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Convenient one-pot synthesis of resin acid Mannich bases as novel anticancer and antifungal agents

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Abstract

The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl esters by formaldehyde and secondary amines was studied for the first time. The novel diethylamino, pyrrolidine, and morpholine-substituted butynyl derivatives of abietic, dehydroabietic, levopimaric, maleopimaric and dihydroquinopimaric acids were obtained. It was shown that synthesis of the abietic acid propargyl ester by the reaction of the abietane diterpenoid with oxalyl chloride and dimethylformamide is accompanied by the formylation of the ring B at the C-7 position and the dehydrogenation of the ring C to form the dehydroabietic acid ester. The cytotoxic, antibacterial and fungicidal activities of the synthesized compounds were studied in vitro. The experimental results showed that the most promising compound was 7-formyl abietic derivative Mannich base with a pyrrolidine substituent, with an MIC of 16 μg/ml against methicillin-resistant S. aureus ATCC 43300, and 8 μg/ml against C. albicans ATCC 90028 and 4 μg/ml against C. neoformans H99; ATCC 208821. The dihydroquinopimaric acid derivative with the diethylamine fragment showed the greatest antiproliferative activity towards twelve tumor cell lines.

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Acknowledgements

This work was financially supported by the Russian Science Foundation (Grant RSF N16-13-10051). The structural studies of the compounds 3-20 were performed with unique equipment in “Agidel” collective usage centre. Antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia).We thank National Cancer Institute for screening of cytotoxicity of compounds 1–5, 7, 8, 11–13, 17–19.

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Authors and Affiliations

  1. Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospect Oktyabrya, Ufa, 450075, Russian Federation

    Elena V. Tret’yakova, Elena V. Salimova, Victor N. Odinokov & Lyudmila V. Parfenova

  2. Bashkir State University, Zaki Validi st. 32, Bashkortostan, Ufa, 450076, Russian Federation

    Gul’sasyak F. Zakirova & Olga S. Kukovinets

Authors
  1. Elena V. Tret’yakova
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  2. Gul’sasyak F. Zakirova
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  3. Elena V. Salimova
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  4. Olga S. Kukovinets
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  5. Victor N. Odinokov
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  6. Lyudmila V. Parfenova
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Correspondence to Elena V. Tret’yakova.

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Tret’yakova, E.V., Zakirova, G.F., Salimova, E.V. et al. Convenient one-pot synthesis of resin acid Mannich bases as novel anticancer and antifungal agents. Med Chem Res 27, 2199–2213 (2018). https://doi.org/10.1007/s00044-018-2227-4

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  • DOI: https://doi.org/10.1007/s00044-018-2227-4

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