Synthesis of Macrocyclic Peptide-Diterpenoid Conjugates by a Sequential Arylation/Peptide Coupling/Click Macrocyclization Procedure

Mariia A. Gromova,^a,b Yurii V. Kharitonov,^b Tatyana S. Golubeva,^cand Elvira E. Shults^b

^aNovosibirsk State Pedagogical University (NSPU), 630126 Novosibirsk, Russia

^bNovosibirsk Institute of Organic Chemistry SB RAS (NIOCH SB RAS), 630090 Novosibirsk, Russia

^cThe Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

^@Corresponding author E-mail: schultz@nioch.nsc.ru

DOI: 10.6060/mhc210945s
Macroheterocycles 2021 14(3) 231-239

An approach relying on a sequential selective arylation of isopimaric acid/peptide coupling/CuAAC-based macrocyclization procedure of alkynyl peptides to azidoditerpenoid, was developed for the preparation of novel triazole-linked peptide - tricyclic diterpenoid conjugates. The process has comprised the synthesis of azidoditerpenoid bearing the azido group at the side chain by the cross-coupling reaction of isopimaric acid with 1-azido-2-iodobenzene as well as the preparation of a small library of dipeptides featuring varied amino acid sequence (Gly-Gly, Gly-Val, Val-Gly and Val-Val). This approach has shown great chemical efficiency and gave macrocyclic compounds in good yields. It was shown that the yield of macrocyclization products depends on the substituent in the dipeptide fragment. The cytotoxicity of the synthesized compounds was evaluated using the conventional MTT assays. It has been found that the introduction of a dipeptide fragment into the structure of isopimaric acid and macrocyclization have a significant effect on toxicity towards human cancer cells MCF-7 and DU-145.

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Synthesis of Macrocyclic Peptide-Diterpenoid Conjugates by a Sequential Arylation/Peptide Coupling/Click Macrocyclization Procedure

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