Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates

Alexey E Machulkin; Dmitry A Skvortsov; Yan A Ivanenkov; Anton P Ber; Mikhail V Kavalchuk; Anastasia V Aladinskaya; Anastasia A Uspenskaya; Radik R Shafikov; Ekaterina A Plotnikova; Raisa I Yakubovskaya; Ekaterina A Nimenko; Nikolay U Zyk; Elena K Beloglazkina; Nikolay V Zyk; Victor E Koteliansky; Alexander G Majouga

doi:10.1016/j.bmcl.2019.06.035

Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2229-2235. doi: 10.1016/j.bmcl.2019.06.035. Epub 2019 Jun 20.

Authors

Alexey E Machulkin¹, Dmitry A Skvortsov², Yan A Ivanenkov³, Anton P Ber⁴, Mikhail V Kavalchuk⁴, Anastasia V Aladinskaya⁵, Anastasia A Uspenskaya⁴, Radik R Shafikov⁴, Ekaterina A Plotnikova⁶, Raisa I Yakubovskaya⁶, Ekaterina A Nimenko⁴, Nikolay U Zyk⁴, Elena K Beloglazkina⁴, Nikolay V Zyk⁴, Victor E Koteliansky⁴, Alexander G Majouga⁷

Affiliations

¹ Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation; Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Oktyabrya Prospekt 71, 450054 Ufa, Russian Federation. Electronic address: alekseymachulkin@rambler.ru.
² Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation. Electronic address: skvorratd@mail.ru.
³ 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; ChemDiv, San Diego, CA, USA; Institute of Biochemistry and Genetics Ufa Science Centre Russian Academy of Sciences (IBG RAS), Oktyabrya Prospekt 71, 450054 Ufa, Russian Federation.
⁴ Lomonosov Moscow State University, Chemistry Dept., Leninskie gory, Building 1/3, GSP-1, Moscow 119991, Russian Federation.
⁵ Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.
⁶ P. A. Herzen Moscow Oncology Research Institute, 3, 2th Botkinsky Driveway, Moscow 125284, Russian Federation.
⁷ 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: 31248772
DOI: 10.1016/j.bmcl.2019.06.035

Abstract

Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC.

Keywords: Drug delivery; Paclitaxel; Prostate cancer; Prostate-specific membrane antigen.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Delivery Systems / methods*
Humans
Male
Mice
Paclitaxel / chemical synthesis*
Prostatic Neoplasms / drug therapy*

Substances

Paclitaxel