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  1. 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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  2. 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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    Zs.MB 1: Show issues

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