Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines
Abstract
:1. Introduction
2. Results and Discussion
2.1. Syntheses of Alicyclic and Monoterpene-Based 1,3-Amino Alcohols
2.2. Syntheses of 2-Imino-1,3-thiazine Derivatives
General Structure | R1 | R2 | R3 | Compound No. |
---|---|---|---|---|
Me | H | Ph | 19a | |
H | H | Ph | 21a | |
H | H | 4-MeC6H4 | 21b | |
H | H | 4-FC6H4 | 21c | |
H | H | 3-MeOC6H4 | 21d | |
H | H | Ph | 22a | |
H | CH2Ph | Ph | 23a | |
Me | H | Ph | 20a | |
Me | H | Ph | 29a | |
H | H | Ph | 31a | |
H | H | 4-MeC6H4 | 31b | |
H | H | 4-FC6H4 | 31c | |
H | H | 3-MeOC6H4 | 31d | |
H | H | Ph | 32a | |
H | CH2Ph | Ph | 33a | |
H | H | H | 30a |
General Structure | R1 | R2 | R3 | Compound No. |
---|---|---|---|---|
Me | H | Ph | 24a | |
H | H | Ph | 26a | |
H | H | 4-MeC6H4 | 26b | |
H | H | 4-FC6H4 | 26c | |
H | H | 3-MeOC6H4 | 26d | |
H | H | Ph | 27a | |
H | CH2Ph | Ph | 28a | |
Me | H | Ph | 25a |
2.3. Antiproliferative Activities
Compnd. | Conc. | Growth Inhibition, % ± SEM a | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
HeLa | A2780 | MCF7 | A431 | |||||||
24a | 10 µM | - | 67.45 ± 0.83 | 39.40 ± 2.41 | 73.01 ± 1.52 | |||||
30 µM | 25.59 ± 1.93 | 86.02 ± 0.27 | 62.08 ± 1.78 | 83.15 ± 1.25 | ||||||
25a | 10 µM | - | 65.24 ± 1.65 | 65.91 ± 0.96 | 60.54 ± 1.79 | |||||
30 µM | 96.40 ± 0.28 | 96.42 ± 0.15 | 86.09 ± 1.20 | 94.17 ± 0.51 | ||||||
26a | 10 µM | - | - | 26.52 ± 2.79 | 67.70 ± 1.49 | |||||
30 µM | 22.03 ± 1.57 | 68.93 ± 0.97 | 50.45 + 1.79 | 85.68 ± 0.74 | ||||||
26b | 10 µM | - | 45.45 ± 2.01 | - | 65.20 ± 1.47 | |||||
30 µM | 37.02 ± 2.20 | 58.67 ± 1.29 | 43.66 ± 2.32 | 74.49 ± 1.02 | ||||||
26c | 10 µM | 44.90 ± 0.88 | 40.02 ± 0.88 | 21.55 ± 0.99 | 32.93 ± 1.20 | |||||
30 µM | 53.60 ± 1.07 | 56.86 ± 1.17 | 30.93 ± 1.29 | 34.20 ± 1.02 | ||||||
26d | 10 µM | 27.40 ± 0.52 | 20.87 ± 1.87 | - | 34.92 ± 2.66 | |||||
30 µM | 33.67 ± 2.61 | 92.17 ± 0.51 | 63.84 ± 2.36 | 82.46 ± 1.11 | ||||||
27a | 10 µM | - | 37.26 ± 2.35 | 43.83 ± 0.99 | 77.32 ± 0.94 | |||||
30 µM | 21.57 ± 0.92 | 42.80 ± 2.78 | 47.15 ± 2.93 | 80.05 ± 1.15 | ||||||
28a | 10 µM | 46.83 ± 1.42 | 23.10 ± 1.00 | - | - | |||||
30 µM | 42.24 ± 2.48 | 50.23 ± 0.52 | 23.84 ± 1.08 | - | ||||||
35 | 10 µM | - | - | - | - | |||||
30 µM | - | - | - | - | ||||||
42 | 10 µM | - | - | - | - | |||||
30 µM | - | 41.23 ± 1.30 | - | - | ||||||
43 | 10 µM | - | - | - | - | |||||
30 µM | 24.07 ± 2.96 | - | 32.59 ± 1.49 | - | ||||||
Cisplatin | 10 µM | 42.61 ± 2.33 | 83.57 ± 1.21 | 53.03 ± 2.29 | 88.54 ± 0.50 | |||||
30 µM | 99.93 ± 0.26 | 95.02 ± 0.28 | 86.90 ± 1.24 | 90.18 ± 1.78 |
3. Experimental Section
3.1. General Information
3.2. Synthesis
3.2.1. General Procedure for the Synthesis of Thioureas 21–23
3.2.2. General Procedure for the Reactions of Thioureas 19–23 with CDI to Yield Intermediates 29–33
3.2.3. General Procedure for the Synthesis of 2-Imino-1,3-thiazines 24–28 and 2-Thioxo-1,3-oxazines 34–37
3.2.4. Alternative Procedure for the Synthesis of 2-Thioxo-1,3-oxazines 35 and 36
3.2.5. General Procedure for the Synthesis of 2-Imino-1,3-thiazines 42 and 43
3.2.6. Determination of Antiproliferative Activities
3.2.7. X-ray Crystallographic Studies
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
- Lait, S.M.; Rankic, D.A.; Keay, B.A. 1,3-Amino alcohols and their derivatives in asymmetric organic synthesis. Chem. Rev. 2007, 107, 767–796. [Google Scholar]
- Lázár, L.; Fülöp, F. 1,3-Oxazines and their benzo derivatives. In Comprehensive Heterocyclic Chemistry. III; Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier: Oxford, UK, 2008; pp. 373–459. [Google Scholar]
- Szakonyi, Z.; Fülöp, F. Monoterpene-based chiral β-amino acid derivatives prepared from natural sources: Syntheses and applications. Amino Acids 2011, 41, 597–608. [Google Scholar]
- Andrés, C.; Gonzáles, I.; Nieto, J.; Rosón, C.D. Lewis acid mediated diastereoselective keto-ene cyclization on chiral perhydro-1,3-benzoxazines: Synthesis of enantiopure cis-3,4-disubstituted 3-hydroxypyrrolidines. Tetrahedron 2009, 65, 9728–9736. [Google Scholar]
- Andrés, C.; Infante, R.; Nieto, J. Perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol as ligands for the catalytic enantioselective addition of diethylzinc to aldehydes. Tetrahedron: Asymmetry 2010, 21, 2230–2237. [Google Scholar]
- Jaworska, M.; Blocka, E.; Kozakiewicz, A.; Welniak, M. α-Pinene-type chiral schiff bases as tridentate ligands in asymmetric addition reactions. Tetrahedron: Asymmetry 2011, 22, 648–657. [Google Scholar]
- Evans, P.A.; Brandt, T.A. Enantioselective allylic substitution using a novel (phosphino-1,3-oxazine)palladium catalyst. Tetrahedron Lett. 1996, 37, 9143–9146. [Google Scholar]
- Evans, P.A.; Brandt, T.A. Enantioselective palladium-catalyzed allylic alkylation using E- and Z-vinylogous sulfonates. Org. Lett. 1999, 1563–1565. [Google Scholar]
- Szakonyi, Z.; Balázs, Á.; Martinek, T.A.; Fülöp, F. Enantioselective addition of diethylzinc to aldehydes catalyzed by γ-amino alcohols derived from (+)- and (−)-α-pinene. Tetrahedron: Asymmetry 2006, 17, 199–204. [Google Scholar]
- Li, X.; Lou, R.; Yeung, C.-H.; Chan, A.S.C.; Wong, W.K. Asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by a new aminophosphine phosphinite ligand derived from ketopinic acid. Tetrahedron: Asymmetry 2000, 11, 2077–2082. [Google Scholar]
- De las Casas Engel, T.; Maroto, B.L.; García Martínez, A.; de la Moya Cerero, S. N/N/O versus N/O/O and N/O amino isoborneols in the enantioselective ethylation of benzaldehyde. Tetrahedron: Asymmetry 2008, 19, 269–272. [Google Scholar]
- Sánches-Carnerero, E.M.; de las Casas Engel, T.; Maroto, B.L.; de la Moya Cerero, S. Polyoxygenated ketopinic-acid-derived γ-amino alcohols in the enantioselective diethylzinc addition to benzaldehyde. Tetrahedron: Asymmetry 2009, 20, 2655–2657. [Google Scholar]
- Szakonyi, Z.; Martinek, T.A.; Hetényi, A.; Fülöp, F. Synthesis and transformations of enantiomeric 1,2-disubstituted monoterpene derivatives. Tetrahedron: Asymmetry 2000, 11, 4571–4579. [Google Scholar]
- Koneva, E.A.; Volcho, K.P.; Korchagina, D.V.; Komarova, N.I.; Kochnev, A.I.; Salakhutdinov, N.F.; Tolstikov, A.G. New chiral Schiff bases derived from (+)- and (−)-α-pinenes in the metal complex catalyzed asymmetric oxidation of sulfides. Russ. Chem. Bull. 2008, 57, 108–117. [Google Scholar]
- Koneva, E.A.; Volcho, K.P.; Korchagina, D.V.; Salakhutdinov, N.F.; Tolstikov, G.A. Synthesis of new chiral schiff bases from (+)-3-carene and their use in asymmetric oxidation of sulfides catalyzed by metal complexes. Russ. J. Org. Chem. 2009, 815–824. [Google Scholar]
- Koneva, E.A.; Suslov, E.V.; Korchagina, D.V.; Genaev, A.M.; Volcho, K.P.; Salakhutdinov, N.F. Catalytic asymmetric addition of diethylzinc to benzaldehyde using α-pinene-derived ligands. Open Catal. J. 2011, 4, 107–112. [Google Scholar]
- Koneva, E.A.; Khomenko, T.M.; Kurbakova, S.Y.; Komarova, N.I.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F.; Tolstikov, A.G.; Tolstikov, G.A. Synthesis of optically active omeprazole by catalysis with vanadyl complexes with chiral Schiff bases. Russ. Chem. Bull. Int. Ed. 2008, 57, 1680–1685. [Google Scholar]
- Koneva, E.A.; Korchagina, D.V.; Gatilov, Y.V.; Genaev, A.M.; Krysin, A.P.; Volcho, K.P.; Tolstikov, A.G.; Salakhutdinov, N.F. New chiral ligands based on (+)-α-pinene. Russ. J. Org. Chem. 2010, 46, 1109–1115. [Google Scholar]
- Fülöp, F.; Bernáth, G.; Pihlaja, K. Synthesis, stereochemistry and transformations of cyclopentane-, cyclohexane-, cycloheptane-, and cyclooctane-fused 1,3-oxazines, 1,3-thiazines, and pyrimidines. Adv. Heterocycl. Chem. 1998, 69, 349–477. [Google Scholar]
- Xu, X.; Qian, X.; Li, Z.; Song, G.; Chen, W. Synthesis and fungicidal activity of fluorine-containing phenylimino-thiazolidines derivatives. J. Fluorine Chem. 2005, 126, 297–300. [Google Scholar]
- Woltering, T.J.; Wostl, W.; Hilpert, H.; Rogers-Evans, M.; Pinard, E.; Maywega, A.; Göbel, M.; Banner, D.W.; Benz, J.; Travagli, M.; et al. BACE1 inhibitors: A head group scan on a series of amides. Bioorg. Med. Chem. Lett. 2013, 23, 4239–4243. [Google Scholar]
- Kai, H.; Morioka, Y.; Murashi, T.; Morita, K.; Shinonome, S.; Nakazato, H.; Kawamoto, K.; Hanasaki, K.; Takahashi, F.; Mihara, S.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 1: Discovery of CB2 receptor selective compounds. Bioorg. Med. Chem. Lett. 2007, 17, 4030–4034. [Google Scholar]
- Kai, H.; Morioka, Y.; Tomida, M.; Takahashi, T.; Hattori, M.; Hanasaki, K.; Koike, K.; Chiba, H.; Shinohara, S.; Kanemasa, T.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: Orally bioavailable compounds. Bioorg. Med. Chem. Lett. 2007, 17, 3925–3929. [Google Scholar]
- Kai, H.; Morioka, Y.; Koriyama, Y.; Okamoto, K.; Hasegawa, Y.; Hattori, M.; Koike, K.; Chiba, H.; Shinohara, S.; Iwamoto, Y.; et al. 2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 3: Synthesis and activity of isosteric analogs. Bioorg. Med. Chem. Lett. 2008, 18, 6444–6447. [Google Scholar]
- Blokhina, S.V.; Volkova, T.V.; Ol’khovich, M.V.; Sharapova, A.V.; Proshin, A.N.; Bachurin, S.O.; Perlovich, G.L. Synthesis, biological activity, distribution and membrane permeability of novel spiro-thiazines as potent neuroprotectors. Eur. J. Med. Chem. 2014, 77, 8–17. [Google Scholar]
- Szakonyi, Z.; Fülöp, F. Mild and efficient ring opening of monoterpene-fused β-lactam enantiomers. Synthesis of novel β-amino acid derivatives. Arkivoc 2003, 2003, 225–232. [Google Scholar]
- Gyónfalvi, S.; Szakonyi, Z.; Fülöp, F. Synthesis and transformation of novel cyclic β-amino acid derivatives from (+)-3-carene. Tetrahedron: Asymmetry 2003, 14, 3965–3972. [Google Scholar]
- Szakonyi, Z.; Martinek, T.A.; Sillanpää, R.; Fülöp, F. Regio- and stereoselective synthesis of constrained enantiomeric β-amino acid derivatives. Tetrahedron: Asymmetry 2008, 19, 2296–2303. [Google Scholar]
- Fülöp, F.; Szakonyi, Z. Chiral cyclic β-amino acids and their derivates, pharmaceutical compositions containing them and the use of such compounds. WO2008059299 A1, 22 May 2008. [Google Scholar]
- Szakonyi, Z.; Balázs, Á.; Martinek, T.A.; Fülöp, F. Stereoselective synthesis of pinane-based β- and γ-amino acids via conjugate addition of lithium amides and nitromethane. Tetrahedron: Asymmetry 2010, 21, 2498–2504. [Google Scholar]
- Fülöp, F.; Szakonyi, Z.; Pallai, P.V. 1,3-Heterocycles Condensed with Monoterpene Skeleton, Their Use and Pharmaceutical Compositions Comprising Such Compounds. WO 2010070365 A1, 24 June 2010. [Google Scholar]
- Sohár, P.; Stájer, G.; Szabó, A.; Fülöp, F.; Szúnyog, J.; Bernáth, G. Stereochemical studies. Part 89. Saturated heterocycles. Part 84. Preparation and nuclear magnetic resonance study of norbornane-norbornene-fused 2-phenylimino-1,3-oxazines and -thiazines. J. Chem. Soc. Perkin Trans. 2 1987. [Google Scholar] [CrossRef]
- Fülöp, F; Csirinyi, G.; Bernáth, G. Saturated heterocycles, 135. Cyclic amino alcohols and related compounds, 29. Synthesis of condensed-skeleton cis- and trans-2-phenylimino- and 2-methyliminotetrahydro-1,3-thiazines and 1,3-oxazines. Acta Chim. Hung. 1988, 125, 193–199. [Google Scholar]
- Kim, T.H.; Cha, M.-H. Efficient synthesis of 2-methylaminothiazolines via Mitsunobu reaction of N-(2-hydroxyethyl)-N'-methyl-thioureas. Tetrahedron Lett. 1999, 40, 3125–3128. [Google Scholar]
- Bernacki, A.L.; Zhu, L.; Hennings, D.D. A selective and convenient method for the synthesis of 2-phenylaminothiazolines. Org. Lett. 2010, 12, 5526–5529. [Google Scholar]
- Berényi, A.; Minorics, R.; Iványi, Z.; Ocsovszki, I.; Ducza, E.; Thole, H.; Messinger, J.; Wölfling, J.; Mótyán, G.; Mernyák, E.; et al. Synthesis and investigation of the anticancer effects of estrone-16-oxime ethers in vitro. Steroids 2013, 78, 69–78. [Google Scholar]
- Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 6, 55–63. [Google Scholar]
- Kanizsai, I.; Szakonyi, Z.; Sillanpää, R.; D’Hooghe, M.; de Kimpe, N.; Fülöp, F. Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine. Tetrahedron: Asymmetry 2006, 17, 2857–2863. [Google Scholar]
- Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, A64, 112–122. [Google Scholar]
- Farrugia, L.J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837–838. [Google Scholar]
- Sample Availability: Samples of the compounds are available from the authors.
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Szakonyi, Z.; Zupkó, I.; Sillanpää, R.; Fülöp, F. Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines. Molecules 2014, 19, 15918-15937. https://doi.org/10.3390/molecules191015918
Szakonyi Z, Zupkó I, Sillanpää R, Fülöp F. Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines. Molecules. 2014; 19(10):15918-15937. https://doi.org/10.3390/molecules191015918
Chicago/Turabian StyleSzakonyi, Zsolt, István Zupkó, Reijo Sillanpää, and Ferenc Fülöp. 2014. "Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines" Molecules 19, no. 10: 15918-15937. https://doi.org/10.3390/molecules191015918