Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates

  • Bioorg Med Chem Lett. 2018 Feb 1;28(3):382-387. doi: 10.1016/j.bmcl.2017.12.032.
Rostislav A Petrov  1 ,  Svetlana Yu Maklakova  1 ,  Yan A Ivanenkov  2 ,  Stanislav A Petrov  1 ,  Olga V Sergeeva  3 ,  Emil Yu Yamansarov  1 ,  Irina V Saltykova  1 ,  Igor I Kireev  4 ,  Irina B Alieva  4 ,  Ekaterina V Deyneka  5 ,  Alina A Sofronova  6 ,  Anastasiia V Aladinskaia  5 ,  Alexandre V Trofimenko  5 ,  Renat S Yamidanov  7 ,  Sergey V Kovalev  1 ,  Victor E Kotelianski  8 ,  Timofey S Zatsepin  3 ,  Elena K Beloglazkina  1 ,  Alexander G Majouga  9
Affiliations
  • 1. Lomonosov Moscow State University, Chemistry Dept, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.
  • 2. Lomonosov Moscow State University, Chemistry Dept, 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; Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Prosp. Oktybrya 71, Ufa, Bashkortostan 450054, Russian Federation. Electronic address: [email protected].
  • 3. Lomonosov Moscow State University, Chemistry Dept, Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation; Skolkovo Institute of Science and Technology, 100 Novaya St., 143025 Skolkovo, Russian Federation.
  • 4. Lomonosov Moscow State University, A.N. Belozersky Institute of Physico-Chemical Biology, Leninskye Gory, House 1, Building 40, Moscow 119992, Russian Federation.
  • 5. Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.
  • 6. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russia.
  • 7. Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Prosp. Oktybrya 71, Ufa, Bashkortostan 450054, Russian Federation.
  • 8. Skolkovo Institute of Science and Technology, 100 Novaya St., 143025 Skolkovo, Russian Federation.
  • 9. Lomonosov Moscow State University, Chemistry Dept, 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.
PMID: 29269214 DOI: 10.1016/j.bmcl.2017.12.032
Abstract

Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and Anticancer drug - paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro Anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC.

Keywords
ASGP-R; Cancer; Paclitaxel; Targeted drug delivery.