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Proceeding Paper

An Original Method for the Synthesis and Study of the Biological Activity of Natural Lembehyne B Aromatic Analogs †

by
Alexey A. Makarov
*,
Elina Kh. Makarova
,
Lilya U. Dzhemileva
and
Usein M. Dzhemilev
Institute of Petrochemistry, Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, 450075 Ufa, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, Online, 1–30 November 2021; Available online: https://ecsoc-25.sciforum.net/.
Chem. Proc. 2022, 8(1), 30; https://doi.org/10.3390/ecsoc-25-11630
Published: 12 November 2021
(This article belongs to the Proceedings of The 25th International Electronic Conference on Synthetic Organic Chemistry)
Browse Figure
Versions Notes

Abstract

:
In the development of earlier-initiated studies on the synthesis of natural and synthetic neuritogenic alkynols, lembehynes A–C—which simultaneously exhibit high antitumor activity—we developed a method for the synthesis of an analogue of natural lembehyne B containing a phenyl radical in its structure. It is shown that the synthesized aromatic analogue of lembehyne B exhibits higher antitumor activity in vitro than a number of tumor cell lines (Jurkat, K562 and U937).

1. Introduction

Lembehynes are a unique class of natural compound that exhibit a wide range of biological activities and have neuritogenic, antitumor and antibacterial properties [1,2,3,4,5,6,7,8,9,10].
Earlier, we reported on the complete synthesis of natural lembehyne B, as well as the preparation of synthetic derivatives of lembehyne B containing a 1,3-diyne fragment in their structure. The synthesized lembehynes showed cytotoxicity toward tumor cells of the Jurkat, U937, K562, HeLa and Hek293 lines and neuritogenic activity toward Neuro 2A mouse neuroblastoma cells [11,12].
It is known that the π–π stacking interaction of aromatic radicals, which are biologically active compounds with nitrogenous bases of the DNA or RNA of tumor cells, can lead to disruption of the processes of transcription and replication, leading to apoptosis [13,14].
Based on the results obtained earlier, we have synthesized a number of aromatic derivatives of lembehyne B using terminal allenes at the key stage of the catalytic cross-cyclomagnesiation reaction (Dzhemilev reaction) [14,15,16,17,18,19,20,21,22,23,24,25].

2. Results and Discussion

Cross-cyclomagnesiation reactions of 1,2-dienes containing aromatic radicals 2(a–c) and tetrahydropyran esters of 13,14-pentadecadienol 3 using EtMgBr in the presence of metallic Mg and a Cp2TiCl2 catalyst (10 mol%), through the stage of formation of magnesacyclopentanes 4(a–c), the hydrolysis of which gave tetrahydropyran ethers 13Z,17Z-dienes 5(a–c) in 79–82% yields. Successive reactions of the removal of tetrahydropyranyl protection and the oxidation of unsaturated alcohols 6(a–c) using Dess–Martin periodinane led to 13Z,17Z-diene aldehydes 7(a–c) in ~78–82% yields. As a result of the reaction of pre-synthesized lithium (trimethylsilyl)acetylenide with aldehydes 7(a–c) and the removal of the trimethylsilyl protection with TBAF, racemic lembehyne B 1(a–c) derivatives were formed in ~80–84% yields (Scheme 1).
For the synthesized compounds, the in vitro antitumor activity was assessed on Jurkat, K562, HL-60, and U937 cell lines and fibroblasts, including the determination of IC50 using flow cytometry and multiplex analysis.

3. Conclusions

An effective method was developed for the preparation of aromatic derivatives of lembehyne B, using, at the key stage of synthesis, the reaction of catalytic cross-cyclomagnesiation of terminal 1,2-dienes (Dzhemilev reaction). Moreover, their antitumor activity was also studied using the modern methods of flow cytometry and multiplex analysis.

4. Experimental Part

Commercially available reagents (Sigma-Aldrich and Acros) were used. Reactions with organomagnesium compounds were carried out under a dried argon atmosphere. 1,2-dienes were prepared according to the known procedure. Reaction products were analyzed on a Carlo Erba chromatograph (a Hewlett Packard Ultra-1 glass capillary column, 25 m × 0.2 mm, flame ionization detector, operating temperature 50–170 °C, carrier gas helium). TLC was performed on Silufol UV-254 plates. The elemental composition of compounds was determined using a Carlo Erba-1106 instrument. Mass spectra were obtained using a Bruker MALDI-TOF/TOF Autoflex III instrument. The 1H and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer (100.62 MHz for 13C, and 400.13 MHz for 1H).
Cross-cyclomagnesiation of 1,2-diene (2(a–c)) and 2-(pentadeca-13,14-dien-1-yloxy)tetrahydro-2H-pyran (3) with EtMgBr in the presence of Mg metal and Cp2TiCl2 catalyst was carried out, according known procedure [11]. 2-(((13Z,17Z)-19-phenylnonadeca-13,17-dien-1-yl)oxy)tetrahydro-2H-pyran (5a). Yield, 79%; Rf = 0.45; 1H NMR (400 MHz, CDCl3) δ: 1.34‒1.93 (28H, m, CH2), 2.03‒2.29 (8H, m, CH2), 3.40‒3.96 (4H, m, CH2-O), 4.64 (1H, t, J = 6 Hz, CH-O), 5.42‒5.68 (2H, m, CH=), 7.21‒7.44 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 19.71, 25.63, 26.26, 27.36, 27.40, 27.53, 29.41–29.86, 30.84, 33.61, 62.17, 67.65, 98.76, 125.85, 128.36, 128.39, 128.49, 128.94, 130.26, 130.60, 141.08; MS (MALDI-TOF), m/z: 440 [M]+; C30H48O2; found (%): C, 81.61; H, 10.89; calc. for C30H48O2 (%): C, 81.76; H, 10.97. 2-(((13Z,17Z)-20-phenylicosa-13,17-dien-1-yl)oxy)tetrahydro-2H-pyran (5b). Yield, 78%; Rf = 0.44; 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.91 (30H, m, CH2), 2.00‒2.29 (8H, m, CH2), 3.41‒3.96 (4H, m, CH2-O), 4.63 (1H, t, J = 6 Hz, CH-O), 5.42‒5.68 (2H, m, CH=), 7.21‒7.45 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 19.70, 25.66, 26.26, 26.90, 27.36, 27.41, 27.53, 29.41–29.86, 30.84, 33.61, 62.17, 67.65, 98.76, 125.85, 128.36, 128.39, 128.49, 128.94, 130.26, 130.61, 141.08; MS (MALDI-TOF), m/z: 454 [M]+; C31H50O2; found (%): C, 81.84; H, 11.10; calc. for C31H50O2 (%): C, 81.88; H, 11.08. 2-(((13Z,17Z)-21-phenylhenicosa-13,17-dien-1-yl)oxy)tetrahydro-2H-pyran (5c). Yield, 82%; Rf = 0.46; 1H NMR (400 MHz, CDCl3) δ: 1.34‒1.90 (32H, m, CH2), 2.03‒2.29 (8H, m, CH2), 3.40‒3.96 (4H, m, CH2-O), 4.64 (1H, t, J = 6 Hz, CH-O), 5.42‒5.68 (2H, m, CH=), 7.21‒7.44 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 19.71, 25.63, 26.26, 26.90, 27.36, 27.40, 27.53, 29.41–29.86, 30.84, 33.61, 62.17, 67.65, 98.76, 125.85, 128.36, 128.39, 128.49, 128.94, 130.26, 130.60, 141.08; MS (MALDI-TOF), m/z: 468 [M]+; C32H52O2; found (%): C, 81.94; H, 11.11; calc. for C32H52O2 (%): C, 81.99; H, 11.08.
THP-deprotection of ether (5(a–c)) was carried out with p-TsOH in CH2Cl2/MeOH using known method [26]. (13Z,17Z)-19-phenylnonadeca-13,17-dien-1-ol (6a). Yield, 78%; Rf = 0.42 (hexane/EtOAc—5:1); 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.69 (22H, m, CH2), 1.94‒2.28 (6H, m, CH2), 3.66 (2H, t, J = 6 Hz, CH2-O), 5.39‒5.65 (4H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.78, 27.32, 27.49, 29.36‒29.77, 32.80, 33.57, 63.05, 125.85, 128.37, 128.40, 128.45, 128.94, 130.30, 130.66, 141.15; MS (MALDI-TOF), m/z: 356 [M]+; C25H40O; found (%): C, 84.13; H, 11.22; calc. for C25H40O (%): C, 84.20; H, 11.30. (13Z,17Z)-20-phenylicosa-13,17-dien-1-ol (6b). Yield, 79%; Rf = 0.42 (hexane/EtOAc—5:1); 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.69 (24H, m, CH2), 1.94‒2.28 (6H, m, CH2), 3.66 (2H, t, J = 6 Hz, CH2-O), 5.39‒5.65 (4H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.78, 27.32, 27.49, 29.36‒29.77, 32.80, 33.57, 63.05, 125.85, 128.37, 128.40, 128.45, 128.94, 130.30, 130.66, 141.15; MS (MALDI-TOF), m/z: 370 [M]+; C26H42O; found (%): C, 84.22; H, 11.44; calc. for C26H42O (%): C, 84.26; H, 11.42. (13Z,17Z)-20-phenylhenicosa-13,17-dien-1-ol (6c). Yield, 77%; Rf = 0.42 (hexane/EtOAc—5:1); 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.69 (26H, m, CH2), 1.94‒2.28 (6H, m, CH2), 3.66 (2H, t, J = 6 Hz, CH2-O), 5.39‒5.65 (4H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.78, 27.32, 27.49, 29.36‒29.77, 32.80, 33.57, 63.05, 125.85, 128.37, 128.40, 128.45, 128.94, 130.30, 130.66, 141.15; MS (MALDI-TOF), m/z: 370 [M]+; C27H44O; found (%): C, 84.33; H, 11.50; calc. for C27H44O (%): C, 84.31; H, 11.53.
The oxidation of the alcohol (6(a–c)) with Dess–Martin periodinane was carried out according known procedure [27]. (13Z,17Z)-19-phenylnonadeca-13,17-dienal (7a). Yield, 82%; 1H NMR (400 MHz, CDCl3) δ: 0.88‒1.69 (18H, m, CH2), 2.00‒2.28 (6H, m, CH2), 2.43 (2H, dt, CH2), 3.43 (2H, d, Ph-CH2), 5.31‒5.63 (4H, m, =CH), 7.19‒7.33 (5H, m, CH=), 9.78 (1H, t, J = 6 Hz, O=CH); 13C NMR (100.62 MHz, CDCl3) δ: 22.11, 27.31, 27.34, 27.48, 29.19–29.76, 33.57, 43.93, 125.85, 128.37, 128.40, 128.45, 128.95, 130.29, 130.62, 141.14, 202.93; MS (MALDI-TOF), m/z: 354 [M]+; C25H38O; found (%): C, 84.53; H, 10.71; calc. for C25H38O (%): C, 84.68; H, 10.80. (13Z,17Z)-20-phenylicosa-13,17-dien-1-ol (7b). Yield, 78%; Rf = 0.42 (hexane/EtOAc—5:1); 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.69 (24H, m, CH2), 1.94‒2.28 (6H, m, CH2), 3.66 (2H, t, J = 6 Hz, CH2-O), 5.39‒5.65 (4H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.78, 27.32, 27.49, 29.36‒29.77, 32.80, 33.57, 63.05, 125.85, 128.37, 128.40, 128.45, 128.94, 130.30, 130.66, 141.15; MS (MALDI-TOF), m/z: 370 [M]+; C26H42O; found (%): C, 84.24; H, 11.44; calc. for C26H42O (%): C, 84.26; H, 11.42. (13Z,17Z)-21-phenylhenicosa-13,17-dien-1-ol (7c). Yield, 80%; Rf = 0.41 (hexane/EtOAc—5:1); 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.69 (26H, m, CH2), 1.94‒2.28 (6H, m, CH2), 3.66 (2H, t, J = 6 Hz, CH2-O), 5.39‒5.65 (4H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.78, 27.32, 27.49, 29.36‒29.77, 32.80, 33.57, 63.05, 125.85, 128.37, 128.40, 128.45, 128.94, 130.30, 130.66, 141.15; MS (MALDI-TOF), m/z: 384 [M]+; C27H44O; found (%): C, 84.32; H, 11.50; calc. for C27H44O (%): C, 84.31; H, 11.53.
Procedure for preparation of alkyne (8(a–c)) was carried out according to known procedure [11]. (15Z,19Z)-21-phenyl-1-(trimethylsilyl)henicosa-15,19-dien-1-yn-3-ol (8a). Yield, 90%; 1H NMR (400 MHz, CDCl3) δ: 0.22 (9H, s, CH3), 1.31‒1.75 (22H, m, CH2), 1.98‒2.27 (6H, m, CH2), 3.45 (2H, d, Ph-CH2), 4.38 (1H, t, J = 5.0 Гц), 5.38–5.66 (2H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: -0.06, 25.15, 27.33, 27.35, 27.49, 29.27–29.78, 33.58, 37.73, 62.90, 89.23, 107.07, 125.86, 128.38, 128.42, 128.46, 128.95, 130.30, 130.65, 141.14; MS (MALDI-TOF), m/z: 453[M]+; C30H48OSi; found (%): C, 79.46; H, 10.54; calc. for C30H48OSi (%): C, 79.57; H, 10.68. (15Z,19Z)-22-phenyl-1-(trimethylsilyl)docosa-15,19-dien-1-yn-3-ol (8b). Yield, 91%; 1H NMR (400 MHz, CDCl3) δ: 0.22 (9H, s, CH3), 1.31‒1.75 (24H, m, CH2), 1.98‒2.27 (6H, m, CH2), 3.45 (2H, d, Ph-CH2), 4.38 (1H, t, J = 5.0 Гц), 5.38–5.66 (2H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: -0.06, 25.15, 27.33, 27.35, 27.49, 29.27–29.78, 33.58, 37.73, 62.90, 89.23, 107.07, 125.86, 128.38, 128.42, 128.46, 128.95, 130.30, 130.65, 141.14; MS (MALDI-TOF), m/z: 466[M]+; C31H50OSi; found (%): C, 79.77; H, 10.81; calc. for C31H50OSi (%): C, 79.76; H, 10.80. (15Z,19Z)-23-phenyl-1-(trimethylsilyl)tricosa-15,19-dien-1-yn-3-ol (8c). Yield, 91%; 1H NMR (400 MHz, CDCl3) δ: 0.22 (9H, s, CH3), 1.31‒1.75 (26H, m, CH2), 1.98‒2.27 (6H, m, CH2), 3.45 (2H, d, Ph-CH2), 4.38 (1H, t, J = 5.0 Гц), 5.38–5.66 (2H, m, =CH), 7.20‒7.34 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: −0.06, 25.15, 27.33, 27.35, 27.49, 29.27–29.78, 33.58, 37.73, 62.90, 89.23, 107.07, 125.86, 128.38, 128.42, 128.46, 128.95, 130.30, 130.65, 141.14; MS (MALDI-TOF), m/z: 480 [M]+; C30H48OSi; found (%): C, 79.95; H, 10.88; calc. for C32H52OSi (%): C, 79.93; H, 10.90.
Procedure for preparation of alkyne (1(а–с)) was carried out according to known procedure [11]. (15Z,19Z)-21-phenylhenicosa-15,19-dien-1-yn-3-ol (1a). Yield, 80%; 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.78 (22H, m, CH2), 1.92‒2.26 (8H, m, CH2), 2.48 (1H, d, CH), 3.43 (2H, d, Ph-CH2), 4.39 (1H, t, J = 5.0 Гц), 5.38–5.63 (2H, m, =CH), 7.18‒7.33 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.04, 27.32, 27.34, 27.48, 29.27–29.77, 33.57, 37.68, 62.36, 72.84, 85.07, 125.85, 128.37, 128.41, 128.45, 128.95, 130.31, 130.65, 141.16; MS (MALDI-TOF), m/z: 380 [M]+; C27H42O; found (%): C, 85.11; H, 10.63; calc. for C27H42O (%): C, 85.20; H, 10.59. (15Z,19Z)-22-phenyldocosa-15,19-dien-1-yn-3-ol (1b). Yield, 82%; 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.78 (24H, m, CH2), 1.92‒2.26 (8H, m, CH2), 2.48 (1H, d, CH), 3.43 (2H, d, Ph-CH2), 4.39 (1H, t, J = 5.0 Гц), 5.38–5.63 (2H, m, =CH), 7.18‒7.33 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.04, 27.32, 27.34, 27.48, 29.27–29.77, 33.57, 37.68, 62.36, 72.84, 85.07, 125.85, 128.37, 128.41, 128.45, 128.95, 130.31, 130.65, 141.16; MS (MALDI-TOF), m/z: 396 [M]+; C28H44O; found (%): C, 84.77; H, 11.13; calc. for C28H44O (%): C, 84.79; H, 11.18. (15Z,19Z)-23-phenyltricosa-15,19-dien-1-yn-3-ol (1c). Yield, 84%; 1H NMR (400 MHz, CDCl3) δ: 1.30‒1.78 (20H, m, CH2), 1.92‒2.26 (8H, m, CH2), 2.48 (1H, d, CH), 3.43 (2H, d, Ph-CH2), 4.39 (1H, t, J = 5.0 Гц), 5.38–5.63 (2H, m, =CH), 7.18‒7.33 (5H, m, CH=); 13C NMR (100.62 MHz, CDCl3) δ: 25.04, 27.32, 27.34, 27.48, 29.27–29.77, 33.57, 37.68, 62.36, 72.84, 85.07, 125.85, 128.37, 128.41, 128.45, 128.95, 130.31, 130.65, 141.16; MS (MALDI-TOF), m/z: 410 [M]+; C29H46O; found (%): C, 84.78; H, 11.25; calc. for C29H46O (%): C, 84.81; H, 11.29.

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

Data available on request.

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. The biological studies of bicycles were done in the Laboratory of Molecular Design and Drug Bioscreening at the Institute of Petrochemistry and Catalysis.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemproc 08 00030 sch001 550
Scheme 1. Synthesis of aromatic derivatives of lembehyne B.
Scheme 1. Synthesis of aromatic derivatives of lembehyne B.
Chemproc 08 00030 sch001
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Makarov, A.A.; Makarova, E.K.; Dzhemileva, L.U.; Dzhemilev, U.M. An Original Method for the Synthesis and Study of the Biological Activity of Natural Lembehyne B Aromatic Analogs. Chem. Proc. 2022, 8, 30. https://doi.org/10.3390/ecsoc-25-11630

AMA Style

Makarov AA, Makarova EK, Dzhemileva LU, Dzhemilev UM. An Original Method for the Synthesis and Study of the Biological Activity of Natural Lembehyne B Aromatic Analogs. Chemistry Proceedings. 2022; 8(1):30. https://doi.org/10.3390/ecsoc-25-11630

Chicago/Turabian Style

Makarov, Alexey A., Elina Kh. Makarova, Lilya U. Dzhemileva, and Usein M. Dzhemilev. 2022. "An Original Method for the Synthesis and Study of the Biological Activity of Natural Lembehyne B Aromatic Analogs" Chemistry Proceedings 8, no. 1: 30. https://doi.org/10.3390/ecsoc-25-11630

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