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. 2023 Jul 11;24(14):11327.
doi: 10.3390/ijms241411327.

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates

Nikolai Y Zyk  1 , Anastasiia S Garanina  2 , Ekaterina A Plotnikova  3 , Anton P Ber  1 , Ekaterina A Nimenko  1 , Natalia S Dashkova  1 , Anastasiia A Uspenskaia  1 , Radik R Shafikov  1   4 , Dmitry A Skvortsov  1 , Stanislav A Petrov  1 , Andrey A Pankratov  3 , Nikolai V Zyk  1 , Alexander G Majouga  5 , Elena K Beloglazkina  1 , Aleksei E Machulkin  1
Affiliations

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates

Nikolai Y Zyk et al. Int J Mol Sci. .

Abstract

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.

Keywords: bimodal conjugates; monomethyl auristatin E; prostate cancer; prostate-specific membrane antigen; targeted drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General structure of PSMA-targeted bimodal conjugates.
Scheme 1
Scheme 1
General scheme for obtaining compounds 2a–c.
Scheme 2
Scheme 2
Scheme for the solid-phase synthesis of peptide fragments 3a–b. Reagents and conditions: i, SOCl2, DMF, DCM, 40 °C; ii, Fmoc-Lys(Boc)-OH, HBTU, HOBt, DIPEA, DMF; iii, 20% solution of 4-methylpiperidine in DMF; iv, Fmoc-Phe-OH or Fmoc-Tyr(OtBu)-OH, HBTU, HOBt, DIPEA, DMF; v, 20% solution of 4-methylpiperidine in DMF; vi, Fmoc-Phe-OH, HBTU, HOBt, DIPEA, DMF; vii, 20% solution of 4-methylpiperidine in DMF.
Scheme 3
Scheme 3
Scheme for producing PSMA ligands 6a–d. Reagents and conditions: i, HBTU, HOBt, DIPEA, DMF; ii, 0.75% solution of TFA in DCM; iii, 3-azidopropylamine, HBTU, HOBt, DIPEA, DMF; iv, TFA/DCM/TIPS/H2O (50/40/5/5 v/v, %).
Figure 2
Figure 2
Structure of comparison ligands.
Scheme 4
Scheme 4
Scheme for the synthesis of bimodal conjugates 10a–d. Reagents and conditions: i, DIPEA, DMF; ii, CuSO4*5H2O, sodium ascorbate, DMF/H2O (3/1).
Scheme 5
Scheme 5
Scheme for the synthesis of bimodal conjugates 13a–d and 15. Reagents and conditions: i, CuSO4*5H2O, sodium ascorbate, DMF/H2O (3/1); ii, 7, DIPEA, DMF; iii, 14, DIPEA, DMF.
Figure 3
Figure 3
Structure of Docetaxel.
Figure 4
Figure 4
Graphical representation of the results of the in vitro experiment on prostate cancer cell lines: (A) LNCaP; (B) 22Rv1; (C) PC-3.
Figure 5
Figure 5
Structures of the reference compounds; I—monomodal conjugate with MMAE; II—monomodal conjugate with abiraterone.
Figure 6
Figure 6
Tumor growth plots of 22Rv1 (A) and PC-3 (B) in mice with intravenous triple injection of 13a, 15 and MMAE (single dose of 132.3 nM/kg). Arrows indicate days of injection.
Figure 7
Figure 7
Dynamics of tumor growth inhibition ratio (TGI) in the 22Rv1 and PC-3 xenograft models.
See this image and copyright information in PMC

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