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

Alexander S. Filatov; Nickolay A. Knyazev; Stanislav V. Shmakov; Alexey A. Bogdanov; Mikhail N. Ryazantsev; Andrey A. Shtyrov; Galina L. Starova; Alexander P. Molchanov; Anna G. Larina; Vitali M. Boitsov; Alexander V. Stepakov

doi:10.1055/s-0037-1611059

Synthesis, Table of Contents

Synthesis 2019; 51(03): 713-729
DOI: 10.1055/s-0037-1611059

paper

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

Alexander S. Filatov

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

,

Nickolay A. Knyazev

^bSaint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation Email: bovitali@yandex.ru

^cInstitute of Cytology of the Russian Academy of Science, Tikhoretsky pr. 4, St. Petersburg 194064, Russian Federation

,

Stanislav V. Shmakov

^bSaint-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

^dITMO University, Kronverksky pr. 49, St. Petersburg 197101, Russian Federation

^eSt. 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

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

,

Andrey A. Shtyrov

^bSaint-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

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

,

Alexander P. Molchanov

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

,

Anna G. Larina

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

,

Vitali M. Boitsov*

^bSaint-Petersburg Academic University – Nanotechnology Research and Education Centre RAS, ul. Khlopina 8/3, St. Petersburg 194021, Russian Federation Email: bovitali@yandex.ru

^fInstitute of macromolecular compounds, Bolshoy pr. 31, St. Petersburg 199004, Russian Federation

^gSaint-Petersburg Scientific Center of the Russian Academy of Sciences, Universitetskaya Nab. 5, St. Petersburg 199034, Russian Federation

,

Alexander V. Stepakov*

^aSaint-Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation Email: alstepakov@yandex.ru

^hSaint-Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg 190013, Russian Federation

› Author Affiliations

Abstract

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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.

Key words

one-pot synthesis - azomethine ylides - 1,3-dipolar cycloaddition - cyclopropenes - tryptanthrin - α-amino acids - peptides

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References

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