Next Article in Journal
New Caffeine Derivatives as Multitarget Agents for the Therapy of Alzheimer’s Disease
Previous Article in Journal
Extraction of Sodium Alginate from Charophyceae Algae
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Chemistry Proceedings
Volume 12
Issue 1
10.3390/ecsoc-26-13525
chemproc-logo
Submit to this Journal
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Proceeding Paper

Synthesis of 1,3-Diyne Derivatives of Lembehyne B with Antitumor and Neuritogenic Activity †

by
Elina Kh. Makarova
1,*,
Lilya U. Dzhemileva
2,
Alexey A. Makarov
1 and
Usein M. Dzhemilev
2
1
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Prosp. Oktyabrya 141, 450075 Ufa, Russia
2
Institute of Organic Chemistry, N.D. Zelinskiy RAS, Leninsky Prosp., 47, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 26th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2022; Available online: https://sciforum.net/event/ecsoc-26.
Chem. Proc. 2022, 12(1), 61; https://doi.org/10.3390/ecsoc-26-13525
Published: 14 November 2022
(This article belongs to the Proceedings of The 26th International Electronic Conference on Synthetic Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The report presents data from our studies on obtaining lembehyne B derivatives with cytotoxic and neuritogenic activity. The methods and approaches to the synthesis of the above-mentioned lembehynes presented in the report are based on the use of the catalytic cross-cyclomagnesiation of 1,2-dienes (the Dzhemilev reaction) at the key stage of the synthesis.

1. Introduction

Natural polyacetylenes are compounds containing two or more carbon–carbon triple bonds in their structure. Naturally occurring polyacetylenes have a wide range of structural diversity and are widely distributed in plants, fungi, marine invertebrates, etc. Acetylene metabolites exhibit a wide range of biological activities, including antifungal, antimicrobial and antitumor activities, inhibition of HIV reverse transcriptase, which makes them interesting for medicine, pharmacology, medicinal chemistry, and the pharmaceutical industry [1,2,3].
Some secondary metabolites identified in various sponge species have antitumor activity. Sea sponges are leaders in their content of biologically active substances in comparison with other marine invertebrates. Some compounds isolated from sponges have complex structures and exhibit biological activity at very low doses [4,5].
The polyacetylenic compounds halicynones A (1) and B (2) were isolated from the marine sponge Haliclona sp., possessing antifungal activities against Candida glabrata and a high cytotoxicity against human colon tumor cells (HCT). Additionally, pellynols A (3) and B (4) showed strong cytotoxicity against some melanoma and ovarian cancer cells [6,7,8]. Acetylene alcohols, strongylodiols A (5), and C (6) were obtained from the Okinawan marine sponge belonging to the genus Strongylophora (Figure 1). Each of these compounds was a mixture of enantiomers in different ratios and exhibited cytotoxic activity against human T-lymphocytic leukemia (MOLT-4) cells [9].
Lembehynes A–C (7–9), long chain acetylenic alcohols, were isolated from the Indonesian marine sponge Haliclona sp. Lembehyne A (7) induces bipolar neuritogenesis of Neuro 2A cells, and also enhances the activity of Neuro2A acetylcholinesterase. Lembehynes B (8) and C (9) also exhibit neuritogenic activity against the Neuro 2A neuroblastoma cell line [10,11,12] (Figure 2).

2. Results and Discussion

We have synthesized new 1,3-diyne derivatives of lembehyne B using the catalytic cross-cyclomagnesiation of O-containing and aliphatic allenes at the key stage [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. At the first stage, (13Z,17Z)-tetraconta-13,17-dienal (4) was obtained by the reaction of cross-cyclomagnesiation of 1,2-nonadecadiene (10) and 2-tetradec-12,13-dien-1-yl-1,3-dioxolane (11) with EtMgBr in the presence of metallic Mg and catalytic amounts of Cp2TiCl2 (10 mol.%) (10:11:EtMgBr:Mg:[Ti] = 12:10:30:20:0.1, Et2O, 20–22 °C, 7 h), giving a 79% yield (Scheme 1). At the second stage, successive reactions of aldehyde (13) with preliminarily obtained 1-lithium-4-trimethylsilyl-1,3-butadiine and removal of the trimethylsilyl group with trimethylbutylammonium fluoride (TBAF) in THF gave the target 1,3-diyne analogue of rac-lembehyne B (15) with a ~66% yield (Scheme 1).
In order to elucidate the influence of the stereoconfiguration of the hydroxyl group in the acetylenic derivatives of lembehyne B, we developed an original method for the synthesis of the latter, with the R-configuration of the hydroxyl group, by adding the corresponding 1-bromoalkynes directly to the molecule of lembehyne B synthesized from aldehyde (13) (Scheme 2).
Thus, according to the developed scheme, we carried out the synthesis of racemic (17) and natural lembehyne B (8) by successive reactions of the addition of lithium trimethylsilylacetylenide to aldehyde (13), deprotection of the resulting alkyne (16), oxidation of alcohol (17), and stereoselective reduction of ketone (18) at the final stage of synthesis. Reactions of natural lembehyne B (8) with 1-bromo-2-trimethylsilylacetylene or 1-bromo-2-(ω-hydroxyalkyl)acetylenes under the action of CuCl led to the synthesis of the target 1,3-diyne analogs of lembehyne B (19) and (20a–d) in high yields (50–67%). For the synthesized 1,3-diyne derivatives of lembehynes B, apoptosis-inducing activity against five tumor cell lines Jurkat, K562, U937, HeLa, and HEK293 and neuritogenic activity against PC12, PC9, and Neuro2A cell cultures were studied in detail.

Experimental Section

1H and 13C NMR spectra and the general procedure for all the synthesized compounds are presented in previously published articles [22,23,24,25,26,27,28].

3. Conclusions

Thus, we have synthesized, for the first time, 1,3-diyne analogues of lembehyne B containing a Z,Z-diene group using the cross-cyclomagnesiation reaction of aliphatic and O-containing 1,2-dienes catalyzed by Cp2TiCl2 at the key stage of the synthesis, and also studied their antitumor activity using modern methods of flow cytometry and multiplex analysis.

Author Contributions

Conceptualization, U.M.D. and L.U.D.; methodology, A.A.M.; validation, E.K.M., resources, E.K.M.; data curation, U.M.D.; writing—original draft preparation, E.K.M., A.A.M.; writing—review and editing, U.M.D. and L.U.D.; visualization, E.K.M.; supervision, U.M.D.; project administration, A.A.M.; funding acquisition, A.A.M. All authors have read and agreed to the published version of the manuscript.

Funding

The work was done within approved plans for research projects at the IPC RAS State Registration No. FMRS-2022-0075.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The structural studies of the synthesized compounds were performed with the use of Collective Usage Centre “Agidel” at the Institute of Petrochemistry and Catalysis of RAS.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Listunov, D.; Maraval, V.; Chauvin, R.; Genisson, Y. Chiral alkynylcarbinols from marine sponges: Asymmetric synthesis and biological relevance. Nat. Prod. Rep. 2015, 32, 49–75. [Google Scholar] [CrossRef]
  2. Dembitsky, V.M.; Levitsky, D.O.; Gloriozova, T.A.; Poroikov, V.V. Acetylenic Aquatic Anticancer Agents and Related Compounds. Nat. Prod. Commun. 2006, 1, 773–811. [Google Scholar] [CrossRef]
  3. Minto, R.E.; Blacklock, B.J. Biosynthesis and function of polyacetylenes and allied natural products. Prog. Lipid Res. 2008, 47, 233–306. [Google Scholar] [PubMed]
  4. Balansa, W.; Trianto, A.; de Voogd, N.J.; Tanaka, J. A New Cytotoxic Polyacetylenic Alcohol from a Sponge Callyspongia sp. Nat. Prod. Commun. 2017, 12, 1909–1911. [Google Scholar] [CrossRef]
  5. Dembitsky, V.M. Anticancer Activity of Natural and Synthetic Acetylenic Lipids. Lipids 2006, 41, 883–924. [Google Scholar] [PubMed]
  6. Zhou, G.-X.; Molinski, T. Long-chain Acetylenic Ketones from the Micronesian Sponge Haliclona sp. Importance of the 1-Yn-3-ol Group for Antitumor Activity. Mar. Drugs 2003, 1, 46–53. [Google Scholar] [CrossRef]
  7. Rashid, M.; Gustafson, K.R.; Boyd, M.R. Pellynol I, a New Cytotoxic Polyacetylene from the Sponge Pellina sp. Nat. Prod. Lett. 2000, 14, 387–392. [Google Scholar] [CrossRef]
  8. Fu, X.; Abbas, S.A.; Schmitz, F.J.; Vidavsky, I.; Gross, M.L.; Laney, M.; Schatzman, R.C.; Cabuslay, R.D. New Acetylenic Metabolites from the Marine Sponge Pellina triangulate. Tetrahedron 1997, 53, 799–814. [Google Scholar] [CrossRef]
  9. Watanabe, K.; Tsuda, Y.; Hamada, M.; Omori, M.; Mori, G.; Iguchi, K.; Naoki, H.; Fujita, T.; Van Soest, R.W.M. Acetylenic Strongylodiols from a Petrosia (Strongylophora) Okinawan Marine Sponge. J. Nat. Prod. 2005, 68, 1001–1005. [Google Scholar] [CrossRef]
  10. Aoki, S.; Matsui, K.; Tanaka, K.; Satari, R.; Kobayashi, M. Lembehyne A, a Novel Neuritogenic Polyacetylene, from a Marine Sponge of Haliclona sp. Tetrahedron. 2000, 56, 9945–9948. [Google Scholar] [CrossRef]
  11. Aoki, S.; Matsui, K.; Takata, T.; Hong, W.; Kobayashi, M. Lembehyne A, a Spongean Polyacetylene, Induces Neuronal Differentiation in Neuroblastoma Cell. Biochem. Biophys. Res. Commun. 2001, 289, 558–563. [Google Scholar] [CrossRef]
  12. Aoki, S.; Matsui, K.; Wei, H.; Murakami, N.; Kobayashi, M. Structure–activity relationship of neuritogenic spongean acetylene alcohols, lembehynes. Tetrahedron 2002, 58, 5417–5422. [Google Scholar] [CrossRef]
  13. D’yakonov, V.A.; Makarov, A.A.; Dzhemileva, L.U.; Makarova, E.K.; Khusnutdinova, E.K.; Dzhemilev, U.M. The facile synthesis of the 5Z,9Z-dienoic acids and their topoisomerase I inhibitory activity. Chem. Commun. 2013, 49, 8401–8403. [Google Scholar] [CrossRef]
  14. D’yakonov, V.A.; Makarov, A.A.; Makarova, E.K.; Dzhemilev, U.M. Novel organomagnesium reagents in synthesis. Catalytic cyclomagnesiation of allenes in the synthesis of N-, O-, and Si-substituted 1Z,5Z-dienes. Tetrahedron 2013, 69, 8516–8526. [Google Scholar] [CrossRef]
  15. D’yakonov, V.A.; Dzhemileva, L.U.; Makarov, A.A.; Mulyukova, A.R.; Baev, D.S.; Khusnutdinova, E.K.; Tolstikova, T.G.; Dzhemilev, U.M. Stereoselective Synthesis of 11-Phenylundeca-5Z,9Z-dienoic Acid and Investigation of its Human Topoisomerase I and IIα Inhibitory Activity. Bioorganic Med. Chem. Lett. 2015, 25, 2405–2408. [Google Scholar] [CrossRef]
  16. D’yakonov, V.A.; Dzhemileva, L.U.; Makarov, A.A.; Mulyukova, A.R.; Baev, D.S.; Khusnutdinova, E.K.; Tolstikova, T.G.; Dzhemilev, U.M. nZ,(n+4)Z-Dienoic fatty acid: A new method for the synthesis and inhibitory action on topoisomerase I and II α. Med. Chem. Res. 2016, 25, 30–39. [Google Scholar] [CrossRef]
  17. Makarov, A.A.; Dzhemileva, L.U.; Salimova, A.R.; Makarova, E.K.; Ramazanov, I.R.; D’yakonov, V.A.; Dzhemilev, U.M. New Synthetic Derivatives of Natural 5Z,9Z-Dienoic Acids: Stereoselective Synthesis and Study of the Antitumor Activity. Bioorg. Chem. 2020, 104, 104303. [Google Scholar] [CrossRef] [PubMed]
  18. D’yakonov, V.A.; Makarov, A.A.; Dzhemileva, L.U.; Makarova, E.K.; Dzhemilev, U.M. Natural Trienoic Acids as a Possible Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis Cell Signaling and Targeting Mitochondria Studies. Cancers. 2021, 13, 1808. [Google Scholar] [CrossRef]
  19. D’yakonov, V.A.; Dzhemileva, L.U.; Makarov, A.A.; Mulyukova, A.R.; Baev, D.S.; Khusnutdinova, E.K.; Tolstikova, T.G.; Dzhemilev, U.M. 11-Phenylundeca-5Z,9Z-dienoic Acid: Stereoselective Synthesis and Dual Topoisomerase I/IIα Inhibition. Curr. Cancer Drug Targets 2015, 15, 504–510. [Google Scholar] [CrossRef] [PubMed]
  20. D’yakonov, V.A.; Dzhemileva, L.U.; Tuktarova, R.A.; Makarov, A.A.; Islamov, I.I.; Mulyukova, A.R.; Dzhemilev, U.M. Catalytic cyclometallation in steroid chemistry III: Synthesis of steroidal derivatives of 5Z,9Z-dienoic acid and their human topoisomerase I inhibitory activity. Steroids 2015, 102, 110–117. [Google Scholar] [CrossRef]
  21. D’yakonov, V.A.; Dzhemileva, L.U.; Makarov, A.A.; Mulyukova, A.R.; Tuktarova, R.A.; Islamov, I.I.; Dzhemilev, U.M. Synthesis and transformations of metallacycles. Communication 45. Cross-cyclomagnesiation of 1,2-dienes in the synthesis of 5Z,9Z-dienic acids-effective inhibitors of topoisomerase I. Russ. Chem. Bull. 2015, 9, 2135–2140. [Google Scholar] [CrossRef]
  22. D’yakonov, V.A.; Dzhemilev, U.M.; Makarov, A.A.; Andreev, E.N.; Dzhemileva, L.U. A short and efficient route for the synthesis of lembechin B with neuritogenic activity. J. Org. Chem. 2016, 52, 1850–1852. [Google Scholar] [CrossRef]
  23. Dzhemileva, L.U.; D’yakonov, V.A.; Makarov, A.A.; Andreev, E.N.; Yunusbaeva, M.M.; Dzhemilev, U.M. The first total synthesis of the marine acetylenic alcohol, lembehyne B−a selective inducer of early apoptosis in leukemia cancer cells. Org. Biomol. Chem. 2017, 15, 470–476. [Google Scholar] [CrossRef]
  24. D’yakonov, V.A.; Makarov, A.A.; Dzhemileva, L.U.; Andreev, E.N.; Dzhemilev, U.M. The first total synthesis of Lembehyne B. Mendeleev Commun. 2017, 27, 122–124. [Google Scholar] [CrossRef]
  25. D’yakonov, V.A.; Makarov, A.A.; Dzhemileva, L.U.; Andreev, E.N.; Dzhemilev, U.M. Total Synthesis of Neuritogenic Alkynes: Lembehyne B and Key Intermediate of Lembehyne A. Chem. Sel. 2017, 2, 1211–1213. [Google Scholar] [CrossRef]
  26. D’yakonov, V.A.; Islamov, I.I.; Makarov, A.A.; Dzhemilev, U.M. Ti-Catalyzed cross-cyclomagnesiation of 1,2-dienes in the stereoselective synthesis of insect pheromones. Tetrahedron Lett. 2017, 58, 1755–1757. [Google Scholar] [CrossRef]
  27. Dzhemileva, L.U.; Makarov, A.A.; Andreev, E.N.; Yunusbaeva, M.M.; Makarova, E.K.; D’yakonov, V.A.; Dzhemilev, U.M. New 1,3-Diynoic Derivatives of Natural Lembehyne B: Stereoselective Synthesis, Anticancer and Neuritogenic Activity. ACS Omega 2020, 5, 1974–1981. [Google Scholar] [CrossRef]
  28. D’yakonov, V.A.; Makarov, A.A.; Dzhemileva, L.U.; Andreev, E.N.; Makarova, E.K.; Dzhemilev, U.M. Total Synthesis of Natural Lembehyne C and Investigation of Its Cytotoxic Properties. J. Nat. Prod. 2020, 83, 2399–2409. [Google Scholar] [CrossRef]
  29. D’yakonov, V.A. Dzhemilev Reactions in Organic and Organometallic Synthesis; Nova Science Publisher: New York, NY, USA, 2010; p. 96. ISBN 978-1-60876-683-3. [Google Scholar]
  30. Dzhemilev, U.M.; D’yakonov, V.A. Hydro-, Carbo- and Cycloalumination of Unsaturated Compounds In Modern Organoaluminum Reagents: Preparation, Structure, Reactivity and Use; Woodward, S., Dagorne, S., Eds.; Springer: Berlin/Heidelberg, Germany, 2013; Volume 41, p. 312. ISBN 978-3-642-33671-3. [Google Scholar] [CrossRef]
  31. D’yakonov, V.A.; Dzhemileva, L.U.; Dzhemilev, U.M. Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors. Stud. Nat. Prod. Chem. 2017, 54, 21–86. [Google Scholar] [CrossRef]
  32. Dzhemilev, U.M.; D’yakonov, V.A. Catalytic cyclomagnesiation and cycloalumination of unsaturated compounds-new in the synthesis of metallocarbocycles (Perspective points of growth and challenges of organoelement chemistry). Adv. Chem. 2018, 87, 393–507. [Google Scholar]
Chemproc 12 00061 g001 550
Figure 1. Natural polyacetylene compounds.
Figure 1. Natural polyacetylene compounds.
Chemproc 12 00061 g001
Chemproc 12 00061 g002 550
Figure 2. Lembehynes A–C.
Figure 2. Lembehynes A–C.
Chemproc 12 00061 g002
Chemproc 12 00061 sch001 550
Scheme 1. Synthesis of the new 1,3-diyne derivatives of lembehyne B. (a) EtMgBr, Mg, Cp2TiCl2, Et2O, rt; (b) H+; (c) 1-lithium-4-trimethylsilyl-1,3-butadiine, THF, rt, 85%; (d) TBAF, THF, rt, 99%.
Scheme 1. Synthesis of the new 1,3-diyne derivatives of lembehyne B. (a) EtMgBr, Mg, Cp2TiCl2, Et2O, rt; (b) H+; (c) 1-lithium-4-trimethylsilyl-1,3-butadiine, THF, rt, 85%; (d) TBAF, THF, rt, 99%.
Chemproc 12 00061 sch001
Chemproc 12 00061 sch002 550
Scheme 2. Synthesis of the new 1,3-diyne analogs of lembehyne B. (a) Lithium trimethylsilylacetylenide, THF, rt, 90%; (b) TBAF, THF, rt, 99%; (c) Dess–Martin periodinane, CH2Cl2, rt, 86%; (d) B-3-pinanyl-9-borabicyclo[3.3.1]nonane, THF, rt, 84% (95% ee); (e) 1-bromo-2-trimethylsilylacetylene, CuCl, NH2OH, n-BuNH2, H2O, rt,; (f) TBAF, THF, rt, 97%; (g) 1-bromo-2-(ω-hydroxyalkyl)acetylene, CuCl, NH2OH, n-BuNH2, H2O, rt, 99%; n = 1–3.
Scheme 2. Synthesis of the new 1,3-diyne analogs of lembehyne B. (a) Lithium trimethylsilylacetylenide, THF, rt, 90%; (b) TBAF, THF, rt, 99%; (c) Dess–Martin periodinane, CH2Cl2, rt, 86%; (d) B-3-pinanyl-9-borabicyclo[3.3.1]nonane, THF, rt, 84% (95% ee); (e) 1-bromo-2-trimethylsilylacetylene, CuCl, NH2OH, n-BuNH2, H2O, rt,; (f) TBAF, THF, rt, 97%; (g) 1-bromo-2-(ω-hydroxyalkyl)acetylene, CuCl, NH2OH, n-BuNH2, H2O, rt, 99%; n = 1–3.
Chemproc 12 00061 sch002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Makarova, E.K.; Dzhemileva, L.U.; Makarov, A.A.; Dzhemilev, U.M. Synthesis of 1,3-Diyne Derivatives of Lembehyne B with Antitumor and Neuritogenic Activity. Chem. Proc. 2022, 12, 61. https://doi.org/10.3390/ecsoc-26-13525

AMA Style

Makarova EK, Dzhemileva LU, Makarov AA, Dzhemilev UM. Synthesis of 1,3-Diyne Derivatives of Lembehyne B with Antitumor and Neuritogenic Activity. Chemistry Proceedings. 2022; 12(1):61. https://doi.org/10.3390/ecsoc-26-13525

Chicago/Turabian Style

Makarova, Elina Kh., Lilya U. Dzhemileva, Alexey A. Makarov, and Usein M. Dzhemilev. 2022. "Synthesis of 1,3-Diyne Derivatives of Lembehyne B with Antitumor and Neuritogenic Activity" Chemistry Proceedings 12, no. 1: 61. https://doi.org/10.3390/ecsoc-26-13525

Article Metrics

Back to TopTop