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

• Published in: Synthesis (Stuttgart) 2019-02, Vol.51 (3), p.713-729
• Main Authors: Filatov, Alexander S., Knyazev, Nickolay A., Shmakov, Stanislav V., Bogdanov, Alexey A., Ryazantsev, Mikhail N., Shtyrov, Andrey A., Starova, Galina L., Molchanov, Alexander P., Larina, Anna G., Boitsov, Vitali M., Stepakov, Alexander V.
• Format: Article
• Language: English
• ISSN: 0039-7881; 1437-210X
• DOI: 10.1055/s-0037-1611059

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.