Article
Biochemistry & Molecular Biology
Elizaveta D. Gladkova, Arina A. Chepanova, Ekaterina S. Ilina, Alexandra L. Zakharenko, Johannes Reynisson, Olga A. Luzina, Konstantin P. Volcho, Olga I. Lavrik, Nariman F. Salakhutdinov
Summary: Novel polycyclic berberine derivatives with sultone ring showed high inhibitory activity against DNA-repair enzyme Tdp1, making them potential candidates for adjuvant therapy against cancer. The active compounds demonstrated micromolar and submicromolar activity levels, while inactive acyclic analogs and sulfonates were not effective. Molecular modeling confirmed the significance of sultone cycle and bromine substituent in binding with the enzyme, showing potential synergy with clinical topoisomerase 1 poison topotecan.
Article
Biochemistry & Molecular Biology
Oksana V. Salomatina, Nadezhda S. Dyrkheeva, Irina I. Popadyuk, Alexandra L. Zakharenko, Ekaterina S. Ilina, Nina I. Komarova, Johannes Reynisson, Nariman F. Salakhutdinov, Olga I. Lavrik, Konstantin P. Volcho
Summary: The deoxycholic acid amide derivatives were found to inhibit both TDP1 and TDP2, with tryptamide 5 and para-bromoanilide 8 showing excellent activity and enhancing the cytotoxicity of topotecan.
Article
Biology
Victoria Marini, Fedor Nikulenkov, Pounami Samadder, Sissel Juul, Birgitta R. Knudsen, Lumir Krejci
Summary: DNA-protein cross-links (DPCs) are harmful DNA lesions that can be formed through various pathways. This study found that MUS81 and TDP1 play independent roles in repairing CPT-induced DNA damage, suggesting they could be new therapeutic targets for cancer treatment in combination with TOP1 inhibitors.
Article
Oncology
V. P. Nikolin, N. A. Popova, V. Kaledin, O. A. Luzina, A. L. Zakharenko, N. F. Salakhutdinov, O. Lavrik
Summary: The enamine derivative of usnic acid is a potential Tdp1 inhibitor that can sensitize tumor cells to Top1 poison, leading to a decrease in tumor volume and metastases. The method of administration plays a crucial role in demonstrating the sensitizing properties of the compound.
CLINICAL & EXPERIMENTAL METASTASIS
(2021)
Article
Biochemistry & Molecular Biology
Nadezhda S. Dyrkheeva, Aleksandr S. Filimonov, Olga A. Luzina, Alexandra L. Zakharenko, Ekaterina S. Ilina, Anastasia A. Malakhova, Sergey P. Medvedev, Johannes Reynisson, Konstantin P. Volcho, Suren M. Zakian, Nariman F. Salakhutdinov, Olga Lavrik
Summary: Usnic acid derivatives show potential in cancer treatment as inhibitors that bind to topoisomerase 1, with low cytotoxicity. In experiments, some compounds had effects on the cytotoxicity of the anticancer drug topotecan in both cancerous and non-cancerous cells.
Article
Biochemistry & Molecular Biology
Irina A. Chernyshova, Aleksandra L. Zakharenko, Nikolay N. Kurochkin, Nadezhda S. Dyrkheeva, Tatyana E. Kornienko, Nelly A. Popova, Valeriy P. Nikolin, Ekaterina S. Ilina, Timofey D. Zharkov, Maxim S. Kupryushkin, Vladimir E. Oslovsky, Mikhail S. Drenichev, Olga I. Lavrik
Summary: The use of cancer chemotherapy sensitizers is a promising approach to enhance the effect of clinically used anticancer treatments. In this study, we focused on Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, and investigated its inhibition as a strategy to sensitize cells towards the effect of the Topoisomerase 1 (Top1) inhibitor topotecan (Tpc). We synthesized lipophilic derivatives of purine nucleosides that efficiently suppressed Tdp1 activity and demonstrated their ability to enhance DNA damage induced by topotecan, both in vitro using human cell lines and in vivo using a mice ascitic Krebs-2 carcinoma model.
Article
Biochemistry & Molecular Biology
Somenath Roy Chowdhury, Subhendu K. Das, Bijoylaxmi Banerjee, Srijita Paul Chowdhuri, Hemanta K. Majumder, Benu Brata Das
Summary: This study reveals the important role of Tyrosyl DNA-phosphodiesterase 1 (TDP1) in protecting Leishmania donovani parasites from oxidative stress-induced DNA damage and resistance to certain antileishmanial drugs.
Article
Chemistry, Medicinal
Kseniya Kovaleva, Olga Yarovaya, Konstantin Ponomarev, Sergey Cheresiz, Amirhossein Azimirad, Irina Chernyshova, Alexandra Zakharenko, Vasily Konev, Tatiana Khlebnikova, Evgenii Mozhaytsev, Evgenii Suslov, Dmitry Nilov, Vytas Svedas, Andrey Pokrovsky, Olga Lavrik, Nariman Salakhutdinov
Summary: In this study, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds showed promising inhibitory activities against TDP1 and low cytotoxicity in T98G glioma cell line. Molecular docking analysis suggested that adamantane derivatives of resin acids bind to TDP1 covalent intermediate, forming interactions with specific residues and the substrate fragment.
Article
Genetics & Heredity
Alexandra L. Zakharenko, Nadezhda S. Dyrkheeva, Olga A. Luzina, Aleksandr S. Filimonov, Evgenii S. Mozhaitsev, Anastasia A. Malakhova, Sergey P. Medvedev, Suren M. Zakian, Nariman F. Salakhutdinov, Olga I. Lavrik
Summary: This study discovered a class of compounds derived from (-)-usnic acid that are capable of inhibiting both Tdp1 and Tdp2 DNA repair enzymes. These compounds protect wild-type cells from the cytotoxic effect of etoposide, but potentiate its action in Tdp2 knockout cells. The study suggests that the sensitizing effect of the compounds in the absence of Tdp2 may be due to their inhibition of Tdp1, which could take over the functions of Tdp2.
Review
Chemistry, Inorganic & Nuclear
Qian Zhang, Cong Su, Jian-Ge Qiu, Bing-Hua Jiang, Chun-yang Zhang
Summary: To maintain the stability and integrity of cellular genomic DNA, DNA repair enzymes play a crucial role in repairing DNA damage caused by various factors. Abnormal DNA repair enzyme activity can lead to cell death, cancer, and other human diseases. To accurately monitor DNA repair enzymes in cells, enzyme-free nucleic acid amplification approaches have been introduced for real-time imaging. These approaches provide new insights into the dynamic changes of DNA repair enzymes at the single-cell level.
COORDINATION CHEMISTRY REVIEWS
(2023)
Article
Nanoscience & Nanotechnology
Ji Zhuang, Ya-Ting Qin, Yu-Sheng Feng, Zheng-Chen Su, Xi-Wen He, Wen-You Li, Yu-Kui Zhang
Summary: A novel nanoparticle inhibitor, PB@MIP, was prepared by synthesizing molecularly imprinted polymers on the Prussian Blue surface. It achieved combined tumor starvation and photothermal therapy by inhibiting the catalytic activity of hexokinase (HK) and downregulating the ATP-dependent expression of heat shock proteins (HSPs). This improved the therapeutic effect of photothermal therapy by sensitizing tumors to hyperthermia.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Biochemistry & Molecular Biology
Nadezhda S. Dyrkheeva, Anastasia A. Malakhova, Aleksandra L. Zakharenko, Larisa S. Okorokova, Dmitriy N. Shtokalo, Sophia V. Pavlova, Sergey P. Medvedev, Suren M. Zakian, Anna A. Nushtaeva, Alexey E. Tupikin, Marsel R. Kabilov, Svetlana N. Khodyreva, Olga A. Luzina, Nariman F. Salakhutdinov, Olga I. Lavrik
Summary: Topoisomerase 1 (TOP1) is a key enzyme in DNA replication, recombination, and other processes. Tyrosyl-DNA phosphodiesterase 1 (TDP1) can eliminate TOP1cc and interfere with the action of topotecan. Poly(ADP-ribose) polymerase 1 (PARP1) controls the repair of TOP1cc. Transcriptomic analysis revealed significant differences in gene expression between wild-type and PARP1 knockout cells treated with topotecan and TDP1 inhibitor OL9-119 alone or in combination.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Sangheeta Bhattacharjee, Ishita Rehman, Saini Basu, Souvik Nandy, Julia M. Richardson, Benu Brata Das
Summary: This study reveals the crucial role of arginine methylation in regulating the stability and activity of TDP1, promoting the repair of trapped Top1cc.
Article
Biochemistry & Molecular Biology
Maria J. J. Solares, Deborah F. F. Kelly
Summary: Genetic mutations in tumor suppressor genes can lead to cancer, with mutations in p53 potentially exacerbating toxic effects and impeding DNA interactions, emphasizing the need for new studies to assist in redesigning targeted therapies based on protein structure.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Leonie Hacker, Annika Dorn, Janina Enderle, Holger Puchta
Summary: The research reveals that Arabidopsis thaliana has two main repair pathways for TOP2cc, mediated by TDP2 and WSS1A, while MUS81 plays a major role in global DPC repair. Additionally, TDP1 and TDP2 function in TOP1cc repair, preventing erroneous pathways.
Article
Virology
Evgenii S. S. Mozhaitsev, Evgeniy V. V. Suslov, Daria A. A. Rastrepaeva, Olga I. I. Yarovaya, Sophia S. S. Borisevich, Edward M. M. Khamitov, Dmitry S. S. Kolybalov, Sergey G. G. Arkhipov, Nikolai I. I. Bormotov, Larisa N. N. Shishkina, Olga A. A. Serova, Roman V. V. Brunilin, Andrey A. A. Vernigora, Maxim B. B. Nawrozkij, Alexander P. P. Agafonov, Rinat A. A. Maksyutov, Konstantin P. P. Volcho, Nariman F. F. Salakhutdinov
Summary: Although the variola virus has been eradicated, the search for new small molecules with activity against orthopoxviruses is still important, especially due to recent outbreaks of monkeypox. A series of benzoic acid amide derivatives containing an adamantane fragment were obtained, most of which showed activity against vaccinia virus. The leader compound 18a exhibited a high selectivity index (SI = 18,214). The IC50 values of the compounds correlated with the binding energy to the assumed biological target, the p37 viral protein (R-2 = 0.60).
Article
Chemistry, Organic
Alexandra V. Podturkina, Nikolai S. Li-Zhulanov, Konstantin P. Volcho, Nariman F. Salakhutdinov
Summary: Parkinson's disease is a progressive neurodegenerative disorder characterized by movement dysfunction. A new Prottremin derivative was synthesized by opening the epoxide ring with 1-(4-isopropylbenzyl)piperazine, with a product yield of 48% after purification.
Article
Biochemistry & Molecular Biology
Yulia Aleksandrova, Aldar Munkuev, Evgenii Mozhaitsev, Evgenii Suslov, Dmitry Tsypyshev, Kirill Chaprov, Roman Begunov, Konstantin Volcho, Nariman Salakhutdinov, Margarita Neganova
Summary: Novel monoterpene-based hydroxamic acids were synthesized, consisting of compounds with a hydroxamate group directly bound to monoterpene scaffolds or connected through aliphatic or aromatic linkers. Some of these compounds showed powerful HDAC6 inhibitory activity, with a hexa- and heptamethylene linker and (-)-perill fragment exhibiting the most excellent activity. Moderate antiradical activity was also observed. Compounds with an aromatic linker based on para-substituted cinnamic acids demonstrated the ability to suppress aggregation of beta-amyloid peptide 1-42. The lead compound 35a showed neuroprotective effects on in vivo Alzheimer's disease models. This research suggests the potential use of monoterpene-derived hydroxamic acids in Alzheimer's disease treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Dmitry I. Ivankin, Tatyana E. Kornienko, Marina A. Mikhailova, Nadezhda S. Dyrkheeva, Alexandra L. Zakharenko, Chigozie Achara, Johannes Reynisson, Victor M. Golyshev, Olga A. Luzina, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik
Summary: A novel series of 3,5-disubstituted thiazolidine-2,4-diones were synthesized and tested for their activity against TDP1. Compounds 20d and 21d showed the highest activity with IC50 values in the submicromolar range. However, these compounds did not exhibit cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the concentration range of 1-100 μM, and they also did not sensitize cancer cells to the cytotoxic effect of topotecan.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Tatyana M. M. Khomenko, Alexandra L. L. Zakharenko, Tatyana E. E. Kornienko, Arina A. A. Chepanova, Nadezhda S. S. Dyrkheeva, Anastasia O. O. Artemova, Dina V. V. Korchagina, Chigozie Achara, Anthony Curtis, Johannes Reynisson, Konstantin P. P. Volcho, Nariman F. F. Salakhutdinov, Olga I. I. Lavrik
Summary: A series of new 5-hydroxycoumarin derivatives containing monoterpene moieties were synthesized and shown to have high inhibitory properties against TDP1. The most potent inhibitor was a geraniol derivative 33a with an IC50 of 130 nM. Docking simulations indicated a good fit with TDP1 and blocking of the catalytic pocket. These derivatives sensitized cancer cells to the cytotoxic effect of topotecan.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Alexandra L. Zakharenko, Olga A. Luzina, Arina A. Chepanova, Nadezhda S. Dyrkheeva, Nariman F. Salakhutdinov, Olga I. Lavrik
Summary: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the DNA. Inhibition of TDP1 can sensitize tumor cells to the action of anticancer drugs. This review provides information about methods for determining TDP1 activity and describes inhibitors of TDP1 derived from natural biologically active substances.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Yu. V. Meshkova, D. S. Baev, I. V. Sorokina, I. I. Popadyuk, O. V. Salomatina, N. A. Zhukova, T. G. Tolstikova, N. F. Salakhutdinov
Summary: A low-toxic 5-AR inhibitor was synthesized based on deoxycholic acid, which showed similar prostate protection effects to finasteride but with lower toxicity. The compound demonstrated promising potential as a candidate for preclinical trials.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anna A. Shtro, Artem M. Klabukov, Anzhelika V. Garshinina, Anastasia V. Galochkina, Yulia V. Nikolaeva, Tatyana M. Khomenko, Danila E. Bobkov, Aleksey A. Lozhkov, Konstantin V. Sivak, Kirill S. Yakovlev, Andrey B. Komissarov, Sophia S. Borisevich, Konstantin P. Volcho, Nariman F. Salakhutdinov
Summary: This article discusses the mechanism of action of compound K142 against respiratory syncytial virus (RSV), showing that its interaction with RSV surface proteins is crucial for its antiviral activity. However, in vivo studies have indicated weak antiviral activity, suggesting the need for further modifications to enhance its efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Elmira Gibadullina, Margarita Neganova, Yulia Aleksandrova, Hoang Bao Tran Nguyen, Alexandra Voloshina, Mikhail Khrizanforov, Thi Thu Nguyen, Ekaterina Vinyukova, Konstantin Volcho, Dmitry Tsypyshev, Anna Lyubina, Syumbelya Amerhanova, Anna Strelnik, Julia Voronina, Daut Islamov, Rakhmetulla Zhapparbergenov, Nurbol Appazov, Beauty Chabuka, Kimberley Christopher, Alexander Burilov, Nariman Salakhutdinov, Oleg Sinyashin, Igor Alabugin
Summary: This study explores the biological activity of a family of new hybrid molecules that combine sterically hindered phenols (SHPs) with additional urea/thiourea fragments. It finds that these compounds exhibit cytotoxic activity against tumor cells and have dual properties of pronounced antioxidant activity and increased reactive oxygen species generation. Molecular docking analysis reveals a potential target for these compounds. The most promising compounds can induce apoptosis in cancer cells through the intrinsic mitochondrial pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Vladlena S. Makeeva, Nadezhda S. Dyrkheeva, Olga I. Lavrik, Suren M. Zakian, Anastasia A. Malakhova
Summary: The spectrum of neurodegenerative diseases is extensive, and their research and treatment are complex and diverse. Despite years of research on common pathologies, like Alzheimer's and Parkinson's, cures have not been found. However, Huntington's disease, although affecting a smaller population, still attracts researchers. Understanding the mechanisms of this orphan disease is challenging, but accumulated data provide a foundation for further research.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Jonathan P. Dolan, Sanaz Ahmadipour, Alice J. C. Wahart, Aisling Ni Cheallaigh, Suat Sari, Chatchakorn Eurtivong, Marcelo A. Lima, Mark A. Skidmore, Konstantin P. Volcho, Johannes Reynisson, Robert A. Field, Gavin J. Miller
Summary: This study used virtual screening and experimental validation to discover a new compound that can inhibit the synthesis of alginate in Pseudomonas aeruginosa. The compound showed stronger inhibition than existing inhibitors, offering a potential pathway for the development of new selective antibacterial drugs.
RSC CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Olexander M. Semenenko, Victoria V. Lipson, Alina O. Sadchenko, Olga V. Vashchenko, Natalia A. Kasian, Liliia Sviechnikova, Longin M. Lisetski, Mykola L. Babak, Volodymyr M. Vakula, Oleksandr Borysov, Yuliia Holota, Sergey O. Zozulya, Petro O. Borysko, Olexander Mazepa
Summary: An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids has been developed and their structures and properties have been fully established. The hybrids showed inferior interactions with artificial lipid membranes, possibly due to their increasing lipophilicity.
Article
Biochemistry & Molecular Biology
Mohadese Yaghoobi Anzabi, Piotr Cmoch, Roman Luboradzki, Zbigniew Pakulski
Summary: Friedelin and 3-acetoxyfriedel-3-en-2-one, known as friedelane triterpenoids, have been isolated from cork smoker wash solids and used as starting materials for the synthesis of new friedelane derivatives. Reduction reactions result in the formation of friedelinol and epi-cerin derivatives.
Article
Biochemistry & Molecular Biology
Detlef Thieme, Aniko Krumbholz, Martin Bidlingmaier, Christoph Geffert, Annika Hameder, Andreas Stoever, Matthias Graw, Annekathrin M. Keiler
Summary: Ethanol can affect testosterone metabolism and potentially influence steroid biosynthesis and blood steroid profiles. The study emphasizes the importance of sufficient time interval from food and ethanol intake during blood sampling, particularly for diagnostics in doping control.
Article
Biochemistry & Molecular Biology
Masanobu Murao, Tetsuo Imano, Yoshinobu Sato, Masaaki Nakajima
Article
Biochemistry & Molecular Biology
Jingyuan Wang, Ye Feng, Brian Liu, Wen Xie
Summary: Sulfation and desulfation of steroids are opposing processes that regulate steroid homeostasis and are involved in steroid-related diseases. Cytosolic sulfotransferase and steroid sulfatase modify and regulate steroids to affect hormonal dysregulation, metabolic diseases, and cancer.
Article
Biochemistry & Molecular Biology
Noah K. Babel, Brian J. Feldman
Summary: Our research identified a previously unrecognized ADAMTS1-PTN-Wnt pathway in regulating adipose precursor cell behavior. The non-muscle myosin protein MYH9 was found to be a key target of this pathway for modulating adipogenesis. These findings offer potential for developing novel therapeutics for obesity and related metabolic disorders.
Article
Biochemistry & Molecular Biology
Martiniano Bello
Summary: This study explores the structural and thermodynamic basis of molecular recognition between ERβ and DPN and its derivatives using molecular dynamics simulations and end-point methods. The results show that the MMGBSA approach is able to reproduce experimental trends and identify eight residues that strongly interact with the ligands.