Article
Chemistry, Medicinal
Jingsong Qiu, Xiangling Feng, Huanhua Chen, Wenwu Liu, Wenjie Liu, Limeng Wu, Xudong Gao, Yanfang Liu, Yaoguang Huang, Hao Gong, Yiming Qi, Zihua Xu, Qingchun Zhao
Summary: Multitarget-directed ligands (MTDLs) have shown superior effectiveness in the treatment of Alzheimer's disease (AD) by targeting multiple factors. In this study, a series of novel harmine derivatives were designed and synthesized, and their inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was evaluated. Among these compounds, ZLQH-5 exhibited the most potent inhibitory effect against both GSK-3 beta and DYRK1A, and showed promising pharmacokinetic properties and low cytotoxicity. Furthermore, ZLQH-5 attenuated tau hyperphosphorylation in a cell model, suggesting its potential as a dual-target drug candidate for AD treatment.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Wenwu Liu, Xin Liu, Wenjie Liu, Yaping Gao, Limeng Wu, Yaoguang Huang, Huanhua Chen, Deping Li, Lijun Zhou, Nan Wang, Zihua Xu, Xiaowen Jiang, Qingchun Zhao
Summary: This study identifies a novel series of harmine derivatives with potential value for the treatment of Alzheimer's disease (AD). Compound ZLWH-23 shows significant anti-acetylcholinesterase activity, selective inhibition of butyrylcholinesterase, and acceptable inhibition of glycogen synthase kinase-3 beta. Furthermore, ZLWH-23 exhibits good selectivity for GSK-3 beta over other kinases and reduces tau hyperphosphorylation in a cell model. Harmine-based derivatives could be considered as drug leads for AD therapies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Geriatrics & Gerontology
Ning Cao, Shuping Li, Aimin Xu, Manlin Li, Xiaoguang Zou, Zunji Ke, Gang Deng, Xuemei Cheng, Changhong Wang
Summary: The study found that harmine is a main compound found in rats, mice, and humans, which can be detected in the plasma and brain of newborn rats without exogenous consumption. The concentration of harmine in rat plasma decreases with age and growth, showing a high dependence on physiological and pathological status.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Deping Li, Wenwu Liu, Yaoguan Huang, Mingyue Liu, Caizhi Tian, Hongyuan Lu, Hui Jia, Zihua Xu, Huaiwei Ding, Qingchun Zhao
Summary: This study designed and synthesized a series of novel beta-carbolines and evaluated their antitumor activity. Among them, compounds ZDLD13 and ZDLD20 exhibited potent anti-proliferative activity and CDK4 enzymatic inhibition activity. The in vitro and in vivo studies showed that ZDLD13 and ZDLD20 had significant antitumor effects.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Woong Sub Byun, Hyewon Lim, Junhwa Hong, Eun Seo Bae, Seok Beom Lee, Younggwan Kim, Jeeyeon Lee, Sang Kook Lee, Suckchang Hong
Summary: The compound MC0704, a synthetic STAT3 pathway inhibitor, showed potential antitumor activity in docetaxel-resistant TNBC cells. It effectively inhibited the metastatic potential of the cells in vitro and exhibited strong antitumor activity when combined with docetaxel in a xenograft mouse model. MC0704 could be a potential therapeutic agent for TNBC patients with docetaxel resistance.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Xin Liu, Ling-yun Lai, Jiang-xia Chen, Xiang Li, Nan Wang, Li-jun Zhou, Xiao-wen Jiang, Xiao-long Hu, Wen-wu Liu, Xin-ming Jiao, Zhen-tong Qi, Wen-jie Liu, Li-meng Wu, Yao-guang Huang, Zi-hua Xu, Qing-chun Zhao
Summary: In this study, the harmine derivatives ZDWX-12 and ZDWX-25 were found to effectively inhibit Tau hyperphosphorylation. The inhibition effect of ZDWX-25 was superior to that of ZDWX-12, as demonstrated by cell-based and mouse models. These findings suggest that ZDWX-25 is a promising drug for the treatment of Alzheimer's disease.
Article
Chemistry, Multidisciplinary
Sivanath Musunuri, Reddymasu Sreenivasulu, Kit-Kay Mak, Mallikarjuna Rao Pichika, Mandava Venkata Basaveswara Rao
Summary: Molecules with harmine moiety have been shown to have strong fungicidal and bactericidal activities. Various quinozilinium tetrafluoroborate salts were synthesized in this study and characterized via multiple analytical techniques, showing potential for the preparation of a library of small molecules useful in medicinal chemistry and drug discovery.
Article
Chemistry, Medicinal
Zhongwen Luo, Shang Li, Yonglei Zhang, Fucheng Yin, Heng Luo, Xinye Chen, Ningjie Cui, Siyuan Wan, Xinxin Li, Lingyi Kong, Xiaobing Wang
Summary: Neuronal cells overexpressing phosphorylated Tau proteins increase susceptibility to oxidative stress. Regulation of GSK-3 beta and reduction of Tau protein hyperphosphorylation, as well as alleviation of oxidative stress, may be effective in preventing or treating Alzheimer's disease (AD). The compound KWLZ-9e showed potential GSK-3 beta inhibition and neuroprotective capacity, and it could alleviate oxidative stress and improve learning and memory impairments in an AD model, making it a promising lead for AD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Teresa Pardo-Moreno, Anabel Gonzalez-Acedo, Antonio Rivas-Dominguez, Victoria Garcia-Morales, Francisco Jose Garcia-Cozar, Juan Jose Ramos-Rodriguez, Lucia Melguizo-Rodriguez
Summary: This article discusses the treatment approaches for Alzheimer's disease, including approved drugs, investigational therapies, and alternative methods to improve lifestyle.
Article
Neurosciences
Longfei Li, Jin Miao, Dandan Chu, Nana Jin, Yunn Chyn Tung, Chun-Ling Dai, Wen Hu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Summary: Findings from this study suggest that the monoclonal tau antibody 77G7 effectively suppresses the seeding activity of AD O-tau and could potentially be developed as an immunotherapeutic drug to inhibit the propagation of tau pathology in AD and related tauopathies.
CNS NEUROSCIENCE & THERAPEUTICS
(2022)
Review
Chemistry, Medicinal
Neha Chauhan, Swati Paliwal, Smita Jain, Kanika Verma, Sarvesh Paliwal, Swapnil Sharma
Summary: Alzheimer's disease is a major health and socioeconomic burden worldwide, characterized by neuronal loss, memory loss, and cognitive impairment. GSK-3 beta plays a significant role in the molecular mechanisms of AD progression, making it a potential therapeutic target for the disease.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yanwen Wang, Miao Cai, Yue Lou, Siran Zhang, Xiaoli Liu
Summary: The study demonstrated that the upregulation of LncRNA ZBTB20-AS1 suppressed the expression of ZBTB20 and promoted the expression of GSK-3 beta and phosphorylation of Tau, thus contributing to the development of Alzheimer's disease.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Peng Zeng, Hong-Fei Su, Chao-Yuan Ye, Shuo-Wen Qiu, Qing Tian
Summary: This study utilized a network pharmacology strategy to identify key alkaloids in Uncaria rhynchophylla for the treatment of Alzheimer's disease. Through high-performance liquid chromatography, 10 alkaloids were identified that correlated with AD pathophysiological processes, with specific key alkaloids for Aβ and tau pathology identified. Core targets such as JUN, STAT3, and MAPK3 were highlighted, providing potential candidate compounds for drug research and development targeting specific AD pathological processes.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Richard A. Hartz, Vijay T. Ahuja, Guanglin Luo, Ling Chen, Prasanna Sivaprakasam, Hong Xiao, Carol M. Krause, Wendy J. Clarke, Songmei Xu, John S. Tokarski, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R. Burton, John E. Macor, Gene M. Dubowchik
Summary: Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cellular functions, implicated in diseases such as Alzheimer's disease, mood disorders, diabetes, and cancer. Its role in the production of abnormal tau protein in neurofibrillary tangles associated with Alzheimer's disease has been established. The synthesis and evaluation of pyrimidine-based GSK-3 inhibitors led to the identification of highly potent compounds that effectively lowered phosphorylated tau levels in a mouse model of Alzheimer's disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Goran Poje, Marina Marinovic, Kristina Pavic, Marija Mioc, Marijeta Kralj, Lais Pessanha de Carvalho, Jana Held, Ivana Perkovic, Zrinka Rajic
Summary: This study presents the design, synthesis, and evaluation of harmicens, a new class of hybrids with structural diversity. The harmicens showed moderate antiplasmodial activity against malaria and significant and selective antiproliferative activity against cancer cell lines. Cell localization and cycle analysis revealed different mechanisms of action.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)