V ol. 24 o. 2 2 0 0 3 2 CHEM ICAL JOU RAL O F CH I ESE U IV ERS IT IES 260 264 1, 3- -1, 3- -2H- 1, 2, 2, 2 (1. ; 2., 610041) ΑvΒ3 R GD,, 5 52 21, 32 21, 32 22H 2,, ( ECV 304) R GD ; ; 1, 32 21, 32 22H 2 ; ; O 621 A 025120790 (2003) 0220260205 (angiogenesis),,,, [1 ].,, (integrin) ΑvΒ3 [2 ], ΑvΒ3 2 2 (A rg2gly2a sp, R GD ), R GD [3 ],,,, R GD, R GD (A rg) (A sp), A rg A sp, [4, 5 ], ΑvΒ3, (S ) 2 (thalidom ide),, Β3 2Α(T F2Α) [6 ] ;,, [7 ]. R GD :,, ΑvΒ3, R GD,, R GD (A rg) (A sp), 5 52 21, 32 21, 32 22H 2, : : 2002201214. : (1970 ),,,, E2m ail: dengyongy@ sohu. com
o. 2 : 1, 32 21, 32 22H 2 261 1 1. 1 Carlo2E rba 1106 ; icolet 560, KB r ; B ruker A C2E200 V arian IOVA 2400, CDC l3 DM SO 2d6, TM S ; IA 6304. 1. 2 (- ) -5- -1, 3- -1, 3- -2H- -2- (4- ) (1a) (- ) 2 4. 99 g (0. 01 mol) 42 1. 93 g (0. 01 mol) 3. 20 ml (0. 022 mol) 50 ml, 5. 0 h,,, g, 3. 91 g, m. p. 162 164, 78. 0%. 1. 3 (- ) -5-{[ (2- ) ] }-1, 3- -1, 3- -2H- -2- (4- ) (2a) A : 1H 2 222 3. 30 g (15. 0 mmol) 1a 5. 01 g (10. 0 mmol) 200. 0 ml, 0, 3. 1 g (30. 0 mmol),, 0. 16 g (1. 0 mmol) DM A P, 3. 0 g (14. 54 mmol) DCC 3. 0 g (20. 0 mmol) HOB t, 0 5 2. 0 h,,,, a2co 3 (35 ml 2) (50 ml ), a2so 4 ; CH 2C l2,, CHC l32ch 3OH ( 10 1), 4. 1g, m. p. 71 72, 65. 0%. B : 1a 5. 01 g (10. 0 mmol) 80. 0 ml, 3. 0 h,,,, 1H 2 222 3. 30 g (15. 0 mmol) 200. 0 ml 5. 45 g (52. 5 mmol) 10. 0 ml, 0, 100 ml CH 2C l2, 1 h, ;, a2co 3 (75 ml ) (50 ml ), a2so 4 ; CH 2C l2, 2 ( 1 1), 4. 72 g, m. p. 71 72, 75. 0%. IR 1 H M R A 1. 4 (- ) -5-{[ (2- ) ] }-1, 3- -1, 3- -2H- -2- (4- ) (3a) 2a 3. 80 g (6. 03 mmol) 50 ml 5% PdgC, H 2 12 h;,,,,, 2. 17 g, m. p. 123 124, 80. 0%. C 22H 18 4O 7 (%, ) : C 58. 91 (58. 67), H 4. 08 (4. 00), 12. 20 (12. 44)., 3b 3e. 1. 5 (ECV 304), ECV 304 5% R PM I21640, 96, 2 3, 37, 5% CO 2 24 h, ; (
262 V ol. 24 10-6 molgl ) 100 ΛL g ; 37, 5% CO 2 72 h, M T T PBS ( 5 m ggml ) 10 ΛL g, 4. 0 h,, 100 ΛL g DM SO, 1 m in, 570 nm (OD ), 2 1 2. Table 1 Structures and physica l properties of the in termedia te and target compounds a Compd. R 1 R 2 n Form ula Yield (% ) m. p. g Appearance 1a COOCH 2Ph 2 C28H 23O 8 78. 0 162 164 W hite needle 1b COOCH 2Ph 1 C27H 21O 8 88. 3 134 135 W hite needle 1c H 1 C19H 15O 6 85. 0 109 110 W hite needle 2a COOCH 2Ph b 2 C36H 30 4O 7 65. 0 71 72 W hite solid 2b COOCH 2Ph c 2 C37H 32 4O 7 70. 0 152 154 W hite solid 2c COOCH 2Ph c 1 C36H 30 4O 7 73. 0 112 114 W hite solid 2d H b 1 C27H 22 4O 5 65. 0 165 166 W hite solid 2e H c 1 C28H 24 4O 5 76. 5 180 182 W hite solid 3a COOH b 2 C22H 18 4O 7 80. 0 123 124 W hite pow d 3b COOH c 2 C23H 20 4O 7 87. 2 240 242 W hite pow d 3c COOH c 1 C22H 18 4O 7 77. 0 193 194 W hite pow d 3d H b 1 C20H 16 4O 5 85. 0 272 273 W hite pow d 3e H c 1 C21H 18 4O 5 82. 0 262 264 W hite pow d a. C, H, analyses w ere w ithin 0. 3% of the calcd. values; b. R 2= H CH 2; c. R 2= Table 2 The IR and 1 H M R da ta of the in termedia tes and target compounds H CH 2CH 2. Compd. IR, Μ π gcm - 1 1 H M R (CDCl3gDM SO 2d6), 1a 3 257, 1 773, 1 716, 1 381, 1 214, 1 153, 908, 739, 702 1b 3 235, 1 773, 1 719, 1 381, 1 214, 1 150, 906, 739, 702 8. 50 (2H, m ), 7. 96 (1H, d, J = 7. 8 Hz), 7. 31 (10H, m ), 5. 20 (2H, s), 5. 06 (2H, s), 5. 02 (1H, m ), 2. 60 (2H, m ), 2. 45 (2H, m ) 8. 52 (1H, d, J = 1. 20 Hz), 8. 47 (1H, dd, J 1= 1. 20 Hz, J 2= 7. 80 Hz), 7. 94 (1H, d, J = 7. 8 Hz), 7. 29 (5H, s), 7. 25 (5H, s), 5. 46 (1H, dd, J 1= 5. 80 Hz, J 2= 9. 20 Hz), 5. 17 (2H, s), 5. 06 (2H, s), 3. 42 (1H, dd, J 1= 5. 80 Hz, J 2= 16. 7 Hz), 3. 26 (1H, dd, J 1= 9. 20 Hz, J 2= 16. 7 Hz) 1c 3 465, 1 774, 1 724, 1 621, 1 384, 1 315, 1 195, 1 113, 8. 46 (2H, m ), 7. 93 (1H, d, J = 7. 7 Hz), 7. 30 (5H, s), 5. 10 (2H, s), 4. 10 (2H, t, J = 7. 0 Hz), 2. 80 (2H, t, J = 7. 0 Hz) 727, 690 2a 3 432, 1 774, 1 720, 1 648, 1 544, 1 449, 1 383, 1 169, 738, 697 2b 3 438, 1 772, 1 716, 1 640, 1 552, 1 381, 1 264, 1 196, 725, 699 2c 3 343, 1 779, 1 720, 1 639, 1 550, 1 383, 1 271, 1 167, 731, 697 9. 61 (1H, t, J = 6. 0 Hz), 8. 42 (1H, d, J = 1. 2 Hz), 8. 38 (1H, dd, J 1= 1. 2 Hz, J 2= 8. 0 Hz), 7. 82 (1H, d, J = 8. 0 Hz), 7. 49 (2H, m ), 7. 28 (10H, m ), 7. 20 (2H, m ), 5. 17 (2H, d, J = 5. 6 Hz ), 5. 02 (2H, s), 4. 97 (1H, dd, J 1= 4. 8 Hz, J 2= 10. 0 Hz), 4. 85 (2H, d, J = 6. 0 Hz), 2. 66 (1H, m ), 2. 54 (1H, m ), 2. 42 (2H, t, J = 6. 0 Hz) 8. 30 (1H, brt, J = 5. 6 Hz), 8. 27 (1H, d, J = 1. 6 Hz), 8. 21 (1H, dd, J 1 = 1. 6 Hz, J 2 = 8. 0 Hz), 7. 85 (1H, d, J = 8. 0 Hz), 7. 57 (2H, m ), 7. 28 (10H, m ), 7. 23 (2H, m ), 5. 17 (2H, d, J = 4. 4 Hz), 5. 03 (2H, s), 4. 98 (1H, dd, J 1= 5. 2 Hz, J 2= 10. 4 Hz), 4. 02 (2H, q, J = 5. 6 Hz), 3. 26 (2H, t, J = 7. 2 Hz), 2. 68 (1H, m ), 2. 55 (1H, m ), 2. 41 (2H, t, J = 6. 0 Hz) 8. 34 (1H, brt, J = 5. 6 Hz), 8. 23 (1H, d, J = 1. 6 Hz), 8. 18 (1H, dd, J 1= 1. 60 Hz, J 2= 7. 6 Hz), 7. 81 (1H, d, J = 7. 6 Hz), 7. 54 (2H, m ), 7. 26 (10H, m ), 7. 21 (2H, m ), 5. 43 (1H, dd, J 1= 5. 6 Hz, J 2= 9. 2 Hz), 5. 15 (2H, d, J = 1. 2 Hz), 5. 04 (2H, d, J = 3. 6 Hz), 4. 02 (2H, q, J = 6. 0 Hz), 3. 40 (1H, dd, J 1= 5. 6 Hz, J 2= 16. 4 Hz), 3. 25 (2H, t, J = 6. 0 Hz), 3122 (1H, dd, J 1= 9. 2 Hz, J 2= 16. 4 Hz) 2d 3 323, 1 775, 1 716, 1 645, 1 600, 1 543, 1 203, 1 163, 730, 616 12. 39 (1H, brs), 9. 62 (1H, t, J = 5. 4 Hz), 8. 41 (1H, s), 8. 36 (1H, d, J = 7. 8 Hz), 8. 00 (1H, d, J = 7. 8 Hz), 7. 51 (2H, m ), 7. 32 (5H, s), 7. 17 (2H, m ), 5. 07 (2H, s), 4. 95 (2H, d, J = 5. 4 Hz), 3. 89 (2H, t, J = 7. 0 Hz), 2. 78 (2H, t, J = 7. 0 Hz)
o. 2 : 1, 32 21, 32 22H 2 263 Continued Compd. IR, Μ π gcm - 1 1 H M R (CDCl3gDM SO 2d6), 2e 3 322, 1 775, 1 715, 1 636, 1 599, 1 551, 1 200, 1 190, 730, 612 3a 3 427, 1 777, 1 714, 1 653, 1 544, 1 385, 1 303, 1 263, 1 218, 1 113, 732, 613 3b 3 430, 1 773, 1 715, 1 654, 1 382, 1 213, 740, 613 12. 35 (1H, brs), 9. 09 (1H, t, J = 4. 95 Hz), 8. 28 (1H, s), 8. 25 (1H, d, J = 8. 0 Hz), 7. 94 (1H, d, J = 8. 0 Hz), 7. 47 (2H, m ), 7. 29 (5H, s), 7. 13 (2H, m ), 5. 04 (2H, s), 3. 86 (2H, t, J = 7. 0 Hz), 3. 74 (2H, q, J = 7. 05 Hz), 3. 11 (2H, t, J = 7. 05 Hz), 2. 76 (2H, t, J = 7. 0 Hz) 12. 36 (3H, brs), 9. 59 (1H, t, J = 5. 6 Hz), 8. 45 (1H, d, J = 1. 6 Hz), 8. 39 (1H, dd, J 1= 1. 6 Hz, J 2= 7. 6 Hz), 8. 04 (1H, d, J = 7. 6 Hz), 7. 50 (2H, m ), 7. 15 (2H, m ), 4. 84 (1H, dd, J 1= 4. 8 Hz, J 2 = 10. 0 Hz), 4. 75 (2H, d, J = 5. 6 Hz), 2. 37 (1H, m ), 2. 31 (2H, t, J = 6. 0 Hz), 2. 26 (1H, m ) 12. 43 (3H, brs), 9. 08 (1H, t, J = 6. 0 Hz), 8. 32 (1H, d, J = 1. 2 Hz), 8. 29 (1H, dd, J 1= 1. 2 Hz, J 2= 8. 0 Hz), 8. 00 (1H, d, J = 8. 0 Hz), 7. 48 (2H, m ), 7. 12 (2H, m ), 4. 80 (1H, dd, J 1= 4. 8 Hz, J 2= 10. 4 Hz), 3. 76 (2H, q, J = 5. 6 Hz), 3. 11 (2H, t, J = 7. 2 Hz), 2. 37 (1H, 3c 3 394, 1 776, 1 715, 1 651, 1 598, 1 546, 1 386, 1 223, 1 111, 731, 642, 618 3d 3 430, 3 372, 1 774, 1 712, 1 653, 1 555, 1 447, 1 304, 1 222, 1 120, 607 3e 3 435, 3 385, 1 773, 1 712, 1 653, 1 555, 1 446, 1 315, 739, 604 m ), 2. 31 (2H, t, J = 7. 2 Hz), 2. 25 (1H, m ) 12. 45 (3H, brs), 9. 09 (1H, t, J = 5. 6 Hz), 8. 33 (1H, d, J = 1. 6 Hz), 8. 30 (1H, dd, J 1= 1. 6 Hz, J 2= 7. 6 Hz), 8. 02 (1H, d, J = 7. 6 Hz), 7. 50 (2H, m ), 7. 14 (2H, m ), 5. 14 (1H, dd, J 1= 6. 8 Hz, J 2= 7. 6 Hz), 3. 76 (2H, q, J = 6. 0 Hz, ), 3. 15 (1H, dd, J 1 = 7. 6 Hz, J 2 = 16. 4 Hz), 3. 12 (2H, t, J = 6. 0 Hz), 2. 90 (1H, dd, J 1= 6. 8 Hz, J 2= 16. 4 Hz) 12. 34 (3H, brs), 9. 59 (1H, t, J = 5. 4 Hz), 8. 41 (1H, s), 8. 36 (1H, d, J = 7. 8 Hz), 8. 02 (1H, d, J = 7. 8 Hz), 7. 50 (2H, m ), 7. 15 (2H, m ), 4. 74 (2H, d, J = 5. 4 Hz), 3. 82 (2H, t, J = 7. 2 Hz), 2. 64 (2H, t, J = 7. 2 Hz) 12. 32 (2H, brs), 9. 09 (1H, t, J = 5. 3 Hz), 8. 29 (1H, s), 8. 25 (1H, d, J = 7. 50 Hz), 7. 96 (1H, d, J = 7. 5 Hz), 7. 47 (2H, m ), 7. 11 (2H, m ), 3. 80 (2H, t, J = 7. 2 Hz), 3. 75 (2H, q, J = 7. 12 Hz), 3. 13 (2H, t, J = 7. 12 Hz), 2. 61 (2H, t, J = 7. 2 Hz) 2. 1 1,, 150 200,,, 50% 70%,,, [ 8 ], 1,, 85%. 2 A : 1 ( ), DCC, DM A P ; 1 12 (HOB t),. B : 1 SOC l2, A, DCU,,,, B, A, (B ). 2,, 5% PdgC,, 2. 2,, 3. Table 3 The inh ibitory activ ity of target compounds to ECV304 (10-6 molgl ) Compd. 3a 3b 3c 3d 3e Inhibitory ratio (% ) 0. 00 4. 1 29. 7 39. 0 21. 9, (M CF27),, 10-5 10-10 molgl, 3c, 3d 3e,
264 V ol. 24,,! [ 1 ] Boehm T., Folkm an J., B row der T. et al.. ature[j ], 1997, 390 (6 657) : 404 407 [ 2 ] B rooks P. C., Clark R. A. F., Cheresh D. A. et al.. Science[J ], 1994, 264 (5 158) : 569 572 [ 3 ] B rooks P. C., M ontgom ery A. M. P., Rosenfeld M. et al.. Cell[J ], 1994, 79 (2) : 1 157 1 164 [ 4 ] Greenspoon., Hershkoviz R., A lon R. et al.. B iochem istry[j ], 1993, 32 (4) : 1 001 1 008 [ 5 ] Bach A. C., E sp ina J. R., Jackson S. A. et al.. J. Am. Chem. Soc. [J ], 1996, 118 (1) : 293 294 [ 6 ] eubert R., H inz., Thidl R. et al.. L ife Sciences[J ], 1996, 58 (4) : 295 316 [ 7 ] Shah J. H., Sw artz G. M., Papathanassiu A. E. et al.. J. M ed. Chem. [J ], 1999, 42 (16) : 3 014 3 017 [ 8 ] Baum garten H. E.. O rganic Syntheses, Coll. Vol. 5[M ], ew York: John W iley & Sons Inc., 1973: 973 975 Syn thesis and An tiangiogen ic Activities of 1, 3-D ihydro- 1, 3-dioxo-2H- isoindole D er ivatives D E G Yong 13, ZHO G Yu2Guo 2, SH E Yi 2, L IU Shao2H ua 2 (1. D ep artm ent of P harm aceutical E ng ineering, Colleg e of Chem ical E ng ineering; 2. W est Ch ina S chool of P harm acy, S ichuan U niversity, Cheng d u 610041, Ch ina) Abstract T he grow th of m alignant tumors has been show n to be dependent on the evelopm ent of new blood vesselṡ B lock ing tum o r2induced angiogenesis is an efficiency strategy to p reven t and cure canceṙ It has been show n that the angiogen ic p rocess depends on vascular endo thelial cellm igration and invasion p ro2 cesses regulated by cell adhesion recep toṙ T he integrin ΑvΒ3 is such a cell adhesion recep toṙ R ecent studies show the integrin ΑvΒ3 and extracellular m atrix can recognize each other th rough A rg2gly2a sp (R GD ) se2 quence, som e pep tides con tain ing R GD sequence an tagon ists can inh ibit em bryon ic neovascularization, tu2 m o r2induced angiogenesis, and tum o r grow th. A cco rding to the structure2activity relation sh ip s and an tian2 giogenic m echanism of R GD sequence, w e use thalidom ide as the leading structure to design and synthesize five 52carboxy21, 32dihydro21, 32dioxo22H 2iso indo le derivativeṡ A ll of them w ere first repo rted and their structures w ere confirm ed by elem entary analysis, IR and 1 H M R spectra. T he results of p relim inary an2 tiangiogenic tests in vitro show ed that most target compounds could inh ibit ECV 304 p roliferation. M ore2 over, it has been p roved that the inh ibition of endothelial cell p roliferation w as not the result of cytotoxic effect of target com poundṡ Keywords R GD sequence; T halidom ide; 1, 32D ihydro21, 32dioxo22H 2isoindole derivatives; Synthesis; A n tiangiogen ic activity (Ed. : H, J, Z)