Article
Chemistry, Medicinal
Denis Babkov, Elena Bezsonova, Viktor Sirotenko, Elias Othman, Vladlen Klochkov, Sergey Sosonyuk, Natalia Lozinskaya, Alexander Spasov
Summary: Development of novel agents that prevent thrombotic events is urgently needed, and GSK3 beta inhibitors showed promising results. The most active compound, 5a, demonstrated significantly higher antiplatelet and antithrombotic activities compared to acetylsalicylic acid. These findings support the potential role of GSK3 beta inhibitors in the development of new antithrombotic agents.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Biochemistry & Molecular Biology
Divya M. Teli, Anuradha K. Gajjar
Summary: Elevated glucose level due to β-cell dysfunction is a key marker of Type-II diabetes. GSK-3, an enzyme involved in glycogen metabolism control, has been explored for its potential as a target for diabetes treatment. This review article examines the structural analysis and molecular modeling of GSK-3, as well as advancements in the development of GSK-3 inhibitors as potential therapeutics for Type II diabetes.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Yifan Zhu, Hui Wang, Yueyue Guo, Jie Cao, Huanqiu Li
Summary: This article provides an overview of the role of GSK3 in various inflammatory diseases and the recent progress in the discovery of GSK3 inhibitors.
MINI-REVIEWS IN MEDICINAL CHEMISTRY
(2023)
Review
Plant Sciences
Yun Song, Ying Wang, Qianqian Yu, Yueying Sun, Jianling Zhang, Jiasui Zhan, Maozhi Ren
Summary: Glycogen synthase kinase 3 (GSK3) family members are highly conserved protein kinases in mammals and plants, playing a pivotal role in the perception and transduction of diverse signals involved in plant development and stress responses. Recent research has shown that GSK3s are involved in plant adaptation to various stresses and their crosstalk with hormones. Understanding the molecular mechanisms of GSK3s in plant stress responses provides opportunities for developing stress-resilient crops using genetic engineering technology.
FRONTIERS IN PLANT SCIENCE
(2023)
Article
Oncology
Roland Houben, Pamela Alimova, Bhavishya Sarma, Sonja Hesbacher, Carolin Schulte, Eva-Maria Sarosi, Christian Adam, Thibault Kervarrec, David Schrama
Summary: The treatment of Merkel cell carcinoma, a deadly skin cancer caused by Merkel cell polyomavirus, is challenging. This study identified a compound, previously described as an inhibitor of Aurora kinase A, that represses the growth of Merkel cell carcinoma cells by inhibiting the expression of viral proteins. However, it was found that the effect is not related to the inhibition of Aurora kinase A, but possibly due to an unknown GSK3-inhibitory activity of the compound, which was demonstrated to have therapeutic potential in immunocompromised mice.
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
Oncology
Kristina Y. Aguilera, Thuc Le, Rana Riahi, Anna R. Lay, Stefan Hinz, Edris A. Saadat, Ajay A. Vashisht, James Wohlschlegel, Timothy R. Donahue, Caius G. Radu, David W. Dawson
Summary: This study found that autophagy and lysosomal activity are enhanced in RNF43-mutant PDAC in response to PORCNi LGK974, which disrupts mitochondrial function and alters transcriptional activity. These findings reveal potential therapeutic targets for combining PORCNi with other drugs for the treatment of PDAC.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Physiology
Gautam Bandyopadhyay, Kechun Tang, Nicholas J. G. Webster, Geert van den Bogaart, Sushil K. Mahata
Summary: Catestatin (CST), a peptide derived from Chromogranin A, promotes hepatic glycogen synthesis by reducing glucose production, increasing glycogen synthesis, inhibiting glycogenolysis, and enhancing downstream insulin signaling.
Article
Chemistry, Physical
Sulekha Sharma, Saina Shaheeda, Kundan Shaw, Alakesh Bisai, Amit Paul
Summary: Dimerized 3-substituted 2-oxindoles were synthesized using TEMPO as a redox mediator and TEMPO+ as an in situ generated electrocatalyst. Two-electron and one-electron transfer pathways were observed depending on the oxidation potentials of the 2-oxindoles. This study also demonstrated the use of electron-transfer rate measurement, prevention of electrode passivation, electrolyte recovery, and mild reaction conditions in greener electro-organic synthesis. Finally, an efficient electrochemical oxidation strategy was employed for the total synthesis of two dimeric alkaloids.
Article
Biochemistry & Molecular Biology
Li Kang, Yujie Liu, Jianzhong He, Yaling Wang, Mengyang Xue, Xin Wu, Zhen Wang, Yunpeng Zhang, Manyu Chu, Jialun Li, Wei Wei, Jiwen Li, Enmin Li, Lujian Liao, Jianru Xiao, Rong Zhang, Liyan Xu, Jiemin Wong
Summary: By screening a small-molecule kinase inhibitor library, GSK3 ss was identified as a critical kinase for promoting the overexpression of SOX2 in ESCC. Inhibition of GSK3 ss selectively impaired the proliferation and stemness of SOX2-positive ESCC cells. Clinical studies also showed a positive correlation between GSK3 ss and SOX2 protein levels in esophageal tumors, indicating the potential of targeting GSK3 ss for the treatment of ESCC.
Article
Biochemistry & Molecular Biology
Sung Jin Kim, Sang Hyuk Lee, Heesu Lee, Myoung-Sook Shin, Jae Wook Lee
Summary: This study aimed to synthesize and evaluate the anti-inflammatory activity of 3-substituted-indolin-2-one derivatives. Among the nineteen derivatives synthesized, 3-(3-hydroxyphenyl)-indolin-2-one showed the highest anti-inflammatory activity by inhibiting nitric oxide production, suppressing TNF-alpha and IL-6 levels, and inhibiting LPS-induced signal pathways. The findings suggest that 3-(3-hydroxyphenyl)-indolin-2-one possesses excellent anti-inflammatory activity and should be further investigated.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Changqing Xu, Yang Liu, Guisen Zhao
Summary: Kinases play a crucial role in tumorigenesis and metastasis by regulating the expression of oncogenes and antioncogenes. 3-substituted indolin-2-one derivatives have shown promising potential as selective kinase inhibitors for cancer therapy, with low nanomolar activity, high efficacy, and good tolerability.
CURRENT MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Antonio P. A. Ferreira, Alessandra Casamento, Sara Carrillo Roas, Els F. Halff, James Panambalana, Shaan Subramaniam, Kira Schutzenhofer, Laura Chan Wah Hak, Kieran McGourty, Konstantinos Thalassinos, Josef T. Kittler, Denis Martinvalet, Emmanuel Boucrot
Summary: The authors demonstrate that Cdk5 and GSK3 beta act as negative regulators of fast Endophilin-mediated endocytosis (FEME), playing critical roles in axon elongation, branching, and growth cone formation in hippocampal neurons.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Chia-Ling Chen, Po-Chun Tseng, Rahmat Dani Satria, Thi Thuy Nguyen, Cheng-Chieh Tsai, Chiou-Feng Lin
Summary: GSK-3 is a vital regulator of glycogen synthesis that plays a crucial role in cellular bioregulation. Abnormal GSK-3 activation and inactivation can lead to liver damage. Targeting GSK-3 with drugs is a potential therapeutic approach for liver protection. Additionally, blocking GSK-3 has a protective effect in IFN-gamma-mediated immune hepatitis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Organic
Manas Jyoti Sarma, K. A. Sudarshana, Srihari Pabbaraja, Goverdhan Mehta
Summary: Spiroannulation of oxindole-3-oxy acrylates with ynones involving two overlapping, base differentiated cascades has been observed. The initial tandem Michael-Michael cascade delivers a pair of spiroannulated diastereomers, while a second multistep cascade involving stereoselective restructuring leads to the formation of 3H-spiro[furan-2,3'-indolin]-2'-ones with functional amplification and scrambling. This new scaffold can be synthesized in one flask from ynones and oxindole-3-oxy acrylates.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Michael D. Tsymliakov, Anita I. Maksutova, Elena N. Bezsonova, Daria Zakharova, Yuri K. Grishin, Victor A. Tafeenko, Sergey E. Sosonyuk, Natalia A. Lozinskaya
Summary: 1-R-2,4-Dinitrobenzenes can be selectively reduced using sodium dithionite at near-neutral pH to produce the product with an amino group ortho to the substituent R. While the yields of the products varied from moderate to good, this procedure avoids the use of transition metals.
MENDELEEV COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Natalia A. Lozinskaya, Elena N. Bezsonova, Meriam Dubar, Daria D. Melekhina, Daniil R. Bazanov, Alexander S. Bunev, Olga B. Grigor'eva, Vladlen G. Klochkov, Elena V. Sokolova, Denis A. Babkov, Alexander A. Spasov, Sergey E. Sosonyuk
Summary: The enzyme NRH:quinone oxidoreductase 2 (NQO2) is involved in the progression of various diseases and is known to be increased in some cancer cell lines. This study examined the activity of 3-arylidene-2-oxindoles, commonly used in the design of new anticancer drugs, as NRH:quinone oxidoreductase inhibitors. The most active compounds showed significant inhibition of NQO2, but there was no correlation between their inhibition activity and cytotoxic effect on cancer cells.
Article
Biochemistry & Molecular Biology
Alexander Spasov, Irina Ovchinnikova, Olga Fedorova, Yulia Titova, Denis Babkov, Vadim Kosolapov, Alexander Borisov, Elena Sokolova, Vladlen Klochkov, Maria Skripka, Yulia Velikorodnaya, Alexey Smirnov, Gennady Rusinov, Valery Charushin
Summary: The problem of lung damage caused by excessive inflammation and cytokine release during infections is still a concern. This study focuses on the design and synthesis of amino derivatives of specific pyrimidines as potential drugs inhibiting IL-6 and NO. Testing on murine macrophages showed that seven compounds inhibited the synthesis of nitric oxide and interleukin 6 at a concentration of 100 μM. The most active compounds demonstrated minimal impact on innate immunity, unlike the reference drug dexamethasone, and showed promising protective activity in an animal model of acute lung injury.
Article
Chemistry, Medicinal
Denis Babkov, Elena Bezsonova, Viktor Sirotenko, Elias Othman, Vladlen Klochkov, Sergey Sosonyuk, Natalia Lozinskaya, Alexander Spasov
Summary: Development of novel agents that prevent thrombotic events is urgently needed, and GSK3 beta inhibitors showed promising results. The most active compound, 5a, demonstrated significantly higher antiplatelet and antithrombotic activities compared to acetylsalicylic acid. These findings support the potential role of GSK3 beta inhibitors in the development of new antithrombotic agents.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Roman O. Eremeev, Olga V. Beznos, Alexander M. Efremov, Natalia B. Chesnokova, Natalia A. Lozinskaya
Summary: Compounds with a 2-oxindole scaffold are important in organic synthesis and the synthesis of bioactive organic compounds. Developing new methods to modify this scaffold is an interesting and urgent task. In this study, a rational approach to the synthesis of 5-amino-substituted derivatives of 2-oxindole has been created, characterized by high total yield and few steps. The one-stage modification of the obtained 5-amino-2-oxindoles leads to compounds with promising antiglaucomic activity, with the most active compound 7a reducing intraocular pressure by 24% in normotensive rabbits (18% for the reference drug timolol).
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Pharmacology & Pharmacy
Ilya A. Shutkov, Yulia N. Okulova, Dmitrii M. Mazur, Nikolai A. Melnichuk, Denis A. Babkov, Elena V. Sokolova, Alexander A. Spasov, Elena R. Milaeva, Alexey A. Nazarov
Summary: The combination of organic and metal-based fragments with antitumor activity is a modern approach to discover new drugs. This study introduces biologically active ligands based on lonidamine into antitumor organometallic ruthenium scaffold. The stability in ligand exchange reactions does not affect cytotoxicity, while the introduction of a second lonidamine fragment doubles the cytotoxicity. The ability to induce apoptosis and caspase activation in tumor cells was also studied.
Review
Pharmacology & Pharmacy
K. Yu. Kalitin, A. A. Spasov, O. Yu. Mukha
Summary: The study provides a summary of the current strategies used to evaluate the neuroinflammatory effects of kappa-opioid ligands in laboratory animals with induced neuroinflammation. Various experimental models of neuroinflammation were evaluated, and the strengths and limitations of each model were assessed to identify the most appropriate approach for investigating the relationship between neuroinflammation and kappa-opioid receptors.
PHARMACY & PHARMACOLOGY-FARMATSIYA I FARMAKOLOGIYA
(2023)
Article
Biochemistry & Molecular Biology
Alexander Ozerov, Darya Merezhkina, Fedor I. Zubkov, Roman Litvinov, Umida Ibragimova, Nikita Valuisky, Alexander Borisov, Alexander Spasov
Summary: This study synthesized and investigated a series of 3-phenacyl substituted thiazolium salts, analogs of Alagebrium, as glycation reaction inhibitors. The leader compound showed high effectiveness against the three examined mechanisms of glycation reaction and was able to suppress the formation of AGEs.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Article
Biochemistry & Molecular Biology
Alexander A. Spasov, Olga V. Fedorova, Nikolay A. Rasputin, Irina G. Ovchinnikova, Rashida I. Ishmetova, Nina K. Ignatenko, Evgeny B. Gorbunov, Gusein A. O. Sadykhov, Aida F. Kucheryavenko, Kseniia A. Gaidukova, Victor S. Sirotenko, Gennady L. Rusinov, Egor V. Verbitskiy, Valery N. Charushin
Summary: The development of new anticoagulants is urgently needed for the treatment of COVID-19 patients, and drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be particularly helpful, especially for patients with concomitant arterial hypertension or diabetes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Anastasiya V. Petrova, Denis A. Babkov, Elmira F. Khusnutdinova, Irina P. Baikova, Oxana B. Kazakova, Elena V. Sokolova, Alexander A. Spasov
Summary: A series of new oleanane-type triterpenic derivatives were synthesized from oleanolic acid through various reactions and were evaluated for their potential as treatments for immunometabolic disorders. The compounds showed strong inhibition against a-glucosidase enzyme but had no activity against PTP1B. One particular compound, N-methylpiperazine methylated 2,3-indolo-oleanolic propargyl amide 15, also demonstrated inhibitory effects on NO synthesis and oxidative bursts, making it a promising prototype drug for immunometabolic defects in type 2 diabetes.
APPLIED SCIENCES-BASEL
(2023)
