2. Academic Validation
  3. Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA

Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA

  • Bioorg Med Chem Lett. 2019 May 15;29(10):1246-1255. doi: 10.1016/j.bmcl.2019.01.040.
Yan A Ivanenkov 1,  Alexey E Machulkin 2,  Anastasia S Garanina 3,  Dmitry A Skvortsov 2,  Anastasia A Uspenskaya 2,  Ekaterina V Deyneka 4,  Alexander V Trofimenko 4,  Elena K Beloglazkina 2,  Nikolay V Zyk 2,  Victor E Koteliansky 2,  Dmitry S Bezrukov 5,  Anastasia V Aladinskaya 4,  Nataliya S Vorobyeva 6,  Maria M Puchinina 4,  Grigory K Riabykh 2,  Alina A Sofronova 7,  Alexander S Malyshev 8,  Alexander G Majouga 9
Affiliations

Affiliations

  • 1 Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russian Federation; 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; ChemDiv, San Diego, California, USA; Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Oktyabrya Prospekt 71, 450054 Ufa, Russian Federation. Electronic address: yai@chemdiv.com.
  • 2 Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.
  • 3 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.
  • 4 Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.
  • 5 Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation; Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Building 3, Moscow 143026, Russian Federation.
  • 6 Centaura LLC, Moscow, Russia.
  • 7 Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russian Federation.
  • 8 Lomonosov Moscow State University, Faculty of Medicine, Moscow, 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: 30904185 DOI: 10.1016/j.bmcl.2019.01.040
Abstract

Prostate-specific membrane antigen (PSMA), also known as glutamate Carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate Cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside Cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, Anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.

Keywords

Doxorubicin; PSMA; Prostate cancer; Targeted drug delivery.

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