Synthesis 2019; 51(03): 713-729
DOI: 10.1055/s-0037-1611059
paper
© Georg Thieme Verlag Stuttgart · New York

Concise Synthesis of Tryptanthrin Spiro Analogues with In Vitro Antitumor Activity Based on One-Pot, Three-Component 1,3-Dipolar Cycloaddition of Azomethine Ylides to Сyclopropenes

Authors

  • Alexander S. Filatov

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
  • Nickolay A. Knyazev

    b   Saint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation   Email: bovitali@yandex.ru
    c   Institute of Cytology of the Russian Academy of Science, Tikhoretsky pr. 4, St. Petersburg 194064, Russian Federation
  • Stanislav V. Shmakov

    b   Saint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation   Email: bovitali@yandex.ru
  • Alexey A. Bogdanov

    d   ITMO University, Kronverksky pr. 49, St. Petersburg 197101, Russian Federation
    e   St. Petersburg Clinical Scientific-Practical Center of Specialized Types of Medical Care (Oncology), Leningradskaya str., 68A, Pesochny village, St. Petersburg 197758, Russian Federation
  • Mikhail N. Ryazantsev

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
  • Andrey A. Shtyrov

    b   Saint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation   Email: bovitali@yandex.ru
  • Galina L. Starova

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
  • Alexander P. Molchanov

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
  • Anna G. Larina

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
  • Vitali M. Boitsov*

    b   Saint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation   Email: bovitali@yandex.ru
    f   Institute of macromolecular compounds, Bolshoy pr. 31, St. Petersburg 199004, Russian Federation
    g   Saint-Petersburg Scientific Center of the Russian Academy of Sciences, Universitetskaya Nab. 5, St. Petersburg 199034, Russian Federation
  • Alexander V. Stepakov*

    a   Saint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation   Email: alstepakov@yandex.ru
    h   Saint-Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg 190013, Russian Federation

We gratefully acknowledge the financial support from the Russian Foundation for Basic Research (Projects No. 18-33-00464 and 18-015-00443), the Program of Fundamental Research ‘Nanostructures: Physics, Chemistry, Biology, and Fundamentals of Technology’ of the Presidium of the Russian Academy of Sciences and SPbAU RAS state order (project 16.9790.2017/BCh). Skolkovo Foundation (grant agreement for Russian educational and scientific organisation no.7 dd. 19.12.2017) and Skolkovo Institute of Science and Technology (general agreement no. 3663-MRA dd. 25.12.2017).
Further Information

Publication History

Received: 19 July 2018

Accepted after revision: 12 September 2018

Publication Date:
10 October 2018 (online)


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Dedicated to the memory of Prof. Rafael Kostikov. Teacher and friend.

Abstract

A simple, efficient and atom-economic method has been developed for the synthesis of complex alkaloid-like compounds with spiro-fused indolo[2,1-b]quinazoline and cyclopropa[a]pyrrolizine or 3-azabicyclo[3.1.0]hexane moieties. We have found that one-pot, three-component 1,3-dipolar cycloaddition reactions allow the desired products to be obtained from various cyclopropene derivatives with tryptanthrin-derived azomethine ylides generated in situ, in good to high yields and excellent diastereoselectivity. The possibility of ylide generation was exemplified by using α-amino acids (l-proline, l-4-thiazolidincarboxylic acid) and simplest peptides (dipeptide Gly-Gly, tripeptide Gly-Gly-Gly). Quantum chemical investigations indicate that the reaction proceeds through the S-shaped azomethine ylide, the interaction of which with cyclopropenes proceeds via a less sterically hindered endo-transition state. The antitumor activity of some of spiro-tryptanthrin derivatives against erythroleukemia (K562), cervical carcinoma (HeLa) and colon carcinoma (CT26) cell lines was evaluated in vitro by MTS-assay.

Supporting Information