Synthesis and initial in vitro evaluation of PSMA-targeting ligands with a modified aromatic moiety at the lysine ε-nitrogen atom

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

“…The next step involves obtaining the immobilized ligand on the resin, its subsequent removal from the solid carrier, modification with 3-azidopropylamine and removal of the protecting groups. Since, in contrast to the previously known ligands [23,24], a lysine residue was introduced into the structure of the peptide linker fragment as a second fragment for subsequent conjugation to one of the therapeutic agents, the affinity of the compounds obtained to PSMA had to be evaluated. The PSMA ligands thus obtained, suitable for bimodal conjugates, were subsequently reacted with modified therapeutic agents to produce target products with the general structural motif shown in Figure 1.…”

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu

“…The previously known structural motifs of PSMA ligands, which demonstrated a high potential for interaction with PSMA in previous publications, were chosen as the basis for the structural motifs of the synthesized six conjugates with DOTA 13A – 13F in this work. , These ligand conjugates are already well-established for the delivery of fluorescent dyes as well as the therapeutic agents abiraterone, docetaxel, and monomethylauristatin E and as a platform for bimodal conjugates …”

“…In previous studies, the development of PSMA ligands lacking three aromatic fragments, two in the peptide part and one at the ε-nitrogen atom of lysine, was carried out. 27,28 Extensive screening of these ligands revealed promising substituents that exhibit the best affinity to the receptor. In particular, the screening of various dipeptide motifs highlighted the effectiveness of L-Phe-L-Phe or L-Phe-L-Tyr fragments, along with certain modifications thereof, as optimal candidates for linker insertion.…”

“…This was achieved by variation of different substituents in the N-ε-Lys benzyl moiety along with variation of dipeptide linkers. These efforts were directed toward synthesizing fluorescent or therapeutic conjugates. − Based on the previous ligand screenings, the most potent benzyl moieties, such as m -Cl, p -Br-, and p -COOH-benzyl residues, were taken into account in this paper along with reference ligands, containing a nonsubstituted-benzyl moiety and ligand without benzyl group. To evaluate the effect of the molecular structure of the linker on the properties of a small-molecule PSMA inhibitor, we introduce 6 polypeptides based on N -[ N -[( S )-1,3-dicarboxypropyl]­carbamoyl]-( S )- l -lysine (DCL) with most standard linkers containing the Phe-Phe or Phe-Tyr peptide sequences and an aromatic fragment at the ε-NH 2 K 2 group of the DCL fragment.…”

“…To evaluate the effect of the molecular structure of the linker on the properties of a small-molecule PSMA inhibitor, we introduce 6 polypeptides based on N -[ N -[( S )-1,3-dicarboxypropyl]­carbamoyl]-( S )- l -lysine (DCL) with most standard linkers containing the Phe-Phe or Phe-Tyr peptide sequences and an aromatic fragment at the ε-NH 2 K 2 group of the DCL fragment. In previous studies, the development of PSMA ligands lacking three aromatic fragments, two in the peptide part and one at the ε-nitrogen atom of lysine, was carried out. , Extensive screening of these ligands revealed promising substituents that exhibit the best affinity to the receptor. In particular, the screening of various dipeptide motifs highlighted the effectiveness of l -Phe- l -Phe or l -Phe- l -Tyr fragments, along with certain modifications thereof, as optimal candidates for linker insertion .…”