V o l. 2 o. 7 2 0 0 2 7 C EM ICAL JU RAL C I ESE U IV ERS IT IES 299 0 5- --, 2,, 2, (., 00072; 2.,, 0007;., 006) DCC ( ) gb t (2 ), 4 52 22, 52% 8%. M R, P M R, IR. 52 22,., L 260 BEL 740. 52 ; ; ; 626 A 02520790 (2002) 072299205 [ ] (PA s), [2, ]..,,, [4 ]., Α2, [5 8 ],. 52 (52 luo rou racil) [9 ],,., [0 2 ],, (T egfu r).,,,, 52 22,, [ ]., [4 6 ]. 52 22,. : B rc 2C K g 2 2 C 2C C 2C 2 4 C 2C 2 () DCCgDM ()DCCgDM,B t (B t ) (2) 2C 2C 2Et (2) 2C (R ) P ( Ph) 2 (5) C 2C C 2C 2E t C 2C C 2C C P ( Ph) 2 2 mo lgl a R: 6a. ; 6b. C ; 6c. Bu; 6d. C 2Ph; 6e. C 6 5; 6f. 2, 42D ich lo ro C6 ; 6g. 42C l C 6 4; 6h. 2 2 C6 4; 6i. 42 2 C6 4; 6j. 42M e C 6 4; 6k. 22M e C6 4; 6l. 42M e C 6 4; 6m. 42C l C6 4; 6n., 42C 2 C6. 6 R : 2002042 : ( : 2997202). : (96 ),,, W ittig. E2m ail: liuxuejun89@ 26. net
00 V o l. 2 B ruker A C2P200 M R (TM S P 4 ), Yanaco C Co rder M T, ico let 5DX IR. (200 00 Λm, ), DM 4A, CC l P 2 5.,.. Α- (5) Α2 [ 7, 8 ].. 2 52 22 (2) 0 mmo l 52 6. 4 g (. 5 mmo l) K 20 ml. 40, 6. 25 g (45 mmo l) 0 ml, 0 m in., C l p 5. 5, 2 h. 6 h. 2 89% ; m. p.,,. > 270 ; 2 h,,, p 2, M R, : 4. 4 (s, 2 ), 8. 02 (d,, J CC = 7. 6 z),. 54 (s, b r, ) ; (% ) : C 8. 49, 2. 75, 4. 70 ( % : C 8., 2. 68, 4. 89).. Α- (5- -- ) () 5 mmo l 52 22 5 mmo l 2 00 ml, 25 ml DM, 0. 0. 25 g (5. 5 mmo l)dcc DM 0 ml, 40 m in., 2 h, 5 mmo l,., DM (5 ml ),,,,, g ( 20 ),. 2, 85% ; m. p. J C= 5. 7 z), 4. 09 (q, 2, 8. 62 ( t,, 228 229 ; M R, :. 9 (t,, J CC= 7. z), 4. 40 (s, 2 ), 8. 02 (d,, J CC= 7. z),. 86 (d, J CC= 7. 6 z), J C = 5. 7 z),. 54 ( s, b r, ) ; (% ), : C 44. 2, 4. 66, 5. 09; : C 4. 96, 4. 4, 5. 8.. 4 Α- (5- -- ) (4) (2 mmo l) Α2(52 22 ) 0 ml 2 mo lgl a, 4 h. p 2, h.,, 45, 4. 4 9% ; m. p. 2 ), 8. 02 (d,, > 270 ; J CC = 7. 6 z), 8. 56 (t,, M R, :. 8 (d, 2, J C = 5. 8 z), 4. 8 (s, J C = 5. 8 z),. 8 (s, b r, ) ; (% ), : C 9. 47,. 5, 7. 20; : C 9. 9,. 29, 7. 4.. 5 Α- [ (5- -- ) ]-Α- ( ) -, - (6a 6n) mmo l Α2(52 22 ) (4) mmo l 2 00 ml, 5 ml DM, 0. 0. 25 g (. 2 mmo l)dcc DM 0 ml, 40 m in., 2 h, mmo l Α2,., DM (5 ml ).,,,, g ( 20 ),. 2 2. 52 22 52 22 [ 9 ], K, 22.
o. 7 : 52 22 0 52 22,,,. 6 M R, IR 2. Α2(52 22 ) Α2(52 22 ), Α2 52 22.,,,, (2% ). DCCgB t 52 22,,,., DCCgB t Table P M R and M R (DM S, ) of compounds 6 Compd. P M R M R 6a 8. 50. 86 (d, 2, J C= 5. 7 z, C 2) ; 4. 2 (dd., 2, PC 2, 2 J PC= 4. 5 z, J C= 7. 0 z) ; 4. 46 ( s 2, C 2C ) ; 7. 8 6. 9 (m, 0, 2C6 5) ; 8. 0 (d,, J CC= 7. z, C= C ) ; 8. 42 ( t,, J C= 5. 7 z, C 2) ; 9. 56 (m,, C 2P) ;. 8 (s,, (C ) 2 ). 6b 5. 80. 44 (dd,, C, J CCP= 8. 2 z, J CC= 7. 6 z) ;. 88 (d, 2, J C= 5. 9 z, C 2) ; 4. 48 ( s, 2, C 2C ) ; 4. 84 4. 9 (m,, PC, ) ; 7. 62 6. 95 (m, 0, 2C 6 5) ; 8. 0 (d,, C= C, J CC= 7. 0 z) ; 8. 4 (t,, J C= 5. 9 z, C 2) ; 9. 65 (m,, C P) ;. 47 (s,, (C ) 2 ). 6c 6. 6 0. 85 (t,, C, J CC= 7. 8 z) ;. 6. 5 (m, 6, C 2C 2C 2) ;. 89 (d, 2, J C= 5. 8 z, C 2) ; 4. 48 (s, 2, C 2C ), 4. 88 (m,, PC ), 7. 65-6. 85 (m, 5, 2C6 5) ; 8. 05 (d,, C= C, J CC= 7. z) ; 8. 45 (t,, J C= 5. 8 z, C 2) ; 9. 49 (m,, C P) ;. 7 (s,, (C ) 2 ). 6d 6. 25. 6. 24 (m, 2, C 2Ph) ;. 88 (d, 2, J C= 5. 7 z, C 2) ; 4. 5 (s, 2, C 2C ) ; 5. 5. 22 (m,, PC ) ; 8. 7. 05 (m, 5, C6 5) ; 8. 02 (d,, C= C, J CC= 7. 6 z) ; 8. 46 ( t,, J C= 5. 8 z, C 2) ; 9. 79 (m,, C P) ;. 50 (s,, (C ) 2 ) 6e 9. 82. 86 (d, 2, J C= 5. 9 z, C 2) ; 4. 50 ( s, 2, C 2C ) ; 5. 89 (dd.,, 2 J PC= 2. 0 z, J C= 8. 5 z, PC ) ; 7. 65 6. 98 (m, 5, C 6 5) ; 8. 02 (d,, C= C, J CC= 7. 6 z) ; 8. 45 (t,, J C = 5. 9 z, C 2) 9. 66 (d,, J C= 8. 5 z, C P). 42 ( s, br,, (C ) 2 ) 6f 9. 22. 89 (d, 2, J C= 5. 9 z, C 2) ; 4. 50 ( s, 2, C 2C ) ; 6. 52 (dd.,, PC, J PC= 24. z, J C= 9. 2 z) ; 7. 58 6. 94 (m,, (C 6 5+ 2, 4 2C l2c 6 ) ; 8. 0 (d,, C= C, J CC= 7. 9 z) ; 8. 48 ( t,, J C= 5. 9 z, C 2) ; 9. 55 (d,, J C= 9. 2 z, C P) ;. 49 (s,, (C ) 2 ). 6g 9. 0. 85 (d, 2, J C= 5. 8 z, C 2) ; 4. 5 ( s, 2, C 2C ) ; 5. 9 (dd.,, J PC= 2. 2 z, J C= 8. 5 z, PC ) ; 7. 62 6. 90 (m, 4, 2C6 5+ 42C lc6 4) ; 8. 02 (d,, C= C, J CC= 7. 6 z) ; 8. 45 (t,, J C= 5. 8 z, C 2) ; 9. 79 (d,, J C= 8. 5 z, C P) ;. 58 (s, br,, (C ) 2 ) 6h 8. 57. 89 (d, 2, J C= 5. 8 z, C 2) ; 4. 52 (s, 2, C 2C ) ; 6. 26 (dd.,, PC, J PC= 22. 7 z, J C= 9. 5 z) ; 8. 56 7. 00 (m, 5, 2 (C6 5+ 2 2C6 4+ C= C ) ; 8. 48 (t,, J C= 5. 8 z, C 2) ; 9. 86 (d, 2, J C= 9. 5 z, C P) ;. 55 (s,, (C ) 2 ) 6i 8. 24. 88 (d, 2, J C= 5. 9 z, C 2) ; 4. 48 ( s, 2, C 2C ) ; 6. 6 (dd.,, J PC= 2. 2 z, J C= 9. z, PC ) ; 8. 28 6. 99 (m, 5, 2 (C6 5+ 42 2C6 4+ C= C ) ; 8. 56 (t,, J C= 5. 9 z, C 2) ; 9. 49 (d,, J C= 9. z, C P) ;. 49 (s, br,, (C ) 2 ) 6j 9. 77 2. 28 (s,, C C6 4) ;. 8 (d, 2, J C= 5. 8 z, C 2) ; 4. 9 ( s, 2, C 2C ) ; 5. 87 (dd.,, 2 J PC= 2. 4 z, J C= 9. z, PC ) ; 7. 47 6. 9 (m, 4, 2C6 5+ 42M ec 6 4) ; 8. 02 (d,, C= C, J CC= 7. 6 z) ; 8. 46 ( t,, J C= 5. 8 z, C 2) 9. 5 (d,, J C= 9. z, C P) ;. 40 ( s, br,, (C ) 2 ) 6k 20. 00. 75 (s,, C C 6 4) ;. 89 (d, 2, J C= 5. 8 z, C 2) ; 4. 46 (s, 2, C 2C ) ; 6. 4 (dd.,, PC, 2 J PC= 22. z, J C= 9. 8 z) ; 7. 69 6. 80 (m, 4, 2C 6 5+ 22M ec 6 4) ; 8. 0 (d,, C= C, J CC= 7. 5 z) ; 8. 45 ( t,, J C= 5. 8 z, C 2) ; 9. 55 (d,, J C= 9. 8 z, C P). 46 (s,, (C ) 2 ) 6l 20. 0. 76 (s,, C C 6 4) ;. 88 (d, 2, J C= 5. 8 z, C 2) ; 4. 42 (s, 2, C 2C ) ; 5. 86 (dd.,, 2 J PC= 2. 6 z, J C= 9. 9 z, PC ) ; 7. 54 6. 9 (m, 4, 2C6 5+ 42M ec 6 4) ; 8. 02 (d,, C= C, J CC= 7. 6 z) ; 8. 5 ( t,, J C= 5. 8 z, C 2) ; 9. (d,, J C= 9. 9 z, C P) ;. 50 ( s, br,, (C ) 2 ) 6m 9. 5. 85 (d, 2, J C= 5. 8 z, C 2) ; 4. 9 ( s, 2, C 2C ) ; 5. 92 (dd.,, J PC= 22. 4 z, J C= 7. 6 z, PC ) ; 7. 62 6. 80 (m, 4, 2C6 5+ 22C lc6 4) ; 8. 0 (d,, C= C, J CC= 7. 5 z) ; 8. 44 ( t,, J C= 5. 8 z, C 2) ; 9. 78 (d,, J C= 7. 6 z, C P) ;. 4 ( s, br,, (C ) 2 ) 6n 9. 47. 88 (d, 2, J C= 5. 7 z, C 2) ; 4. 46 (s, 2, C 2C ) ; 5. 82 (dd.,, PC, J PC= 22. 4 z, J C= 9. 5 z) ; 6. 04 ( s, 2, C 2 ) ; 7. 46 6. 90 (m,, 2C6 5+, 42C 2C6 ) ; 8. 02 (d,, C= C, J CC= 7. 4 z) ; 8. 48 ( t,, J C= 5. 7 z, C 2) ; 9. 60 (d,, J C= 9. 5 z, C P) ;. 48 ( s,, (C ) 2 ).
02 V o l. 2 Table 2 Exper imen tal data of compounds 6 IR, Μ π gcm - Yield Elem ent analysis o. m. p. g C= P= P C (% ) C,, (calculated, % ) 6a 40 708 20 80 8. 2 209 (dec. ) 5. 29,. 90,. 76 (5. 44, 4.,. 42) 6b 4 727 224 79 79. 6 2 (dec. ) 52. 2, 4. 25,. 6 (52. 9, 4. 40,. ) 6c 40 78 256 79 74. 2 226 (dec. ) 55. 24, 5., 0. 55 (54. 95, 5. 6, 0. 25) 6d 42 72 248 68 70. 9 25 (dec. ) 57. 66, 4. 40, 9. 6 (57. 9, 4. 5, 9. 65) 6e 44 72 244 82 69. 2 22 (dec. ) 56. 92, 4. 5, 9. 60 (57. 25, 4. 27, 9. 89) 6f 49 686 22 65 60. 228 (dec. ) 5. 2,. 8, 8. 76 (5. 04,. 49, 8. 82) 6g 424 705 22 72 66. 6 255 (dec. ) 54. 06,. 68, 9. 0 (5. 97,. 86, 9. 2) 6h 450 70 29 76 56. 2 249 (dec. ) 52. 99,. 90,. 69 (5. 04,. 79,. 45) 6i 442 744 224 69 52. 5 254 (dec. ) 5. 6,. 8,. (5. 04,. 79,. 45) 6j 448 709 242 70 68. 4 247 (dec. ) 57. 92, 4. 8, 9. 60 (57. 9, 4. 5, 9. 65) 6k 4 685 20 74 62. 28 (dec. ) 56. 4, 4. 0, 9. 26 (56. 8, 4. 9, 9. 9) 6l 49 724 225 80 67. 4 2 (dec. ) 56. 4, 4. 54, 9. 0 (56. 8, 4. 9, 9. 9) 6m 447 702 225 80 6. 240 (dec. ) 5. 85, 4. 07, 9. 29 (5. 97,. 86, 9. 2) 6n 49 728 27 66 67. 8 229 (dec. ) 55. 09, 4. 0, 9. 24 (55. 09,. 96, 9. 8) 52 22. 2. 2 Α- Α2, (4) (6)., : Α2, Α2, Α2 ;, :.,.,. 2. ( P M R M R ), () P M R 5. 80 20. 0,,. (2) M R, 52 4. 0 4. 52,., [5 ].,,,,,,., Α2,, Α2,,,,., 40 450 cm - ; C 685 72 cm - ; P P C 65 82 cm -. 2. 4 27 256 cm - ; 6a 6n, c= 0-5 mo lgl, L 260 BEL 7404., (L 260 BEL 7404),. Table The inh ibition rate (% ) of the compounds 6a-n (c= 0-5 molgl ) on cell line (L -60 and BEL 7404) Compound 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n L 260 6. 2 69. 5 52. 4 7. 7 60. 7. 89. 9 85. 6 77. 4 64. 8 52. 2 59. 5 64. 8 58. 5 BEL 7404 60. 8 75. 4. 7 68. 5 52. 4 85. 79. 8 86. 84. 9 66. 57. 46. 9 5. 4 60. 5 [ ] ielsen P. E., Egho lm M., Berg R.. et a l.. Science[J ], 99, 254: 497 500 [ 2 ] ielsen P. E., aimm a G.. Chem. Soc. Rev. [J ], 997, 26 (2) : 7 78 [ ] Carlsson C., Jonsson M., o rden B. et a l.. ature[j ], 996, 80: 207 [ 4 ] ZA Yu2en ( ), ZA Guo2 ui( ). E lem ental rganic Chem istry ( ) [M ], Beijing: T sighua U ni2 versity P ress, 998
o. 7 : 52 22 0 [ 5 ] Klenner T., V alenzuele2paz P., Kepp ler B. K. et a l.. Cancer T reaṫ Rev. [J ], 990, 7 (22) : 25 289 [ 6 ] A therton. R., assall C.., L am bert R. W.. J. M ed. Chem. [J ], 986, 29 () : 29 40 [ 7 ] Cassaigne A., L aco ste A. M., euzil E.. A ctual Ch im. T heṙ [J ], 980, 7: 8 22 [ 8 ] LU ai2yan, ZA G an2j ing, C E X in et a l.. Synthetic Comm un. [J ], 998, 28 (0) : 727 76 [ 9 ] D ush indky R., P leven E., eidelberger C.. J. Am. Chem. Soc. [J ], 957, 79: 4 559 4 560 [ 0 ] WA G Yan2Guang ( ), C E Yao2Zu ( ), X IA X in2l iang ( ) et al.. Chem. J. Ch inese U niversities( ) [J ], 995, 6 (6) : 896 899 [ ] WA G Yan2Guang ( ), T IA Xuan ( ), L I J ing2x in ( ) et al.. Chem. J. Ch inese U niversities( ) [J ], 99, 4 (0) : 99 40 [ 2 ] M enger. M., Rourk M. J.. J. rg. Chem. [J ], 997, 62 (26) : 9 08 9 088 [ ] Sem ko T. V., Burov S. V., V lasov G. P.. Edited by Ram age R., Ep ton, R.. Pep ṫ 996, P roc. Euṙ Pep ṫ Symp. 24th [C ], Kingw info rd, U K: M ayflow er Scientific, 996 (pub. 998) : 799 800 [ 4 ] L IU Xue2Jun, C E Ru2Yu.. Ch inese Chem. L etṫ [J ], 999, 0 (9) : 79 740 [ 5 ] L IU Xue2Jun, C E Ru2Yu, W E G L in ong et a l.. eteroatom Chem istry[j ], 2000, (6) : 422 427 [ 6 ] XU E2Jun L iu, RU 2Yu Chen.. Pho spho rus Sulfur Silicon and Relative E lem ent[j ], 200, 76: 0 [ 7 ] lek syszyn J., Subo tkow ska L., M astalerz P.. Synthesis[J ], 979, (2) : 985 986 [ 8 ] Yuan C. Y., W ang G. K., Chen S. J.. Synthesis[J ], 990, (6) : 522 524 [ 9 ] Ko synk ina L., W ang G. K., Chyan L iang T.. T etrahedron L etṫ [J ], 994, 5 (29) : 5 7 5 76 Syn thes is and An ticancer Activ ities of ovel 5-luorourac il--yl Phosphonotr ipeptides L IU Xue2Jun, 2,, C E R u2yu 2, YA G Yuan2Yuan (. S chool of Chem ical E ng ineering, T ianj in U niversity, T ianj in 00072; 2. Institu te and ational K ey L aboratory of E lem ento2 rg anic Chem istry, ankai U niversity, T ianj in 0007;. B ase f or P ostd octoral S cientif ic R esearch ing of T ianj in P harm aceu tical Incoṙ L td. T ianj in 006, Ch ina) Abstract A series of novel 52fluo rou racil22yl pho sphono tripetides w ere syn thesized in yield 52% 8% by pep tide coup ling reaction w ith DCCgB t as the activiating carboxyl group reagen ṫ A ll p roducts w ere characterized by M R, P M R, IR spectra and elem en tal analyses. T he facile m ethod w as u sed to syn thesize 52fluo rou racil22yl acetic acid (an impo rtan t in term ediate ). It w as found tha t tw o m a in facto rs affected the conversion of [ ( 52fluo rou racil22yl ) m ethylfo rm yl ] am inom ethylfo rm ic acid to the t it le com pound s. ne is the app a ren t steric h ind rance of an Α2a ryl group having a bu lky sub stituen t at the o rtho2po sition. A no ther is the electron ic effect of the sub2 stituen t of the Α2aryl group s. T he electron2w ithdraw ing group s decrease the nucleoph ilicity of the am ino group. T he yields of all p roducts con tain ing the strong electron2w ithdraw ing group s w ere low er than tho se of o ther p roducts. T he in vitro an titumo r activity test show ed that som e of the syn thesized compounds are the po ten tial an ticancer agen ṫ Keywords 52 luo rou racil; Pep tide coup ling; Pho sphono tripep tides; A n ticancer activity (Ed. : J, Z)