Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them

Machulkin Aleksei E.; Shafikov Radik R.; Uspenskaya Anastasia A.; Petrov Stanislav A.; Ber Anton P.; Skvortsov Dmitry A.; Nimenko Ekaterina A.; Zyk Nikolay U.; Smirnova Galina B.; Pokrovsky Vadim S.; Abakumov Maxim A.; Saltykova Irina V; Akhmirov Rauf T.; Garanina Anastasiia S.; Polshakov Vladimir I; Saveliev Oleg Y.; Ivanenkov Yan A.; Aladinskaya Anastasiya V; Finko Alexander V; Yamansarov Emil U.; Krasnovskaya Olga O.; Erofeev Alexander S.; Gorelkin Petr V; Dontsova Olga A.; Beloglazkina Elena K.; Zyk Nikolay V; Khazanova Elena S.; Majouga Alexander G.

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Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them

机译：基于芳族残基的PSMA配体的合成与生物学评价和荧光缀合物

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Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.

机译：前列腺特异性膜抗原（PSMA），也称为谷氨酸羧肽酶II（GCPII），由于其在前列腺癌细胞中的过度表达，是抗肿瘤药物和诊断剂的特异性递送的合适靶点。在目前的工作中，我们描述了新型低分子PSMA配体和与荧光染料FAM-5、硫环5和硫环7的共轭物的设计、合成和生物学评价。体外评价合成的PSMA配体对PSMA活性的影响表明，将芳香族氨基酸添加到连接结构中会导致抑制作用显著增加。在体外，最有效的配体与FAM-5和硫环5的结合物对表达PSMA的肿瘤细胞表现出高度的亲和力。PSMA-sulfocycy5和PSMA-sulfocycy7结合物与新型PSMA配体在Balb/c裸鼠体内22Rv1异种移植物中的生物分布显示了PSMA表达肿瘤的良好可视化。此外，结合物PSMA-SULFOCYC7在87.9 mg/kg以下没有任何明显毒性。

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来源
《Journal of Medicinal Chemistry》 |2021年第8期|共21页
作者
Machulkin Aleksei E.; Shafikov Radik R.; Uspenskaya Anastasia A.; Petrov Stanislav A.; Ber Anton P.; Skvortsov Dmitry A.; Nimenko Ekaterina A.; Zyk Nikolay U.; Smirnova Galina B.; Pokrovsky Vadim S.; Abakumov Maxim A.; Saltykova Irina V; Akhmirov Rauf T.; Garanina Anastasiia S.; Polshakov Vladimir I; Saveliev Oleg Y.; Ivanenkov Yan A.; Aladinskaya Anastasiya V; Finko Alexander V; Yamansarov Emil U.; Krasnovskaya Olga O.; Erofeev Alexander S.; Gorelkin Petr V; Dontsova Olga A.; Beloglazkina Elena K.; Zyk Nikolay V; Khazanova Elena S.; Majouga Alexander G.;
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作者单位

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

NN Blokhin Canc Res Ctr Moscow 115478 Russia;

NN Blokhin Canc Res Ctr Moscow 115478 Russia;

Natl Univ Sci &

Technol MISiS Moscow 119049 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Dmitry Mendeleev Univ Chem Technol Russia Moscow 125047 Russia;

Natl Univ Sci &

Technol MISiS Moscow 119049 Russia;

Moscow MV Lomonosov State Univ Fac Fundamental Med Ctr Magnet Tomog &

Spect Moscow 119991 Russia;

Moscow MV Lomonosov State Univ Fac Fundamental Med Ctr Magnet Tomog &

Spect Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Moscow Inst Phys &

Technol Dolgoprudny City 141700 Moscow Region Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

Izvarino Pharma LLC Moscow 108817 Russia;

Lomonosov Moscow State Univ Chem Dept Moscow 119991 Russia;

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中图分类药学;
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Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them

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