
Yuehua Zhang, Zhaoping Pan, Can Chen, Yiwei Tan, Xiaoyun Wang, Lian Wang, Lu Zhang, Yi Chen, Gu He
Summary: By utilizing a multifunctional drug development strategy, new derivatives of BRD4 inhibitors capable of releasing nitric oxide were designed and synthesized, demonstrating excellent antitumor activity and inducing cellular apoptosis and autophagic cell death. This approach holds potential for targeted therapy in ovarian cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ling Li, Jin Liu, Zichao Yang, Huiting Zhao, Bulian Deng, Yichang Ren, Ruiyao Mai, Junli Huang, Jianjun Chen
Summary: A series of novel thieno[2,3-d]pyrimidine analogs were designed and synthesized as KRAS G12D inhibitors. Compound KD-8 exhibited potent antiproliferative activity and antitumor efficacy by decreasing the active form of KRAS and inhibiting Raf and Erk in KRAS G12D mutated cancer cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Jun Mu, Xin Xie, Shanshan Xiong, Yuehua Zhang, Yuting Wang, Qian Zhao, Hongping Zhu, Wei Huang, Gu He
Summary: A series of spirooxindole-ferrocene hybrids with five or four contiguous chiral centers were designed and synthesized through organocatalysis. Compound 5d was identified as the most potent MDM2 inhibitor, suppressing MDM2-mediated p53 degradation, inducing apoptosis, and promoting oxidative damage. Molecular docking studies have shown that 5d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53, providing a basis for the development of novel multifunctional MDM2 inhibitors.
CHINESE CHEMICAL LETTERS
(2021)
Article
Chemistry, Medicinal
Shuai-Jiang Liu, Qian Zhao, Cheng Peng, Qing Mao, Fengbo Wu, Feng-Hua Zhang, Quan-Sheng Feng, Gu He, Bo Han
Summary: A series of highly active compounds containing CF3 group were synthesized as novel inhibitors of GPX4 and MDM2, with compound 3d exhibiting excellent activity in suppressing MDM2-mediated degradation and GPX4 levels in MCF-7 breast cancer cells. Moreover, 3d also showed inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model, inducing ferroptotic and apoptotic cell death in vivo experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Shiou Zhu, Minru Liao, Huidan Tan, Lingjuan Zhu, Yi Chen, Gu He, Bo Liu
Summary: Eukaryotic elongation factor 2 kinase (eEF2K) is a key negative regulator of protein synthesis in tumorigenesis, with potential for cancer therapy improvement through single-target inhibitors, repurposed drugs, dual-target inhibitors, drug combination strategies, and emerging technologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Lian Wang, Xin Xie, Bowen Ke, Wei Huang, Xian Jiang, Gu He
Summary: This review discusses the recent progress of endogenous gasotransmitters in the context of inflammatory dermatological disorders, highlighting their potential therapeutic effects in regulating inflammation, vasodilation, and oxidative stress. The development of effective gas donors and inhibitors is an important direction for future research in treating these disorders.
JOURNAL OF ADVANCED RESEARCH
(2022)
Article
Chemistry, Medicinal
Jifa Zhang, Pan Tang, Ling Zou, Jin Zhang, Juncheng Chen, Chengcan Yang, Gu He, Bo Liu, Jie Liu, Cheng-Ming Chiang, Guan Wang, Tinghong Ye, Liang Ouyang
Summary: The study synthesized a potent BRD4-CK2 dual inhibitor, which showed strong anti-proliferative effects and induced apoptosis and autophagy-related cell death in tumor cells. It has potential therapeutic value for triple-negative breast cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Medicinal
Lu Feng, Guan Wang, Yi Chen, Gu He, Bo Liu, Jie Liu, Cheng-Ming Chiang, Liang Ouyang
Summary: BRD4, a chromatin reader protein in the BET family, regulates cellular processes by binding acetylated histones and non-histone proteins. Designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment.
MEDICINAL RESEARCH REVIEWS
(2022)
Article
Chemistry, Organic
Xiang-Hong He, Xue-Ju Fu, Gu Zhan, Nan Zhang, Xiang Li, Hong-Ping Zhu, Cheng Peng, Gu He, Bo Han
Summary: This study describes an organocatalytic asymmetric [3+3] annulation reaction using isatin-derived MBH carbonates and indolin-2-imines. The reaction provides a novel enantioselective approach for the synthesis of multifunctionalized alpha-carboline-spirooxindole hybrids with high yields and stereoselectivities. The synthesized compounds exhibit significant inhibition of proliferation in colorectal cancer cell lines, and the most potent compound activates autophagy and cytoprotective autophagy in HCT116 cells.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Medicinal
Zhaoping Pan, Yi Chen, Haiying Pang, Xiaoyun Wang, Yuehua Zhang, Xin Xie, Gu He
Summary: A novel class of thieno [2,3-d] pyrimidine derivatives containing resorcinol and morpholine fragments as Hsp90/mTOR dual inhibitors were designed, synthesized, and evaluated. The most potent compound 17o showed remarkable inhibitory activities on Hsp90, mTOR, and SW780 cancer cell, both in vitro and in vivo. Mechanism studies revealed that 17o suppressed cell proliferation through the over-activation of the PI3K/AKT/mTOR pathway regulated by mTOR inhibition and apoptosis regulated by the mitochondrial pathway.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Dong-Ai Li, Xiang-Hong He, Xue Tang, Yuling Wu, Hongli Zhao, Gu He, Cheng Peng, Bo Han, Gu Zhan
Summary: This study successfully developed an efficient strategy for synthesizing spirocyclo-penteneoxindoles, which have potential biological activity. Using the thiourea/silver dual catalytic reaction of 2-(2-oxoindolin-3-yl)malononitrile with ortho-ethynyl substituted nitrostyrene in a (3 + 2)/Conia-ene type reaction, three new C-C bonds were formed within one synthetic step. The yield and selectivity of the indane-fused spirocyclopenteneoxindoles were excellent.
Article
Chemistry, Medicinal
Yuehua Zhang, Zhaoping Pan, Can Chen, Yiwei Tan, Xiaoyun Wang, Lian Wang, Lu Zhang, Yi Chen, Gu He
Summary: By utilizing a multifunctional drug development strategy, new derivatives of BRD4 inhibitors capable of releasing nitric oxide were designed and synthesized, demonstrating excellent antitumor activity and inducing cellular apoptosis and autophagic cell death. This approach holds potential for targeted therapy in ovarian cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Mingxia Liu, Kaiyao Zhang, Qinjue Li, Haiying Pang, Zhaoping Pan, Xiaowei Huang, Lian Wang, Fengbo Wu, Gu He
Summary: In recent years, extensive research has been carried out on the molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. Non-BET BRDs are gaining attention as a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)-associated activating transcription factors, and BRD-containing HATs have been associated with cancer, inflammation, and viral replication. The development of BRD-containing HATs as chemical probes is valuable for understanding the specific biological roles of BRDs in diseases and drug discovery. Different types of BRD-containing HATs, including CBP/P300, PCAF/GCN5, and TAF1, are discussed in terms of their structures, functions, and small-molecule inhibitors. Furthermore, the progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras regarding drug design, biological activity, and disease application is summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Xin Xie, Tingting Yu, Xiang Li, Nan Zhang, Leonard J. Foster, Cheng Peng, Wei Huang, Gu He
Summary: This review focuses on the recent development of drug discovery targeting undruggable proteins and their application in clinic. Strategies including covalent regulation, allosteric inhibition, protein-protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others are discussed.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Chemistry, Medicinal
Leilei Fu, Siwei Chen, Gu He, Yi Chen, Bo Liu
Summary: This article summarizes the oncogenic roles, key signaling network, and single- and dual-target inhibitors of ERK1/2 in cancer therapy. Selective inhibition of ERK1/2 is considered a potential strategy to overcome drug resistance and improve cancer therapeutics.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Xin Xie, Shan-Shan Xiong, Xiang Li, He Huang, Feng-Bo Wu, Peng-Fei Shen, Cheng Peng, Gu He, Bo Han
Summary: This study designed and synthesized a series of spirooxindole-cyclopentene-isoxazole hybrids with multiple chiral centers and active groups, with compound 4z showing the strongest MDM2 inhibitory activity, interacting with the substrate binding site of MDM2 through hydrogen bonds and pi stacking.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Review
Chemistry, Multidisciplinary
Bo Han, Xiang-Hong He, Yan-Qing Liu, Gu He, Cheng Peng, Jun-Long Li
Summary: Asymmetric organocatalysis has made significant contributions to organic synthesis since the early 2000s, especially in medicinal chemistry. This review provides a comprehensive overview of the specific applications of asymmetric organocatalysis in pharmaceutical synthesis, with a focus on the synthesis strategies of various bioactive molecules and their future prospects.
CHEMICAL SOCIETY REVIEWS
(2021)