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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 3; pp. 382 - 387
• Main Authors: Petrov, Rostislav A., Maklakova, Svetlana Yu, Ivanenkov, Yan A., Petrov, Stanislav A., Sergeeva, Olga V., Yamansarov, Emil Yu, Saltykova, Irina V., Kireev, Igor I., Alieva, Irina B., Deyneka, Ekaterina V., Sofronova, Alina A., Aladinskaia, Anastasiia V., Trofimenko, Alexandre V., Yamidanov, Renat S., Kovalev, Sergey V., Kotelianski, Victor E., Zatsepin, Timofey S., Beloglazkina, Elena K., Majouga, Alexander G.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2018; Elsevier
• Subjects: Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; ASGP-R; Asialoglycoprotein Receptor - antagonists & inhibitors; Asialoglycoprotein Receptor - metabolism; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Screening Assays, Antitumor; Galactose - analogs & derivatives; Galactose - chemistry; Galactose - pharmacology; Hep G2 Cells; Humans; Life Sciences & Biomedicine; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Molecular Structure; Paclitaxel; Paclitaxel - chemical synthesis; Paclitaxel - chemistry; Paclitaxel - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Targeted drug delivery; Targeted drug delivery; ASGP-R; Paclitaxel; Cancer; FUNCTIONAL RESERVE; HIGH-AFFINITY; CLUSTER GALACTOSIDES; HEPATIC ASIALOGLYCOPROTEIN RECEPTOR; OLIGONUCLEOTIDES; POSTOPERATIVE LIVER-FUNCTION; DELIVERY SYSTEM; LIGANDS; PREOPERATIVE ESTIMATION; CARBOHYDRATE-RECOGNITION DOMAIN
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2017.12.032

[Display omitted] 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.