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  1. Article ; Online: Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates.

    Zyk, Nikolai Y / Garanina, Anastasiia S / Plotnikova, Ekaterina A / Ber, Anton P / Nimenko, Ekaterina A / Dashkova, Natalia S / Uspenskaia, Anastasiia A / Shafikov, Radik R / Skvortsov, Dmitry A / Petrov, Stanislav A / Pankratov, Andrey A / Zyk, Nikolai V / Majouga, Alexander G / Beloglazkina, Elena K / Machulkin, Aleksei E

    International journal of molecular sciences

    2023  Volume 24, Issue 14

    Abstract: Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. ...

    Abstract Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents.
    MeSH term(s) Male ; Humans ; Androgen Antagonists/therapeutic use ; Cytotoxins/therapeutic use ; Prostate/pathology ; Ligands ; Cell Line, Tumor ; Glutamate Carboxypeptidase II/metabolism ; Antigens, Surface/metabolism ; Prostatic Neoplasms/metabolism
    Chemical Substances Androgen Antagonists ; Cytotoxins ; Ligands ; Glutamate Carboxypeptidase II (EC 3.4.17.21) ; Antigens, Surface
    Language English
    Publishing date 2023-07-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms241411327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Synthesis and initial in vitro evaluation of PSMA-targeting ligands with a modified aromatic moiety at the lysine ε-nitrogen atom.

    Zyk, Nikolai Y / Ber, Anton P / Nimenko, Ekaterina A / Shafikov, Radik R / Evteev, Sergei A / Petrov, Stanislav A / Uspenskaya, Anastasia A / Dashkova, Natalia S / Ivanenkov, Yan A / Skvortsov, Dmitry A / Beloglazkina, Elena K / Majouga, Alexander G / Machulkin, Aleksei E

    Bioorganic & medicinal chemistry letters

    2022  Volume 71, Page(s) 128840

    Abstract: We report an improved series of ligands targeting prostate specific membrane antigen (PSMA). The new compounds were designed by the introduction of changes in the structure of the aromatic fragment at ε-nitrogen atom of lysine that resulted in improved ... ...

    Abstract We report an improved series of ligands targeting prostate specific membrane antigen (PSMA). The new compounds were designed by the introduction of changes in the structure of the aromatic fragment at ε-nitrogen atom of lysine that resulted in improved biological parameters. Some of them demonstrated high selectivity and nanomolar IC
    MeSH term(s) Antigens, Surface ; Cell Line, Tumor ; Glutamate Carboxypeptidase II ; Humans ; Ligands ; Lysine ; Male ; Nitrogen ; Prostatic Neoplasms
    Chemical Substances Antigens, Surface ; Ligands ; Glutamate Carboxypeptidase II (EC 3.4.17.21) ; Lysine (K3Z4F929H6) ; Nitrogen (N762921K75)
    Language English
    Publishing date 2022-05-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2022.128840
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  3. Article ; Online: PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.

    Machulkin, Aleksei E / Uspenskaya, Anastasia A / Zyk, Nikolay Y / Nimenko, Ekaterina A / Ber, Anton P / Petrov, Stanislav A / Shafikov, Radik R / Skvortsov, Dmitry A / Smirnova, Galina B / Borisova, Yulia A / Pokrovsky, Vadim S / Kolmogorov, Vasilii S / Vaneev, Alexander N / Ivanenkov, Yan A / Khudyakov, Alexander D / Kovalev, Sergei V / Erofeev, Alexander S / Gorelkin, Petr V / Beloglazkina, Elena K /
    Zyk, Nikolay V / Khazanova, Elena S / Majouga, Alexander G

    European journal of medicinal chemistry

    2021  Volume 227, Page(s) 113936

    Abstract: Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out ...

    Abstract Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility.
    MeSH term(s) Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Docetaxel/chemical synthesis ; Docetaxel/chemistry ; Docetaxel/pharmacology ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Male ; Mice ; Mice, Inbred ICR ; Molecular Structure ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Prostate-Specific Antigen/antagonists & inhibitors ; Prostate-Specific Antigen/genetics ; Prostate-Specific Antigen/metabolism ; Rabbits ; Rats ; Rats, Wistar ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship
    Chemical Substances Antineoplastic Agents ; Small Molecule Libraries ; Docetaxel (15H5577CQD) ; Prostate-Specific Antigen (EC 3.4.21.77)
    Language English
    Publishing date 2021-10-23
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2021.113936
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 784: Show issues Location:
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  4. Article ; Online: Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates.

    Machulkin, Alexey E / Skvortsov, Dmitry A / Ivanenkov, Yan A / Ber, Anton P / Kavalchuk, Mikhail V / Aladinskaya, Anastasia V / Uspenskaya, Anastasia A / Shafikov, Radik R / Plotnikova, Ekaterina A / Yakubovskaya, Raisa I / Nimenko, Ekaterina A / Zyk, Nikolay U / Beloglazkina, Elena K / Zyk, Nikolay V / Koteliansky, Victor E / Majouga, Alexander G

    Bioorganic & medicinal chemistry letters

    2019  Volume 29, Issue 16, Page(s) 2229–2235

    Abstract: Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side ... ...

    Abstract Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC.
    MeSH term(s) Animals ; Drug Delivery Systems/methods ; Humans ; Male ; Mice ; Paclitaxel/chemical synthesis ; Prostatic Neoplasms/drug therapy
    Chemical Substances Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2019-06-20
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2019.06.035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  5. Article ; Online: Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.

    Machulkin, Aleksei E / Uspenskaya, Anastasia A / Zyk, Nikolay U / Nimenko, Ekaterina A / Ber, Anton P / Petrov, Stanislav A / Polshakov, Vladimir I / Shafikov, Radik R / Skvortsov, Dmitry A / Plotnikova, Ekaterina A / Pankratov, Andrei A / Smirnova, Galina B / Borisova, Yulia A / Pokrovsky, Vadim S / Kolmogorov, Vasilii S / Vaneev, Alexander N / Khudyakov, Alexander D / Chepikova, Olga E / Kovalev, Sergey /
    Zamyatnin, Andrey A / Erofeev, Alexander / Gorelkin, Petr / Beloglazkina, Elena K / Zyk, Nikolay V / Khazanova, Elena S / Majouga, Alexander G

    Journal of medicinal chemistry

    2021  Volume 64, Issue 23, Page(s) 17123–17145

    Abstract: Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we ... ...

    Abstract Prostate cancer is the second most common type of cancer among men. Its main method of treatment is chemotherapy, which has a wide range of side effects. One of the solutions to this challenge is targeted delivery to prostate cancer cells. Here we synthesized a novel small-molecule PSMA-targeted conjugate based on the monomethyl auristatin E. Its structure and conformational properties were investigated by NMR spectroscopy. Cytotoxicity, intracellular reactive oxygen species induction, and stability under liver microsomes and P450-cytochrome species were investigated for this conjugate. The conjugate demonstrated 77-85% tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared with a 37% inhibition level on PC-3 (PSMA (-)) xenografts, in a single dose of 0.3 mg/kg and a sufficiently high therapeutic index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics have shown that the synthesized conjugate is a promising potential agent for the chemotherapy of prostate cancer.
    MeSH term(s) Antigens, Surface/chemistry ; Cell Line, Tumor ; Coordination Complexes/chemical synthesis ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacology ; Glutamate Carboxypeptidase II/chemistry ; Humans ; Male ; Microsomes, Liver/enzymology ; Microsomes, Liver/metabolism ; Oligopeptides/chemistry ; Prostatic Neoplasms/pathology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Antigens, Surface ; Coordination Complexes ; Oligopeptides ; Reactive Oxygen Species ; FOLH1 protein, human (EC 3.4.17.21) ; Glutamate Carboxypeptidase II (EC 3.4.17.21) ; monomethyl auristatin E (V7I58RC5EJ)
    Language English
    Publishing date 2021-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c01157
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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  6. Article ; Online: Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them.

    Machulkin, Aleksei E / Shafikov, Radik R / Uspenskaya, Anastasia A / Petrov, Stanislav A / Ber, Anton P / Skvortsov, Dmitry A / Nimenko, Ekaterina A / Zyk, Nikolay U / Smirnova, Galina B / Pokrovsky, Vadim S / Abakumov, Maxim A / Saltykova, Irina V / Akhmirov, Rauf T / Garanina, Anastasiia S / Polshakov, Vladimir I / Saveliev, Oleg Y / Ivanenkov, Yan A / Aladinskaya, Anastasiya V / Finko, Alexander V /
    Yamansarov, Emil U / Krasnovskaya, Olga O / Erofeev, Alexander S / Gorelkin, Petr V / Dontsova, Olga A / Beloglazkina, Elena K / Zyk, Nikolay V / Khazanova, Elena S / Majouga, Alexander G

    Journal of medicinal chemistry

    2021  Volume 64, Issue 8, Page(s) 4532–4552

    Abstract: Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, ... ...

    Abstract Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7.
    MeSH term(s) Animals ; Antigens, Surface/chemistry ; Antigens, Surface/metabolism ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Fluorescent Dyes/chemistry ; Glutamate Carboxypeptidase II/chemistry ; Glutamate Carboxypeptidase II/metabolism ; Humans ; Ligands ; Male ; Mice ; Mice, Nude ; Optical Imaging ; Prostatic Neoplasms/drug therapy ; Structure-Activity Relationship ; Tissue Distribution ; Transplantation, Heterologous
    Chemical Substances Antigens, Surface ; Antineoplastic Agents ; Fluorescent Dyes ; Ligands ; FOLH1 protein, human (EC 3.4.17.21) ; Glutamate Carboxypeptidase II (EC 3.4.17.21)
    Language English
    Publishing date 2021-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.0c01935
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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