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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.
Affiliation
  • Machulkin AE; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Nimenko EA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Zyk NU; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Uspenskaia AA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Smirnova GB; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., 115478 Moscow, Russia.
  • Khan II; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., 115478 Moscow, Russia.
  • Pokrovsky VS; Biochemistry Department, RUDN University, Miklukho-Maklaya Str.6, 117198 Moscow, Russia.
  • Vaneev AN; N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., 115478 Moscow, Russia.
  • Timoshenko RV; Biochemistry Department, RUDN University, Miklukho-Maklaya Str.6, 117198 Moscow, Russia.
  • Mamed-Nabizade VV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Zavertkina MV; Laboratory of Biophysics, National University of Science and Technology MISiS, 4 Leninskiy pr, 119049 Moscow, Russia.
  • Erofeev A; Laboratory of Biophysics, National University of Science and Technology MISiS, 4 Leninskiy pr, 119049 Moscow, Russia.
  • Gorelkin P; Laboratory of Biophysics, National University of Science and Technology MISiS, 4 Leninskiy pr, 119049 Moscow, Russia.
  • Majouga AG; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Zyk NV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
  • Khazanova ES; Laboratory of Biophysics, National University of Science and Technology MISiS, 4 Leninskiy pr, 119049 Moscow, Russia.
  • Beloglazkina EK; Laboratory of Biophysics, National University of Science and Technology MISiS, 4 Leninskiy pr, 119049 Moscow, Russia.
Molecules ; 27(24)2022 Dec 12.
Article in En | MEDLINE | ID: mdl-36557929
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms Limits: Humans / Male Language: En Journal: Molecules Journal subject: BIOLOGIA Year: 2022 Document type: Article Affiliation country: RUSSIA
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms Limits: Humans / Male Language: En Journal: Molecules Journal subject: BIOLOGIA Year: 2022 Document type: Article Affiliation country: RUSSIA