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Synthesis, in vitro biological activity and docking of new analogs of BIM-23052 containing unnatural amino acids

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Abstract

Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99) d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH2 is a linear SST analog with established in vitro GH-inhibitory activity and high affinity to sstr5, sstr3 and sstr2. The different SSTR subtypes are expressed in different tissues and in some tumor cells. Based on this finding, a series of new analogs of BIM-23052 with expected antitumor activity have been synthesized. The Thr at position 6 in BIM-23052 was replaced by the conformationally hindered Tle, Aib, Ac5c and Ac6c of the new analogs. The peptides were synthesized by standard solid-phase peptide chemistry methods, Fmoc strategy. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29, MDA-MB-23, Hep-G2, HeLa and the normal human diploid cell line Lep-3. All five somatostatin receptor subtypes were modeled and docking was performed to determine the binding affinity of the analogs. The new peptides exhibited different concentration-dependent antiproliferative effect on the tumor cell lines after 24 h of treatment. The compound 3B (Aib6) demonstrated the most pronounced antiproliferative effects on HepG-2 cells with the IC50 = 0.01349 nM. Docking confirmed that all compounds bind well to SST receptors with preference to sstr3 and sstr5, which is most probably the reason for the observed biological effects.

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Funding

This research was funded by Bulgarian National Fund of Scientific Research at the Ministry of Education and Science, Grant No. DN 19/17, 20.12.2017.

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Authors and Affiliations

  1. Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Blvd. 8 Kl. Ohridski, 1756, Sofia, Bulgaria

    Emilia Naydenova & Dancho Danalev

  2. Institute of General and Comparative Pathology, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Bl. 25, 1113, Sofia, Bulgaria

    Diana Wesselinova

  3. Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Bl. 21, 1113, Sofia, Bulgaria

    Svetlana Staykova & Tatyana Dzimbova

  4. South-West University “Neofit Rilski”, 66 Ivan Mihaylov Str, 2700, Blagoevgrad, Bulgaria

    Tatyana Dzimbova

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  1. Emilia Naydenova
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  2. Diana Wesselinova
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Correspondence to Emilia Naydenova.

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Naydenova, E., Wesselinova, D., Staykova, S. et al. Synthesis, in vitro biological activity and docking of new analogs of BIM-23052 containing unnatural amino acids. Amino Acids 51, 1247–1257 (2019). https://doi.org/10.1007/s00726-019-02758-7

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