9 results on '"Nimenko EA"'
Search Results
2. Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate.
- Author
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Machulkin AE, Nimenko EA, Zyk NU, Uspenskaia AA, Smirnova GB, Khan II, Pokrovsky VS, Vaneev AN, Timoshenko RV, Mamed-Nabizade VV, Zavertkina MV, Erofeev A, Gorelkin P, Majouga AG, Zyk NV, Khazanova ES, and Beloglazkina EK
- Subjects
- Male, Humans, Prostate pathology, Androgen Antagonists, Antigens, Surface, Androstenes pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- 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 PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc .
- Published
- 2022
- Full Text
- View/download PDF
3. Synthesis and initial in vitro evaluation of PSMA-targeting ligands with a modified aromatic moiety at the lysine ε-nitrogen atom.
- Author
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Zyk NY, Ber AP, Nimenko EA, Shafikov RR, Evteev SA, Petrov SA, Uspenskaya AA, Dashkova NS, Ivanenkov YA, Skvortsov DA, Beloglazkina EK, Majouga AG, and Machulkin AE
- Subjects
- Antigens, Surface, Cell Line, Tumor, Glutamate Carboxypeptidase II, Humans, Ligands, Male, Nitrogen, Lysine, Prostatic Neoplasms
- 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
50 values. We synthesized and tested two conjugates with a fluorescent label Sulfo-Cy5 as an example of the use of the obtained PSMA inhibitors as a basis for the creation of diagnostic preparations., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
4. PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.
- Author
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Machulkin AE, Uspenskaya AA, Zyk NY, Nimenko EA, Ber AP, Petrov SA, Shafikov RR, Skvortsov DA, Smirnova GB, Borisova YA, Pokrovsky VS, Kolmogorov VS, Vaneev AN, Ivanenkov YA, Khudyakov AD, Kovalev SV, Erofeev AS, Gorelkin PV, Beloglazkina EK, Zyk NV, Khazanova ES, and Majouga AG
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Docetaxel chemical synthesis, Docetaxel chemistry, 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 genetics, Prostate-Specific Antigen metabolism, Rabbits, Rats, Rats, Wistar, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Docetaxel pharmacology, Prostate-Specific Antigen antagonists & inhibitors, Small Molecule Libraries pharmacology
- 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2022
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5. The Importance of Linkers in the Structure of PSMA Ligands.
- Author
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Uspenskaya AA, Nimenko EA, Machulkin AE, Beloglazkina EK, and Majouga AG
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- Cell Line, Tumor, Drug Delivery Systems, Humans, Ligands, Male, Peptides therapeutic use, Structure-Activity Relationship, Prostatic Neoplasms drug therapy
- Abstract
Cancer is one of the leading social problems of the modern world. Today prostate cancer is the second leading cause of cancer deaths among men. Targeted drug delivery is widely used to treat and diagnose prostate cancer. Conjugates selectively binding to prostatespecific membrane antigen-based on urea ligands are being actively developed against this disease. The linker has a significant influence on the biological activity of such conjugates. The linker performs a large number of functions, and its modification is one of the key methods for creating the best pharmacological profile. This review aims to discuss and analyze the main approaches to the method of introduction and synthesis of linkers for this type of conjugates without a description of the influence of biologically active molecules, as well as to establish the key modification methods that have a significant role on the structure-activity relationship. For this purpose, a review of the current scientific literature was performed, both for the conjugates under development and those already undergoing clinical trials. It was found that the optimal structure is a linker containing an aliphatic fragment near the vector- molecule (n(CH2) = 3-6), followed by a polypeptide chain consisting of 2 to 4 amino acid residues. The presence of a Phe-Phe dipeptide chain or the introduction of negatively charged groups also has a positive effect. Ongoing research in this field helps to establish the accurate effect of each linker fragment, and the development of solid-phase synthesis methods makes it much easier to achieve this goal., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2022
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6. Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate.
- Author
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Machulkin AE, Uspenskaya AA, Zyk NU, Nimenko EA, Ber AP, Petrov SA, Polshakov VI, Shafikov RR, Skvortsov DA, Plotnikova EA, Pankratov AA, Smirnova GB, Borisova YA, Pokrovsky VS, Kolmogorov VS, Vaneev AN, Khudyakov AD, Chepikova OE, Kovalev S, Zamyatnin AA Jr, Erofeev A, Gorelkin P, Beloglazkina EK, Zyk NV, Khazanova ES, and Majouga AG
- Subjects
- Cell Line, Tumor, Coordination Complexes chemical synthesis, Humans, Male, Microsomes, Liver enzymology, Microsomes, Liver metabolism, Prostatic Neoplasms pathology, Reactive Oxygen Species metabolism, Xenograft Model Antitumor Assays, Antigens, Surface chemistry, Coordination Complexes chemistry, Coordination Complexes pharmacology, Glutamate Carboxypeptidase II chemistry, Oligopeptides chemistry
- 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.
- Published
- 2021
- Full Text
- View/download PDF
7. Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them.
- Author
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Machulkin AE, Shafikov RR, Uspenskaya AA, Petrov SA, Ber AP, Skvortsov DA, Nimenko EA, Zyk NU, Smirnova GB, Pokrovsky VS, Abakumov MA, Saltykova IV, Akhmirov RT, Garanina AS, Polshakov VI, Saveliev OY, Ivanenkov YA, Aladinskaya AV, Finko AV, Yamansarov EU, Krasnovskaya OO, Erofeev AS, Gorelkin PV, Dontsova OA, Beloglazkina EK, Zyk NV, Khazanova ES, and Majouga AG
- Subjects
- Animals, Antigens, Surface chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Glutamate Carboxypeptidase II chemistry, Humans, Male, Mice, Mice, Nude, Optical Imaging, Prostatic Neoplasms drug therapy, Structure-Activity Relationship, Tissue Distribution, Transplantation, Heterologous, Antigens, Surface metabolism, Antineoplastic Agents metabolism, Fluorescent Dyes chemistry, Glutamate Carboxypeptidase II metabolism, Ligands
- 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. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro . In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.
- Published
- 2021
- Full Text
- View/download PDF
8. Polypeptide-Based Molecular Platform and Its Docetaxel/Sulfo-Cy5-Containing Conjugate for Targeted Delivery to Prostate Specific Membrane Antigen.
- Author
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Petrov SA, Machulkin AE, Uspenskaya AA, Zyk NY, Nimenko EA, Garanina AS, Petrov RA, Polshakov VI, Grishin YK, Roznyatovsky VA, Zyk NV, Majouga AG, and Beloglazkina EK
- Subjects
- Amino Acid Sequence, Chemistry Techniques, Synthetic, Drug Delivery Systems, Molecular Structure, Peptides chemical synthesis, Antigens, Surface administration & dosage, Carbocyanines chemistry, Docetaxel chemistry, Drug Carriers chemistry, Glutamate Carboxypeptidase II administration & dosage, Peptides chemistry
- Abstract
A strategy for stereoselective synthesis of molecular platform for targeted delivery of bimodal therapeutic or theranostic agents to the prostate-specific membrane antigen (PSMA) receptor was developed. The proposed platform contains a urea-based, PSMA-targeting Glu-Urea-Lys (EuK) fragment as a vector moiety and tripeptide linker with terminal amide and azide groups for subsequent addition of two different therapeutic and diagnostic agents. The optimal method for this molecular platform synthesis includes (a) solid-phase assembly of the polypeptide linker, (b) coupling of this linker with the vector fragment, (c) attachment of 3-aminopropylazide, and (d) amide and carboxylic groups deprotection. A bimodal theranostic conjugate of the proposed platform with a cytostatic drug (docetaxel) and a fluorescent label (Sulfo-Cy5) was synthesized to demonstrate its possible sequential conjugation with different functional molecules.
- Published
- 2020
- Full Text
- View/download PDF
9. Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates.
- Author
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Machulkin AE, Skvortsov DA, Ivanenkov YA, Ber AP, Kavalchuk MV, Aladinskaya AV, Uspenskaya AA, Shafikov RR, Plotnikova EA, Yakubovskaya RI, Nimenko EA, Zyk NU, Beloglazkina EK, Zyk NV, Koteliansky VE, and Majouga AG
- Subjects
- Animals, Humans, Male, Mice, Drug Delivery Systems methods, Paclitaxel chemical synthesis, Prostatic Neoplasms drug therapy
- 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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