Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them.

Autor: Machulkin AE; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Shafikov RR; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow 117997, Russian Federation., Uspenskaya AA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Petrov SA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Ber AP; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Skvortsov DA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; Faculty of Biology and Biotechnologies, Higher School of Economics, Myasnitskaya 13, Moscow 101000, Russia., Nimenko EA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Zyk NU; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Smirnova GB; N.N. Blokhin Cancer Research Center, 24 Kashirskoye sh., Moscow 115478 , Russia., Pokrovsky VS; N.N. Blokhin Cancer Research Center, 24 Kashirskoye sh., Moscow 115478 , Russia.; RUDN University, Miklukho-Maklaya str. 6, Moscow 117198, Russian Federation., Abakumov MA; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation., Saltykova IV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Akhmirov RT; Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russian Federation., Garanina AS; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation., Polshakov VI; Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow 119991, Russian Federation., Saveliev OY; Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow 119991, Russian Federation., Ivanenkov YA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation.; The Federal State Unitary Enterprise Dukhov Automatics Research Institute, Moscow 127055, Russia.; Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Oktyabrya Prospekt 71, Ufa 450054, Russian Federation., Aladinskaya AV; Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russian Federation., Finko AV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Yamansarov EU; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Krasnovskaya OO; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation., Erofeev AS; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation., Gorelkin PV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation., Dontsova OA; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences, GSP-7, Ulitsa Miklukho-Maklaya, 16/10, Moscow 117997, Russian Federation., Beloglazkina EK; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Zyk NV; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation., Khazanova ES; Izvarino Pharma LLC, v. Vnukovskoe, Vnukovskoe sh., 5th km., Building 1, Moscow 108817, Russian Federation., Majouga AG; Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.; National University of Science and Technology MISiS, 9 Leninskiy pr., Moscow 119049, Russian Federation.; Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russian Federation.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 4532-4552. Date of Electronic Publication: 2021 Apr 06.
DOI: 10.1021/acs.jmedchem.0c01935
Abstrakt: 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.
Databáze: MEDLINE