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  1. Article ; Online: Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate.

    Machulkin, Aleksei E / Nimenko, Ekaterina A / Zyk, Nikolay U / Uspenskaia, Anastasiia A / Smirnova, Galina B / Khan, Irina I / Pokrovsky, Vadim S / Vaneev, Alexander N / Timoshenko, Roman V / Mamed-Nabizade, Vugara V / Zavertkina, Maria V / Erofeev, Alexander / Gorelkin, Petr / Majouga, Alexander G / Zyk, Nikolay V / Khazanova, Elena S / Beloglazkina, Elena K

    Molecules (Basel, Switzerland)

    2022  Volume 27, Issue 24

    Abstract: Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to ... ...

    Abstract Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of
    Language English
    Publishing date 2022-12-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules27248795
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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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  3. 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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  4. 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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