Synthesis, in vitro biological activity, hydrolytic stability and docking of new analogs of BIM-23052 containing halogen
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ORIGINAL ARTICLE
Synthesis, in vitro biological activity, hydrolytic stability and docking of new analogs of BIM‑23052 containing halogenated amino acids Dancho Danalev1 · Desislava Borisova2 · Spaska Yaneva3 · Maya Georgieva4 · Anelia Balacheva4 · Tatyana Dzimbova4,5 · Ivan Iliev6 · Tamara Pajpanova4 · Zdravka Zaharieva1,7 · Ivan Givechev1,7 · Emilia Naydenova2 Received: 13 May 2020 / Accepted: 6 November 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract One of the potent somatostatin analogs, BIM-23052 (DC-23-99) d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH2, has established in vitro growth hormone inhibitory activity in nM concentrations. It is also characterized by high affinity to some somatostatin receptors which are largely distributed in the cell membranes of many tumor cells. Herein, we report the synthesis of a series of analogs of BIM-23052 containing halogenated Phe residues using standard solid-phase peptide method Fmoc/ OtBu-strategy. The cytotoxic effects of the compounds were tested in vitro against two human tumor cell lines—breast cancer cell line and hepatocellular cancer cell line, as well as on human non-tumorigenic epithelial cell line. Analogs containing fluoro-phenylalanines are cytotoxic in μM range, as the analog containing Phe (2-F) showed better selectivity against human hepatocellular cancer cell line. The presented study also reveals that accumulation of halogenated Phe residues does not increase the cytotoxicity according to tested cell lines. The calculated selective index reveals different mechanisms of antitumor activity of the parent compound BIM-23052 and target halogenated analogs for examined breast tumor cell lines. All peptides tested have high antitumor activity against the HepG2 cell line (IC50 ≈ 100 μM and SI > 5) compared to breast cells. This is probably due to the high permeability of the cell membrane and the higher metabolic activity of hepatocytes. In silico docking studies confirmed that all obtained analogs bind well with the somatostatin receptors with preference to ssrt3 and ssrt5. All target compounds showed high hydrolytic stability at acid and neutral pH, which mimic physiological condition in stomach and human plasma. Keywords Peptides · Analogs of BIM-23052 · Somatostatin · Solid-phase peptide synthesis · Hydrolytic stability · Cytotoxic effects · Docking
Handling editor: P. Meffre. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00726-020-02915-3) contains supplementary material, which is available to authorized users. * Emilia Naydenova [email protected] 1
Biotechnology Department, University of Chemical Technology and Metallurgy, Sofia, Bulgaria
2
Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria
3
Department of Fundamental of Chemical Technology, University of Chemical Technology and Metallurgy, Sofia, Bulgaria
4
Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, Sofia, Bulgaria
5
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