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US 5,089,273 AGranted
Ecteinascidins 729, 743, 745, 759A, 759B and 770
AssigneeThe Board of Trustees of the University of Illinois
InventorsKenneth L. Rinehart, Tom G. Holt
Life of this patent
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Abstract
The present invention relates to novel compositions of matter extracted from the well-known and readily available tropical marine invertebrate, Ecteinascidia turbinata, and designated herein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals.
Claims6
The substantially pure compound Ecteinascidin 729, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.4 -0.28 (3:1 ethyl acetate-methanol), 0.26 (9:1 chloroform-methanol);
- HPLC retention time, 15.7 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH), 202 nm (.epsilon. 61 000), 244 (sh) (11 000), 283 (5 000), 289 (4 700), (0.1N HCl) 204 (61 000), 244 (sh) (9 600), 283 (4 800), 289 (4 500), (0.1N KOH) 215 (33 800), 258 (8 200), 290 (6 400);
- IR (CCl.sub.4), 3555, 3535, 2953, 2927, 2855, 1770, 1742, 1504, 1466, 1462, 1454, 1432, 1369, 1239, 1196, 1168, 1122, 1100, 1086, 1054, 1032, 997, 960 cm.sup.-1 ;
- .sup.1 H NMR (360 MHz, CDCl.sub.3) .epsilon. 6.63 (s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 6.04 (d, J-0.7 Hz, 1H), 5.95 (d, J-0.9 Hz, 1H), 5.15 (d, J-10.7 Hz, 1H), 4.84 (bs, 1H), 4.52 (d, J-3.5 Hz, 1H), 4.48 (bs, 1H), 4.38 (d, J-4.9 Hz, 1H), 4.04 (d, J-11 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.61 (m, 2H), 3.10 (m, 1H), 3.02 (d, J-18 Hz, 1H), 2.90 (dd, J-9, 18 Hz, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.35 (m, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.20 (m, 1H), 2.03 (s, 3H);
- FABMS m/z (rel. intensity) 730.2493 (30), 495 (2), 493 (2), 481 (2), 479 (2), 463 (4), 461 (2), 449 (4), 205 (8), 204 (8), 190 (8);
- B/E linked scan on m/z 729, m/z 711, 696, 683, 509, 495, 481, 479, 461, 449;
- optical rotation [.alpha]sub.D.sup.25 +112.degree. (c 0.01, CH.sub.3 OH).
5 more elements
The substantially pure compound Ecteinascidin 743, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.f -0.58 (3:1 ethyl acetate-methanol), 0.44 (9:1 chloroform-methanol);
- HPLC retention time, 18.8 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH) 202 nm (.epsilon. 81 000), 240 (sh) (15 000), 284 (6 600), 289 (6 400), (0.1N HCl) 205 (76 000), 240 (sh), (12 000), 285 (7 500), 289 (7 200), (0.1N KOH) 216 (50 000), 256 (12 700) 290 (9 000);
- IR (CCl.sub.4) 3549, 3530, 2992 (weak), 2929, 2848, 2803 (weak), 1764, 1739, 1597 (weak), 1511, 1501, 1460, 1445, 1425, 1365, 1350, 1195, 1160, 1115, 1102, 1098, 1082, 1058, 1048, 1024, 990, 950, 915, 907, cm.sup.-1 ;
- .sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. 6.62 (s, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 6.03 (d, J-1.2 Hz, 1H), 5.95 (d, J-1.3 Hz, 1H), 5.7 (bs, exchanges, 1H), 5.14 (dd, J-0.9, 11.3 Hz, 1H), 4.83 (bs, 1H), 4.50 (d, J-3.3 Hz, 1H), 4.50 (bs, 1H), 4.18 (d, J-4.2 Hz, 1H), 4.06 (dd, J-2.5, 11.3 Hz, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 3.59 (bd, J-4.4 Hz, 1H), 3.23 (m, 1H), 3.14 (ddd, J-11, 10, 4 Hz, 1H), 2.91 (bd, J-18 Hz, 1H), 2.88 (dd, J-9, 18 Hz, 1H), 2.82 (m, 1H), 2.62 (ddd, J-16, 10, 4 Hz, 1H), 2.49 (ddd, J-16, 4, 4 Hz, 1H), 2.37 (bd, J-13.9 Hz, 1), 2.33 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.18 (d, J-13.9 Hz, 1H), 2.04 (s, 3H);
- .sup.13 C NMR (75.4 MHz and 125.7 MHz, CDCl.sub.3) .delta. 9.6 (q), 15.7 (1),20.4 (q), 24.1 (t), 28.7 (t), 39.6 (t), 41.3 (q), 42.1 (t), 42.1 (d), 54.8 (d), 55.0 (q), 55. 9 (d), 57.7 (d), 57.8 (d), 60.2 (q), 61.3 (t), 64.6 (s), 82.0 (d), 101.6 (t), 109.8 (d), 112.5 (s), 114.1 (d), 115.9 (s), 118.1 (s), 120.9 (d), 121.9 (s), 126.0 (s), 129.2 (s), 129.2 s), 131.5 (s), 140.5 (s), 141.3 (s), 143.0 (s), 144.3 (s), 144.5 (s), 145.1 (s), 147.5 (s), 168.3 (s), 172.5 (s);
- FABMS m/z (rel. intensity) 744.2648 (100), 699.2766 (4), 495.2064 (15), 477.1979 (15), 475 (9), 463.1837 (25), 281 (39), 204.1027 (71);
- LC/FABMS m/z (rel. intensity) 744 (34), 495 (12), 493 (16), 477 (14), 475 (10), 463 (14), 234 (42), 218 (64), 204 (100), 189 (62), 174 (28), 160 (22);
- EIMS m/z 217.0737305, 191.0941620, 176.0696716;
- ESCA (mole percent) C (73.1), O (20.4), N (5.2), S (1.3);
- optical rotation [.alpha]sub.D.sup.25 +114.degree. (c 0.1, CH.sub.3 OH);
- or a derivative thereof selected from the group consisting of:
- deacetyl-, dioxy-, diacetyl-, monoacetyl-, mono-O-methyl-, di-O-methyl-, monooxy-, tetracetyl-, or p-bromobenzoyl.
10 more elements
The substantially pure compound Ecteinascidin 745, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.4 -0.42 (3:1 ethyl acetate-methanol, 0.38 (9:1 chloroform-methanol);
- HPLC retention time, 29.8 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH) 202 (.epsilon. 52 000), 240 (sh) (11 000), 281 (5 600), 287 (5 400), (0.1N HCL), 204 (51 000), 240 (sh) (9 500), 281 (5 200), 287 (5 200), (0.1N KOH), 215 (36 000), 254 (8 500), 290 (5 900), 298 (5 800);
- IR (CCl.sub.4) 3554, 3535, 2955, 2927, 2871, 2855, 1770, 1744, 1518, 1507, 1270, 1238, 1195, 1163, 1088, 1056 cm.sup.-1 ;
- .sup.1 H NMR (360 MHz, CDCl.sub.3), .delta. 6.62 (s, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 6.02 (d, J-1.2 Hz, 1H), 5.97 (d, J-1.2 Hz, 1H), 5.74 (bs, exchanges, 1H), 5.14 (d, J-11.2 Hz, 1H), 4.5 (bs, 1H), 4.22 (bs, 1H), 4.11 (dd, J-2, 11 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 1H), 3.63 (s, 3H), 3.31 (m, 1H), 3.23 (bs, 1H), 3.11 (m, 2H), 2.93 (m, 2H), 2.69 (m, 2H), 2.54 (m, 2H), 2.44 (d, J-14 Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 2.13 (m, 1H), 2.04 (s, 3H), ;
- FABMS m/z (rel. intensity) 746.2775 (100), 699 (8), 631 (8), 629 (8), 495 (19), 479 (42), 477 (52), 463 (36), 205 (64), 204 (64);
- LC/FABMS m/z (rel. intensity) 746 (44), 495 (18), 477 (20), 463 (32), 218 (42), 204 (100), 189 (62), 176 (32), 160 (20);
- optical rotation [.alpha]sub.D.sup.25 +50.degree. (c 0.1, CH.sub.3 OH).
5 more elements
The substantially pure compound Ecteinascidin 759A, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.f 0.6 (3:1 ethyl acetate-methanol), 0.3 (9:1 chloroform-methanol);
- HPLC retention time, 11.0 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH) 203 nm (.epsilon. 43 000), 250 (sh) (6 500), 281 (3 000), 288 (2 600), (0.1N HCl) 205 (44 000), 250 (sh) (7 600), 281 (4 500), 288 (4 400), (0.1N KOH) 216 (39 000), 249 (3 900), 294 (4 600);
- IR (CCl.sub.4) 3696, 3555, 3532, 2926, 2854, 1770, 1744, 1670, 1466, 1252, 1240, 1194, 1091 cm.sup. -1 ;
- FABMS m/z (rel. intensity) 760.2563 (58), 581 (24), 493 (16), 463 (80), 461 (100);
- LC/FABMS m/z (rel. intensity) 760 (26), 509 (12), 493 (12), 463 (24), 449 (16), 246 (26), 232 (32), 224 (62), 218 (5), 204 (100), 189 (56), 174 (18), 160 (16);
- optical retention [.alpha]sub.D.sup.25 +130.degree. (c 0.05, CH.sub.3 OH).
4 more elements
The substantially pure compound Ecteinascidin 759B, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.f -0.6 (3:1 ethyl acetate-methanol), 0.3 (9:1 chloroform-methanol);
- HPLC retention time, 13.9 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH) 208 nm (.epsilon. 60 000), 288 (4 800), 293 (4 500), (0.1N HCl) 209 (64 000), 288 (7 100), 293 (7 100), (0.1N KOH) 220 (45 000), 260 (10 000), 298 (7 600);
- IR (CCl.sub.4), 3555, 2933, 1770, 1743, 1590, 1514, 1465, 1453, 1446, 1431, 1368, 1356, 1330, 1288, 1264, 1240, 1193, 1163, 1124, 1110, 1089, 1032, 1006, 821 cm.sup.-1 ;
- FABMS m/z (rel. intensity) 760.2519 (100), 744 (71), 730 (19), 493 (29), 477 (43), 463 (76);
- LC/FABMS m/z (rel. intensity) 760 (38), 508 (8), 493 (18), 463 (26), 475 (14), 248 (30), 234 (48), 218 (86), 204 (100), 189 (56), 176 (26), 160 (32);
- optical rotation [.alpha]sub.D.sup.25 +167.degree. (c 0.1, CH.sub.3 OH).
4 more elements
The substantially pure compound Ecteinascidin 770, free of cellular components of the marine tunicate Ecteinascidia turbinata, said compound having the following physicochemical characteristics:
- TLC (SiO.sub.2) R.sub.f -0.6 (3:1 ethyl acetate-methanol), 0.3 (9:1 chloroform-methanol);
- HPLC retention time, 12.0 min. [Whatman Partisil 10 ODS-3, 10.times.250 mm, 70:30 methanol-aqueous Tris (0.05M, pH 7.5), 2.8 mL/min.];
- UV max (CH.sub.3 OH) 342 nm (.epsilon. 3 200), 329 (3 900), 299 (22 000), 263 (25 000), 240 (58 000), 234 (55 000), 216 (66 000), (0.1N HCl) 342 (4 900), 329 (5 700), 299 (24 000), 263 (29 000), 240 (58 000), 234 (57 000), 216 (71 000), (0.1N KOH) 342 (3 700), 329 (4 900), 299 (22 000), 263 (28 000), 240 (58 000), 234 (57 000), 227 (57 000);
- IR (CCl.sub.4) 3555, 3535, 3484, 2929, 2910, 1770, 1742, 1607, 1516, 1509, 1504, 1494, 1462, 1450, 1433, 1325, 1237, 1193 cm.sup.-1 ;
- .sup.1 H NMR (300 MHz, CDCl.sub.3), .epsilon. 6.60 (s, 1H), 6.47 (s, 1H), 6.45 (s, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 5.02 (d, J-11.4 Hz, 1H), 4.57 (bs, 1H), 4.32 (bs, 1H), 4.28 (d, J-5.3 Hz, 1H), 4.18 (d, J-2.5 Hz, 1H), 4.12 (dd, J-2.1, 11.5 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.50 (d, J-5 Hz, 1H), 3.42 (m, 1H), 3.10 (ddd, J-4, 10, 11 Hz, 1H), 2.94 (m, 2H), 2.79 (m, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.34 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 2.09 (m, 1H), 2.04 (s, 3H);
- FABMS m/z (rel. intensity) 771.2700 (48), 760 (8), 744 (20), 723 (12), 488 (12), 463 (14), 461 (20), 205 (50), 204 (80);
- optical rotation [.alpha]sub.D.sup.25 +52.degree. (c 0.1, CH.sub.3 OH).
4 more elements
Dependencies are inferred from the claim text.