Hydantoin Derivatives of L- and D-amino acids: Synthesis and Evaluation of Their Antiviral and Antitumoral Activity
Abstract
:Introduction
Results and Discussion
Chemistry
Biological Results
Conclusions
Experimental
General
Chemistry
N-Btc-amino acid amides 4a-h
General method for the synthesis of 3,5-disubstituted hydantoins 5a-h
Antitumoral Activity Assays
- If (mean ODtest – mean ODtzero) ≥ 0, then:
- PG = 100 x (mean ODtest – mean ODtzero) / (mean ODctrl – meanODtzero)
- If (mean ODtest – mean ODtzero) < 0, then:
- G = 100 x (mean ODtest – mean ODtzero) / ODtzero
Acknowledgements
References
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Compd. | R | R' | Yield (%) | mp (°C) | Molecular formula (Mr) | IR (KBr) νmax (cm-1) |
---|---|---|---|---|---|---|
4a | − | − | 48 | 155−160 | C25H25N5O2 (427.25) | 3287, 2966, 1713, 1650, 1556, 1524 |
5a | | 86 | oil | C19H20N2O2 (308.37) | 3249, 3063, 3030, 2963, 2930, 1772, 1711, 1417 | |
5b | | 88 | 139−141 | C20H22N2O2 (322.40) | 3421, 3265, 3110, 2956, 1773, 1711, 1422 | |
5c | | 73 | 121−124 | C15H18N2O2 (258.32) | 3258, 3091, 2959, 2868, 1760, 1718, 1431 | |
5d | | 85 | 119−120 | C16H20N2O2 (272.34) | 3270, 3093, 2926, 2856, 1768, 1707, 1436 | |
5e | | 80 | 150−153 | C17H22N2O2 (286.37) | 314, 3030, 2924, 2852, 1768, 1698, 1454, 1428 | |
5f | | 29 | 76 (decomp.) | C23H22N2O2 (356.42) | 3269, 3029, 2924, 1774, 1711, 1419 | |
5g | | 37 | 180−184 | C15H18N2O2 (258.32) | 3227, 3098, 3037, 2927, 2856, 1765, 1705, 1429 | |
5h | | 24 | 172−177 | C22H18N2O2 (342.39) | 3230, 3093, 2825, 1774, 1712, 1454, 1423 |
Compd. | R | R' | 1H-NMR (DMSO- d6) δ ppm |
---|---|---|---|
4a | | 9.19 (d, 1H, 3, J = 8.4 Hz), 8.68 (d, 1H, 1'', J = 8.5 Hz), 8.25−7.14 (m, 14H, arom.), 6.20 (d, 1H, 2'', J = 8.5 Hz), 4.49 (d, 1H, 2, J = 7.9 Hz), 2.34−2.23 (m, 1H, 5), 0.96−0.70 (m, 6H, 6, 7) | |
5a | | 8.40 (s, 1H, 1), 7.38−7.23 (m, 10H, arom.), 6.35 (s, 1H, 2''), 4.07−4,06 (d, 1H, 5, J = 3.3 Hz), 2,08−1,97 (m, 1H, 6, J = 3.4 Hz), 0.93−0.91 (d, 3H, 7,J = 6.9 Hz), 0.72−0.70 (d, 3H, 8, J = 6.8 Hz) | |
5b | | 8.51 (s, 1H, 1), 7.38−7.22 (m, 10H, arom.), 6.34 (s, 1H, 2''), 4.20−4.16 (q, 1H, 5, J = 4.1 Hz), 1.79−1.74 (m, 1H, 7, J = 4.7 Hz), 1.56−1.36 (m, 2H, 6,J = 4.7 Hz), 0.88−0.85 (2d, 6H, 8, 9, J = 4.1 Hz) | |
5c | | 8.18 (s, 1H, 1), 7.28−7.13 (m, 5H, arom.), 4.30−4.27 (t, 1H, 5, J = 4.4 Hz), 4.09−4.02 (m, 1H, 2'', J = 7.7 Hz), 2.94−2.93 (d, 2H, 6, J = 4.2 Hz), 1.67−1.42 (m, 8H, 3''−6'') | |
5d | | 8.15 (s, 1H, 1), 7.28−7.13 (m, 5H, arom.), 4.30−4.27 (t, 1H, 5, J = 4.4 Hz), 3.52−3.44 (m, 1H, 2'', J = 3.5 Hz), 2.94−2.92 (t, 2H, 6, J = 3.5 Hz), 1.85−0.94 (m, 10H, 3''−7'') | |
5e | | 8.21 (s, 1H, 1), 7.27−7.14 (m, 5H, arom.), 4.39−4.36 (t, 1H, 5, J = 4.2 Hz), 3.05−2.87 (m, 4H, 6, 2''), 1.61−0.50 (m, 11H, 3''−8'') | |
5f | | 8.44 (s, 1H, 1), 7.30−6.73 (m, 15H, arom.), 6.13 (s, 1H, 2''), 4.53−4.50 (t, 1H, 5, J = 4.3 Hz), 3.07−2.94 (m, 2H, 6) | |
5g | | 8.64 (s, 1H, 1), 7.44−7.29 (m, 5H, arom.), 5.13 (s, 1H, 5), 3.81−3.70 (m, 1H, 2'', J = 3.8 Hz), 2.12−1,02 (m, 10H, 3''−7'') | |
5h | | 8.91 (s, 1H, 1), 7.43−7.20 (m, 15H, arom.), 6.39 (s, 1H, 2''), 5.34 (s, 1H, 5) |
Compd. | R | R' | 13C-NMR (DMSO-d6) δ ppm |
---|---|---|---|
4a | | 169.29 (1), 148.59 (4), 145.45 (1'), 142.00 (3'', 9''), 131.17 (6'), 130.08 (5'), 128.30 (5'', 7'', 11'', 13''), 128.15 (4'', 8''), 127.24 (10'', 14''), 127.15 (6''), 126.99 (12''), 125.61 (4'), 119.82 (3'), 113.37 (2'), 63.90 (2), 56.04 (2'') 30.77 (5), 19.17 (6), 18.20 (7) | |
5a | | 173.63 (4), 156.87 (2), 138.63 (3''), 138.37 (9''), 128.56(4'', 8''), 128.37 (5'', 7''), 128.32 (10'', 14''), 128.22 (11'',13''), 127.64 (6''), 127.53''), 61.06 (2''), 57.14 (5), 29.92 (6), 18.64 (7), 15.84 (8) | |
5b | | 174.34 (4), 156.22 (2), 138.30 (3''), 138.21 (9''), 128.15 (4'', 8'', 10'', 14''), 128.12 (5'', 7'', 11'', 13''), 127.33 (6'', 12''), 56.85 (2''), 54.44 (5), 40.75 (6), 23.96 (7), 22.98 (8), 21.27 (9) | |
5c | | 175.20 (4), 158.25 (2), 136.80 (7), 131.64 (8, 12), 129.81 (9, 11), 128.55 (10), 58.11 (5), 51.90 (2''), 38.30 (6), 30.30 (6''), 30.02 (3''), 26.39 (4'', 5'') | |
5d | | 173.20 (4), 156.22 (2), 134.78 (7), 129.76 (8, 12), 127.82 (9, 11), 126.60 (10), 56.04 (5), 49.64 (2''), 36.28 (6), 28.58 (3''), 28.39 (7''), 25.18 (4'', 6''), 24.68 (5'') | |
5e | | 173.27 (4), 156.60 (2), 134.78 (7), 129.80 (8, 12), 127.82 (9, 11), 126.58 (10), 56.71 (5), 43.37 (2''), 35.95 (6), 35.66 (3''), 29.79 (4''), 29.52 (8''), 25.65 (5''), 25.17 (7''), 25.12 (6'') | |
5f | | 172.87 (4), 155.72 (2), 138.01 (3''), 137.95 (9''), 134.65 (7), 126.78−130.01 (8−12, 4''−8'', 10''−14'') 56.62 (5, 2''), 35.78 (6) | |
5g | | 172.36 (4), 156.61 (2), 135.91 (6), 128.62 (7, 11), 128.23 (8, 10), 126.68 (9), 59.08 (5), 50.22 (2''), 28.92(3''), 28.83 (7''), 25.27 (4''), 25.24 (6''), 24.72 (5'') | |
5h | | 172.35 (4), 156.54 (2), 138.96 (3''), 138.30 (9''), 135.85 (6), 128.94−126.87 (7−11, 4''−8'', 10''−14''), 59.66 (2''), 57.35 (5) |
Compd. | MCCa | EC50b | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
1c | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | ||
5a | 400 | > 80 | 80 | 80 | 16 | 80 | > 80 | > 80 | > 80 | > 80 | 48 | > 80 |
5b | 80 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 | 16 | > 16 |
5c | > 400 | > 400 | 240 | > 80 | 240 | > 400 | 240 | > 400 | > 400 | > 400 | 240 | > 400 |
5d | 80 | > 16 | > 16 | > 16 | > 16 | > 80 | 80 | > 80 | > 80 | > 80 | > 80 | > 80 |
5e | 400 | > 80 | > 80 | > 80 | > 80 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 | > 16 |
5f | 80 | > 16 | > 16 | > 16 | 16 | > 16 | 16 | > 16 | 16 | 16 | 16 | > 16 |
5g | 80 | > 16 | > 16 | > 16 | > 16 | > 80 | > 80 | > 80 | > 80 | > 80 | > 80 | > 80 |
5h | 80 | > 16 | > 16 | > 16 | > 16 | > 16 | 16 | > 16 | 16 | 16 | 16 | > 16 |
acyclovir | > 100 | 0.11 | 0.18 | 13.51 | 67.5 | > 100 | ndd | nd | nd | nd | nd | nd |
ganciclovir | > 25 | 0.02 | 0.02 | 0.2 | 15.3 | > 25 | nd | nd | nd | nd | nd | nd |
ribavirin | > 100 | > 100 | 73.3 | > 100 | 24.4 | > 100 | > 100 | > 100 | 73.3 | 73.3 | 24.4 | 73.3 |
Compds | Tumor cell growth a | ||||||||
---|---|---|---|---|---|---|---|---|---|
1b | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | |
5a | 102 ± 3 | 183 ± 38 | 83 ± 4 | > 100 | 36 ± 13 | 47 ± 5 | 65 ± 35 | 62 ± 20 | 77 ± 23 |
5b | 57 ± 21 | 232±194 | 148 ± 95 | 47 ± 44 | 16 ± 0.6 | 46 ± 29 | 43 ± 1.5 | 31 ± 27 | 42 ± 2 |
5c | > 500 | > 500 | 406 ± 16 | > 100 | 63 ± 14 | > 100 | > 100 | > 100 | > 100 |
5d | 303 ± 9 | 317 ± 12 | 266 ± 15 | 37 ± 141 | 18 ± 1 | 81 ± 10 | > 100 | 78 ± 21 | 55 ± 14 |
5e | 312±128 | > 500 | 246 ± 85 | 38 ± 8 | 22 ± 2 | 70 ± 19 | > 100 | 74 ± 25 | 42 ± 2 |
5f | 42 ± 2 | 53 ± 2 | 48 ± 4 | 13 ± 1.4 | 11 ± 1 | 14 ± 0.9 | 19 ± 4 | 15 ± 2 | 13 ± 5 |
5g | 172 ± 52 | 277 ± 45 | 146 ± 14 | 5.4 ± 13 | 2 ± 1.6 | 58 ± 42 | 58 ± 25 | 60 ± 35 | 1.5 ± 0.3 |
5h | 46 ± 4 | 52 ± 5 | 50 ± 4 | 21 ± 3 | 20 ± 10 | 22 ± 0.7 | 23 ± 0.7 | 21 ± 0.9 | > 100 |
HU | ndc | nd | nd | 42 ± 38 | > 100 | > 100 | > 100 | > 100 | > 100 |
5-FU | nd | nd | nd | 4 ± 1.5 | 15 ± 2 | 10 ± 3 | 2 ± 0.7 | 9 ± 2 | 14 ± 12 |
Cis | nd | nd | nd | 4 ± 3 | 12 ± 6 | 5 ± 1 | 0.3 ± 0.1 | 8 ± 6 | 20 ± 19 |
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Rajic, Z.; Zorc, B.; Raic-Malic, S.; Ester, K.; Kralj, M.; Pavelic, K.; Balzarini, J.; De Clercq, E.; Mintas, M. Hydantoin Derivatives of L- and D-amino acids: Synthesis and Evaluation of Their Antiviral and Antitumoral Activity. Molecules 2006, 11, 837-848. https://doi.org/10.3390/11110837
Rajic Z, Zorc B, Raic-Malic S, Ester K, Kralj M, Pavelic K, Balzarini J, De Clercq E, Mintas M. Hydantoin Derivatives of L- and D-amino acids: Synthesis and Evaluation of Their Antiviral and Antitumoral Activity. Molecules. 2006; 11(11):837-848. https://doi.org/10.3390/11110837
Chicago/Turabian StyleRajic, Zrinka, Branka Zorc, Silvana Raic-Malic, Katja Ester, Marijeta Kralj, Krešimir Pavelic, Jan Balzarini, Erik De Clercq, and Mladen Mintas. 2006. "Hydantoin Derivatives of L- and D-amino acids: Synthesis and Evaluation of Their Antiviral and Antitumoral Activity" Molecules 11, no. 11: 837-848. https://doi.org/10.3390/11110837