酰亚胺衍生物合成与抗肿瘤活性评价
摘要
目的:为了寻找新的酰亚胺类抗肿瘤药物,提高萘酰亚胺和邻苯酰亚胺的抗肿瘤活性,降低5-氟尿嘧啶毒副作用。方法:合成了34个目标化合物(其中酰亚胺-多胺缀合物21个,酰亚胺-5-氟尿嘧啶偶联物13个。除MNIS (2-10c)外,其余33个均为新化合物),对目标化合物进行了抗肿瘤活性评价并进行了化合物2-10f凋亡机制研究等。结果:(1)萘酰亚胺-多胺缀合物体外活性试验表明:7个多胺化合物(不含取代基)体外抗肿瘤活性均优于先导化合物萘酰亚胺,尤其是具有4-4-4多胺骨架的化合物(2-10f),对肝癌细胞和正常肝细胞具有选择性,对拓扑异构酶II有抑制作用,能够通过线粒体途径和膜死亡受体途径诱导肿瘤细胞(B16)凋亡;9个(含取代基)萘酰亚胺-多胺缀合物体外抗肿瘤活性优于Amonafide,对肝癌细胞和正常肝细胞具有选择性;取代基的有无及其种类、侧链的不同、链接链的长短、肿瘤细胞的不同对结果都有不同程度的影响。萘酰亚胺多胺缀合物对DNA有嵌入作用;(2)邻苯酰亚胺-多胺缀合物抗肿瘤活性很弱;(3)体内外活性试验表明部分酰亚胺-5-氟尿嘧啶偶联物对肿瘤细胞和肝癌H22有抑制作用,但由于13个酰亚胺-5-氟尿嘧啶偶联物的结构特殊性和化学稳定性,导致它们的体内外活性均不如5-氟尿嘧啶。结论:(1)萘酰亚胺-多胺缀合物具有较好的抗肿瘤活性和较好的选择性,表明萘酰亚胺-多胺缀合物作为抗肿瘤药具有良好的应用前景,值得作为先导化合物进一步研究;(2)邻苯酰亚胺-多胺抗肿瘤活性弱说明多胺对药物运载具有选择性;(3)酰亚胺-5-氟尿嘧啶偶联物的抗肿瘤活性不如5-氟尿嘧啶,说明它们能否释放出5-氟尿嘧啶是合成酰亚胺- 5-氟尿嘧啶偶联物的关键。
Objective: It was to exploit new imide antitumor angents, enchance naphthalimide and phthalimide antitumor activitives and reduce 5-Fluorouracil side effects. Methodes: Thirty-four compounds including twenty-one imide polyamine and thirteen imide 5-Fluorouracil conjugates, which are new compounds exept MINS (2-10c), were synthesized, bioevaluated and studied on 2-10f inducing B16 cell apoptosis. Results: (1) Naphthalimide polyamine conjugates were evaluated in vitro cytotoxicity, the results revealed seven compounds without substitued groups have more effctive than naphthalimide while the others with different ones have more effctive than Amonafide. Importantly, compound 2-10f can inhibit Top.II and induce B16 cell apoptosis via both the mitochondrial and membrane death receptor pathways. Their antitumor activity was effected by substituent groups, chains and tumor cells. They have also exhibited cell selectivity to cancer cells through the human hepatoma BEL-7402 and human normal hepatocyte QSG-7701 screens and intercalated DNA. (2) Phthalimide polyamine conjugates have little antitumor activity. (3) 5-Fu imide conjugates were less effective than 5-Fu in vitro and in vivo because of their structural speciality and chemical stablity, although some of them effectively inhibited the growth of tumor cells in vitro and liver cancer H22 in vivo. Conclusion: (1) Naphthalimide polyamine conjugates which are insteresting anticaner would lead for further study; (2) It can be deduced that the polyamine has selectivity to carry phthalimide with regard that phthalimide polyamine conjugates have little antitumor activity; (3) It was vital that free 5-fluorouracil be released from imide 5-Fluorouracil conjugates under physiological pH conditions as a result that they were less effective than 5-Fu in vivo.
Objective: It was to exploit new imide antitumor angents, enchance naphthalimide and phthalimide antitumor activitives and reduce 5-Fluorouracil side effects. Methodes: Thirty-four compounds including twenty-one imide polyamine and thirteen imide 5-Fluorouracil conjugates, which are new compounds exept MINS (2-10c), were synthesized, bioevaluated and studied on 2-10f inducing B16 cell apoptosis. Results: (1) Naphthalimide polyamine conjugates were evaluated in vitro cytotoxicity, the results revealed seven compounds without substitued groups have more effctive than naphthalimide while the others with different ones have more effctive than Amonafide. Importantly, compound 2-10f can inhibit Top.II and induce B16 cell apoptosis via both the mitochondrial and membrane death receptor pathways. Their antitumor activity was effected by substituent groups, chains and tumor cells. They have also exhibited cell selectivity to cancer cells through the human hepatoma BEL-7402 and human normal hepatocyte QSG-7701 screens and intercalated DNA. (2) Phthalimide polyamine conjugates have little antitumor activity. (3) 5-Fu imide conjugates were less effective than 5-Fu in vitro and in vivo because of their structural speciality and chemical stablity, although some of them effectively inhibited the growth of tumor cells in vitro and liver cancer H22 in vivo. Conclusion: (1) Naphthalimide polyamine conjugates which are insteresting anticaner would lead for further study; (2) It can be deduced that the polyamine has selectivity to carry phthalimide with regard that phthalimide polyamine conjugates have little antitumor activity; (3) It was vital that free 5-fluorouracil be released from imide 5-Fluorouracil conjugates under physiological pH conditions as a result that they were less effective than 5-Fu in vivo.
引文
[1] Armitage B, Photoleavage of nucleic acids, Chemical Reviews, 1998, 98 (3): 1171~1200
[2] [2a]Saito I, Takayama M, Sugiyama H, et al, Photoinduced DNA cleavage via electron transfer: Demonstration that guanine residues located 5' to guanine are the most electron-donating sites, J Am Chem Soc, 1995, 117 (23): 6406~6407 [2b]曲宝源,含硫(氧)稠环萘酰亚胺DNA嵌入剂和光敏切断剂及其抗肿瘤应用,[硕士学位论文],上海;华东理工大学,2003
[3] Matsugo S, Nakana S, Adachi K, et al, 2-(3-methylthiopropyl)-1H-benz [d,e]isoquinoline-1,3-(2H)-dione derivatives as novel photo-induced DNA cleavers, J Chem Soc Chem Commun, 1995: 311~312
[4] Matsugo S, Kodaira K, Saito I, Transfecting activity of photo irradiatedφx 174 DNA in the presence of hydroperoxynaphthalimides, Bioorg Med Chem Lett, 1993, 3 (8): 1671~1674
[5] Saito I, Photogeneration of carbocation via intramolecular electron transfer: Photoinduced DNA alkylation, J Am Chem Soc, 1994, 116 (6): 2653~2654
[6] Sugiyama H, Saito I, Theoretical studies of GG-specific photocleavage of DNA via electron transfer: Significant lowering of ionization potential and 5, -localization of HOMO of stacked GG bases in B-form DNA, J Am Chem Soc, 1996, 118 (30): 7063~7068
[7] Waring W J, Gonzalez A, Jimenez A, Vazquez D, Intercalative binding to DNA of antitumor drugs derived from 3-nitro-1,8-naphthalic acid, Nucleic Acids Res, 1979, 7 (1): 217~230
[8] Mehrotra J, Misra R K, DNA intercalation and photoinduced cleavage by 4-nitro-N-(6-aminohexyl)-1,8-naphthalimide, Nucleosides Nucleotides, 1994, 13 (4): 963~978
[9] Tao Z F, Qian X H, Wei D Z, 1,8-Naphthalimide hydroperoxides as Novel intercalating DNA cleavers, Dyes and pigments, 1996, 31: 245~251
[10]姚伟,含萘酰亚胺型切断剂合成、性能研究,[博士学位论文],上海;华东理工大学,2000
[11]黄霞宇,含萘酰亚胺型切断剂研究,[硕士学位论文],上海;华东理工大学,2002
[12] [12a]Bra?a M F, Ramos A, Naphthalimides as anticancer agents: Synthesis and biological activity, Curr Med Chem-Anti-Cancer Agents, 2001, 1: 237~255 [12b]李志刚,新型萘系硫杂环类化合物的设计、合成及生物活性研究,[博士学位论文],大连;大连理工大学,2005
[13] Bra?a M F, Castellano J M, Roldan C M, et al, Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitro-1,8- naphthalic acid, Cancer Chem other Pharmaco1, 1980, 4: 61~66
[14] Rosell R, CarlesJ, Abad A, et al, Phase I study of mitonafide in 120 hour continuous infusion in non-small cell lung cancer, Invest NewDrugs, 1992, 10: 171~175
[15] Bra?a M F, Sanz A M, Castellano J M, et al, Syntehsis and cytostatic activity of benz[de]isoquinoline-1,3-diones, structure-activity relationships, Eur J Med Chem Chim Ther, 1981, 16: 207~212
[16] Llombart M, Poveda A, Forner E, et al, Phase I study of mitonafide in solid tumors, Invest New Drugs, 1992, 10: 177~181
[17] Diaz-Rubio E, Martin M, Lopez-Vege J M, et al, Phase I study of mitonafide with a 3-day administration schedule: early interruption due to severe central nervous system toxity, Invest New Drugs, 1994, 12: 277~281
[18] Malviya V K, Liu P Y, Alberts D S, et al, Evaluation of Amonafide in cervical cancer, phase II, Am J Clin Oncol, 1992, 15: 41~44
[19] Ratiain M J, Mick R, Berezin F, et al, Phase I study of amonafide dosing based on acetyl at orphenotype, Cancer Res, 1993, 53: 2304~2308
[20] Waring M J, Gonzalez A, Jimenez A, et al, Intercalative binding to DNA of antitumor drugs derived from 3-nitro-1,8-naphthalic acid, Nucleic Acids Res, 1979, 7: 217~230
[21] Feigon J, Deeny W A, Leupin W, et al, Interaction of antitumor drugs with natural DNA: H NMR study of binding mode and kinetics, J Med Chem, 1984, 27: 450~465
[22] Hsiang Y H, Jiang J B, Liu L F, Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs, Mol Pharmacol, 1989, 36: 371~376
[23] Bra?a M F, Castellano J M, Moran M, et al, Synthesis, structure and antitumor activity of new benz[d,e] isoquinoline-1,3-diones, Arzneim-Forsch, 1995, 45: 1311~1378
[24] Zee C R K Y, Cheng C C, N-(Aminoalkyl)imidea ntineoplastic agents. Synthesis and biological activity, J Med Chem, 1985, 28: 1216~1222
[25] Bra?a M F, Moran M, Perez de Vega M F, et al, Synthesis and cytostatic activity of enynes, enediynes and dienediynes linked to intercalators, Tetrahedron, 1995, 51: 9127-9138
[26] Sami S M, D or R T, Albert D S, et al, 2-Substituted 1,2-dihydro-3H-dibenz [de,h] isoquinoline-1,3-diones. A new class of antitumor agent, J Med Chem, 1993, 36: 765~770
[27] Sami S M, Dorr R T, Solyom A M, et al, Amino-substituted 2-[2'-(dimethyl- amino)ethyl 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Synthsis, anti- tumor activity, and quantitative structure-activity relation-ship, J Med Chem, 1995, 38: 983~993
[28] Sami S M, Dorr R T, Alberts D S, et al, Analogues of aminofide and azonafide with novel ring systems, J Med Chem, 2000, 43: 3067~3073
[29] Bra?a M F, Cacho M, Garcia M A, et al, Synthesis, antitumor activity, molecular modeling, and DNA binding properties of a new series of imidazo- naphthalimides, J Med Chem, 2002, 45: 5813~5816
[30] Quaquebeke E V, Mahieu T, Dumont P, et al, 2,2,2-Trichloro-N-({2-[2- (dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity, J Med Chem, 2007, 50: 4122~4134
[31] Denny W A, Dual topoisomerase I/II poisons as anticancer drugs, Exp Opin Invest Drugs, 1997, 6(12): 1845
[32] Bra?a M F, Castellano J M, Moran M, et al, Bisnaphthalimides: a new class of antitumor agents, Anticancer Drug Des, 1993, 8: 257~268
[33] Kaltenbach R F, Sun J H, Chmrney R, et al, Unsymmetrical mono-3-nitro- bis- naphthalimides as anticancer agents, US, 5376664, 1994-12-27
[34] Sun J H, Highly water soluble bisnaphthalimides useful as anticancer agents, US, 5488110, 1996-1-30
[35] Sun J H, Mates J R, Park C H, et al, Process for preparing for bisnaphthalimides containing amino-acid derived linkers, US, 5461176, 1995-10-24
[36] Sun J H, Bis-naphthalimides containing amino-acid derived linkers as anticancer agents, US, 5206249, 1993-4-27
[37] Weis A L, Chen S F, Reddy P S, et al, Diamine platinum naphthalimide complexes as antitumor agents, US, 5561042, 1996-10-1
[38] Sun J H, Highly water soluble bisnaphthalimides useful as anticancer agents, WO, 9312092, 1993-6-24
[39] Keihauer G, Romerdahl C, Bra?a M F, et al, New bisnaphthalimides for the treatment of cancer, WO, 9505365, 1995-2-23
[40] Weis A L, Chen S F, Reddy P S, et al, Bis-naphthalimide with linkers having heteroatoms and uses there of WO, 9603384, 1996-2-8
[41] Keihauer G, Romerdahl C, Bra?a M F, et al, Bisnaphthalimides for the treatment of cancer, US, 5616589, 1997-4-1
[42] Bra?a M F, Castellano J M, Moran M, et al, Bis-naphthalimides. 2. synthesis and biological activity of 5,6-acenaphthalimidoalkyl-1,8-naphthalimidoakyl amines, Eur J Med Chem, 1995, 30: 235~239
[43] Bra?a M F, Castellano J M, Moran M, et al, Bis-naphthalimides 3: Synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl]alkanedimines, Anticancer Drug Des, 1996, 11: 297~309
[44] Bra?a M F, Castellano J M, Perron D, et al, Chromophore-modified bis- naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]iso- quinoline-1,3- diones, J Med Chem, 1997, 40: 449~454
[45] Bousquet P F, Bra?a M F, Conlon D, et al, Preclinical Evaluation of LU-79553; a novel bisnaphthalimide with potent antitumor activity, Cancer Res, 1995, 55: 1176~1180
[46] [46a]Baily C, Bra?a M F, Waring M J, Sequence-selective intercalation of antitumor bisnaphthalimides into DNA evident for an approach via the major groove, Eur J Biochem, 1996, 240: 195~208 [46b]贺茜,李永刚,抗肿瘤药双萘酰亚胺的研究进展,广州化学,2002,27(2):48~52
[47] Chen S F, Behrens D L, Behrens C H, et al, XB596, a promising bisnaphthal- imide anticancer agent, Anti-Cancer Drugs, 1993, 4: 447~457
[48] Kirshenbaum M R, Chen S F, Behrens C H, et al, (R,R)-2,2'- [1,2-ethanediyl bis[imino(1-methyl-2,1-ethanediyl)]-bis[5-nitro-1H-benz[de]isoquino-line-1,3- (2H)-dione]dimethanesulfonate(DMP-840), a nove bisnaphthalimide with potent nonselective tumoricidal activity in vitro, Cancer Res, 1994, 54: 2199 ~2206
[49] McRipley R J, Burns-Horwitz P E, et al, Efficacy of DMP-840, a novel bisnaphthalimide cytotoxic agent with human solid tumor xenograft selectivity, Cancer Res, 1994, 54: 159~164
[50] Houghton P J, Cheshire P J, Hallman J C, et al, Evaluation of a novel bis- naphthalimide anticancer agent, DMP-840, against human xenograft derived from adult, juvenile and pediatric cancers, Cancer Chemother Pharmacol, 1994, 33 (4): 265 ~272
[51] Lai C M, Garner D M, Gray J E, et al, Determination of bisnafide, a novel bisnaphthalimide anticancer agent, in human plasma by high performance liquid chromatography with UV detection, J Pharm Biomed Anal, 1998, 17 (3): 427~434
[52] Kobb P W, Degen D R, Clark G M, et al, Activity of DMP-840, a new bis- naphthalimide, on primary human tumor colony-forming units, J Natl Cancer Inst, 1994, 86 (19): 1462~1465
[53] Nitiss J L, Zhou J F, Rose A, et al, The bis(naphthalimide)DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase II, Biochemistry, 1998, 37: 3078~3085
[54] Gallego J, Reid B R, Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale, Biochemistry, 1999, 38: 15104~15115
[55] Bra?a M F, Castellano J M, Sanz A M, et al, Synthesis and cytostatic activity of benz [d,e] isoquinolin-1.3-dione, structure-activity relationships, Eur J Med Chem, 1981, 16: 207~212
[56] McRipley R J, Burns-Horwitz P E, Czerniak P M, et al, Efficacy of DMP 840: a novel bisnaphthalimide cytotoxic agent with human solid tumor xenograft selectivity, Cancer Res, 1994, 54 (1): 159~164
[57] Bra?a M F,Cacho M, Garcia M A, et al, New analogues of amonafide and elinafide, containing aromatic heterocycles: synthesis,antitumor activity,molecular modeling, and DNA binding, J Med Chem, 2004, 47: 1391~1399
[58] Pavlov V, Lin Pl K T, Rodilla V, Cytotoxicity, DNA binding and localisation of novel bisnaphthalimidopropyl polyamine derivatives, Chemico-Biological Interactions, 2001, 137: 15~24
[59] McMasters S, Kelly L A,Ground-state Interactions of spermine- substituted naphthalimides with mononucleotides, J Phys Chem B, 2006, 110: 1046~1055
[60] Alison Rodger, Steven Taylor, Gareth Adlam, et al, Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine, Bioorg Med Chem, 1995, 3(6): 861~872
[61] Morris, D R, Marton, L J eds, Polyamines in Biology and Medicine, Marcel Dekker, New York (1981)
[62] Tabor C W, Tabor H, Polyamines in microorganisms, Microbiol Rev, 1985, 49 (1): 81~99
[63] Vassylyev D G, Tomitori H, Kashiwagi K, et al, Crystal structure and mutational analysis of the Escherichia coli putrescine receptor: structural basis for substrate specificity, J Biol Chem, 1998, 273: 17604~17609
[64] [64a]Tabor C W, Rabor H, 1,4-Diaminobutane (putrescine), spermidine, and spermine, Annu Rev Biochem, 1976, 45: 285~306 [64b]Marton L J, Pegg A E, Polyamines as targets for therapeutic intervention, Annu Rev Pharmacol Toxicol, 1995, 35: 55~91 [64c]Pegg A E, Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy, Cancer Res, 1988, 48: 759~774 [64d]Morgan D M L(Ed), Polyamine protocols in methods in molecular biology, (Series Ed: JM Walker), vol 79, Humana Press, Totowa, New Jersey, 1998
[65] [65a]Schipper R G, Penning L C,Verhofstad A A, Involvement of polyamines in apoptosis. Facts and controversies: effectors or protectors? Semi Cancer Biol, 2000, 10 (1): 55~68 [65b]Soulet D, Rivest S, Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system, J Cell Biol, 2003, 162 (2): 257~268
[66] Pieter smid, Hein K A C, Coolen, Hiskias G, et al, Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[ω-(1H-indol-3-yl) alkyl]piperazines, novel potential antipsychotics combining potent dopamineδ2 receptor antagonism with potent serotonin reuptake inhibition, J Med Chem, 2005, 48: 6855~6899
[67] Tabor H, Tabor C W, Biosynthesis and metablism of 1,4-diaminobutane, spermidine, spermine, and relatedamines Adv, Enzymol Relat Areas Mol Biol, 1972, 36: 203~268
[68]竺心影,邵以德,药理学[M](第二版),北京:人民卫生出版社,1986
[69] Cullis P M, Green R E, Merson Davies L, et al, Probing the mechanism of transport and compartmentalisation of polyamines in mammalian cells, Chem Biol, 1999, 6: 717~729
[70] Seiler N, Dezeure F, Polyamine transport in mammalian cells, Int J Biochem, 1990, 22 (3): 211~218
[71] Moulinoux J P, Darcel F, Quemener V, human glioblastoma in nude mice by polyamine deprivation, Anticancer-Res, 1991, 11 (1): 175~179
[72] Phanstiel O, IV, Price H L, Wang L, et al, The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA-intercalator) conjugates, J Org Chem, 2000, 65: 5590~5599
[73] Wang L, Price H L, Juusola J, et al, Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA- intercalator conjugates, J Med Chem, 2001, 44 (22): 3682~3691
[74] Wang C J, Delcros J G, Biggerstaff J, et al, Synthesis and biological evaluation of N1-(Anthracen-9-ylmethyl)triamines as molecular recognition elements for the polyamine transporter, J Med Chem, 2003, 46 (13): 2663~2671
[75] Wang C J, Delcros J G, Biggerstaff J, et al, Molecular requirements for targeting the polyamine transport system. Synthesis and biological evaluation of polyamine-anthracene conjugates, J Med Chem, 2003, 46 (13): 2672~2682
[76] Wang C J, Delcros J G, Cannon L, et al, Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2003, 46(24): 5129~5138
[77] Gardner R A, Delcros J G, Konate F, et al, N1-Substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2004, 47 (24): 6055~6069
[78] Horn Y, Beal S L, Walach N, et al, Further evidence for the use of polyamines as biochemical markers for malignant tumors, Tumors Cancer Res, 1982, 42: 3248~3251
[79] Xie S Q, Liu G C, Ma Y F, et al, Synergistic antitumor effects of anthracenylmethyl homospermidine and alpha-difluoromethylornithine on promyelocytic leukemia HL60 cells, Toxicology in Vitro, 2008, 22: 352~358
[80] Wang J H, Xie S Q, Li Y J, et al, Synthesis and evaluation of unsymmetrical polyamine derivatives as antitumor agents, Bioorg Med Chem, 2008, 16: 7005~7012
[81] Smith M K, Goral M A, Wright JH, et al, Ornithine decarboxylase overexpression leads to increased epithelial tumor invasiveness, Cancer Res, 1997, 57: 2104~2108
[82] Fujimoto S, Igarashi K, Shrestha R D, et al, Antitumor effects of two polyamine antimetabolites combined with mitomycin C on human stomach cancer cells xenotransplanted into nude mice, Int J Cancer, 1985, 35 (6): 821~825
[83] Volkov N, Goldman S S, Flamm E S, et al, Labeled putrescine as a probe in brain tumors, Science, 1983, 221: 673~675
[84] Robert A, Casero, J, Patrick M W, Terminally alkylated polyamine analogues as chemotherapeutic agents, J Med Chem, 2001, 44 (1): 1~26
[85] Marton LJ, Pegg A E, Polyamines as targets for therapeutic intervention, Ann Rev Pharmacol Toxicol, 1995, 35: 55~91
[86] [86a]Casero RA, Go B, Theiss HW, et al, Cytotoxic response of the relatively difluoromethylornithine-resistant human lung tumor cell line NCI H157 to the polyamine analogue N1,N8-Bis (ethyl) spermidine, Cancer Res, 1987, 47 (15): 3964~3967 [86b]Bergeron R J, Neims A H, McManis J S, et al, Synthetic polyamine analogs as antineoplastics, J Med Chem, 1988, 31 (6): 1183~1190 [86c]Edwards M L, Prakash N J, Stemerick D M, et al, Polyamine analogs with antitumor activity, J Med Chem, 1990, 33 (5): 1369~1375 [86d]Bergeron RJ, McManis JS, Weimar WR, Schreier KM, et al, The role of charge in polyamine analog recognition, J Med Chem, 1995, 38 (13): 2278~2285 [86e]Igarashi K, Koga K, He Y, et al, Inhibition of the growth of various human and mouse tumor cells by 1,15-bis(ethylamino)-4,8,12- triazapen- tadecane, Cancer Res, 1995, 55: 2615~2619 [86f] Bergeron R J, Feng Y, Weimar W R, et al, A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics, J Med Chem, 1997, 40 (10): 1475~1494
[87]刘晶华,王岩,刘俊亭,多胺合成和代谢中抗癌药作用新靶点的研究进展,中南药学,2005,3(2):113~115
[88] Gilad G M, Balakrishnan K, Gilad V H, The course of putrescine immunocytochemical appearance in neurons, astroglia and microglia in rat brain cultures, Neurosci Lett, 1999, 268(1): 33~36
[89] Soulet D, Rivest S, Polyamines play a critical role in the control of the innate immune response, J Cell Biol, 2003, 162 (2): 257~268
[90] Masuko T, Kusama E K, Sakata K, et al, J Polyamine transport, accumulation, and release in brain, NeuroChem, 2003, 84 (3): 610~617
[91] Adibhatla R M, Hatcher J F, Sailor K, et al, Polyamine and central nervous system injury: spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats, Brain Res, 2002, 938 (12): 81~86
[92] Gibson D A, Barton R H, Prendergast M A, et al, Polyamines contribute to ethanol withdrawal-induced neurotoxicity in rat hippocampal slice cultures through interactions with the NMDA Receptor, Alcohol Clin Exp Res, 2003, 27 (7): 1099~1106
[93]杨筱珍,陈耀星,佘锐萍,等,多胺与细胞凋亡,动物医学进展,2004,25(2):11~14
[94] Sriptiya V, Veena V, Akira S, et al, Antisense recognition of the HER-2 mRNA: Effects of phosphorothioate substitution and polyamines on DNA·RNA, RNA·RNA, and DNA·DNA duplex stability, Biochemistry, 2005, 44: 303~312
[95]梁峰,魏俊,李朝阳,等,含羟基环多胺金属配合体系切割DNA及其体外抗肿瘤活性研究,高等学校化学学报,2004,25(3):470~473
[96] Rodger A, Taylor S, Adlam G, et al, Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine, Bioorg Med Chem, 1995, 3(6): 861~872
[97] Dipanjan Sengupta, Andrei Blasko, Thomas B, A microgonotropen pentaaza pentabutylamine and its interactions with DNA, Bioorg Med Chem, 1996, 4 (6): 803~813
[98] [98a]Miguel F, Bra?a M C, Maro A, et al, New analogues of Amonafide and Elinafide, containing aromatic heterocycles: Synthesis, antitumor activity, molecular modeling, and DNA binding properties, J Med Chem, 2004, 47: 1391~1399 [98b]Dance A M, Ralton L , Fuller Z, et al, Synthesis and biological activities of bisnaphthalimido polyamines derivatives: cytotoxicity, DNA binding, DNA damage and drug localization in breast cancer MCF 7 cells Biochem, Pharmacology, 2005, 69: 19~27
[99] Heby O, Persson L, Molecular genetics of polyamine synthesis in eukaryotic cells trends in biochemical, Science, 1990, 15: 153~158
[100] Hu X, Washington S, Michael F, et al, Interaction between polyamines and the mitogen-activated protein kinase pathway in the regulation of cell cycle variables in breast cancer cells, Cancer Res, 2005, 65 (23): 11026~11033
[101] Bitonti A J, Dumont J A, Bush T L, et al, Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (plasmodium falciparum) in vitro and in combination withα-difluoromethylornithine cure murine, Malaria Proc, Natl Acad Sci, USA, Medical Sciences, 1989, 86 (2): 651~655
[102] Adina R, Rebecca D P, Louis M, et al, Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine derivatives, J Med Chem, 2003, 46: 542~557
[103] Birkholtz L M, Wrenger C, Joubert F, et al, Parasite- specific inserts in the bifunctional sadenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparu, Biochem J, 2004, 377: 439~448
[104] Piero S D, Ghezzi L, Melchior A, et al, Solvent role on cobalt(II) dioxygen carriers based on simple polyamine ligands, Helvetica Chemica Acta, 2005, 88: 839~853
[105]程鹏飞,多胺-药物缀合物的合成及其生理活性研究,[硕士学位论文],开封;河南大学,2006
[106] [106a]Duschinsky R, et al The synthesis of 5–fluoropyrimidenes, J Am Chem Soc, 1957, 79: 4559~4560 [106b]吴林艳,5-氟尿嘧啶衍生物的合成及抗癌活性研究,[硕士学位论文],成都;四川大学,2003 [106c]李小菊,5-氟尿嘧啶含磷衍生物的合成及其抗肿瘤活性研究,[硕士学位论文],武汉;华中师范大学,2004
[107] Hiller S A, Zhuk R A, Lidak M Y, et al, Analogs of pyrimidine, nucleoside 1-N-(ct-furanydyl)-derivatives of natural pyrimidine, bases and their antimetabolites, SSSR 1967, 176: 332~335
[108]张志义,孙燕,恶性肿瘤化学治疗学,第1版,上海:上海科学技术出版社,1981,11:36
[109] Cook P, Holman J K, Ramer J, et al, Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5'-deoxy-5-fluoropyrimidine nucleosides, J Med Chem, 1979, 22: 1330~1335
[110] Eda H, Tanaka Y, Shitsuka I, 5'-Deoxy-5-fluorouridine improves cachexia by a mechanism independent of its antiproliferative action in colon 26 adenocarcinoma-bearing mice, H Pharmacol, 1991, 29: 1~6
[111] Hoshi A, Ligo M, Yoshida M, et al, Antitumor actrvity of carbamoyl derivatives of 5-fluorouracil oral administration, Jpn J Cancer Res, 1975, 66: 673~674
[112] Hoshi A, Ligo M, Nakamura A, et al, Antitumor activity of 1-hexcarbamoyl -5- fluorouraeil in a variety of expermental tumors, Jpn J Cancer Res, 1976, 67: 725~731
[113] HCFU Clinical Study Group, Absorption and excretion of new oral antitumor drug, 1-hexylcarbamoyl-5-fluorouracil (HCFU), in cancer patients, Jpn J Clin Oncol, 1980, 10: 83~92
[114] Ligo M, Hoshi A, nakamura A, et al, Antiumor activity of L-alkylcarbamoyl derivatives of 5-fluorouracil in a variety of mouse tumors, Cancer Chemother Pharmacol, 1978, 1: 203~208
[115] Ligo M, Hoshi A, nakamura A, et al, Absorption and excretion of a new oral antitumor drug, J Pharm Dyn, 1978, 1: 49~54
[116] Koyama Y, 1-Hexylcarbamoyl-5-fluorouracil (HCFU) a masked 5-fluorinated pyrimidine, Cancer Treat Rev, 1981, 8: 147~156
[117]靳清泉,赵媞萍,卡莫氟的III期临床实验总结报告,中国肿瘤临床,2002,29(7):501~503
[118] Bajetta E, Camaghi C, SommaL, et al, A pilot safety study of ca picetabine, a new oral fluoropyrimidine, inpatients with adcanced neoplastic disesease, Tumori, 1996, 82: 450~452
[119] [119a]郭宗儒编著,药物化学总论,北京:中国医药科技出版社,1994, 304~311 [119b]王卫东,谭祥中,胡茂林,5-氟尿嘧啶衍生物的研究进展,化学试剂,2006,28(11):653~656 [119c]扈靖,刘彦钦,韩士田,等,5-氟尿嘧啶衍生物的合成及其抗癌活性研究进展,河北师范大学学报(自然科学版),2006,30(5):580~584
[120]海俐,吴林艳,黄娟,等,N1-(芳)烷氧酰基烷酰基-5-氟尿嘧啶的合成,四川大学学报(医学版),2004,35(4):552~554
[121] Fredric M M, Michael J, Rourk Synthesis and Reactivity of 5-Fluorou- racil /Cytarabine Mutual Prodrugs, J Org Chem, 1997, 62: 9083~9088
[122] Chung I D, Jung E Y, Lee Y W, et al, Syntheses, antitumor activities, and antiangiogenesis of exo-3,6-Epoxy-1,2,3,6–tetrahydro-phthalimidoethanoyl 5- fluorouracil and its polymers, Journal of Polymer Science: Part A: Polymer Chemistry, 2000, 38: 4272~4281
[123] Bajetta E, Camaghi C, SommaL, et al, A pilot safety study of ca picetabine, a new oral fluoropyrimidine, inpatients with adcanced neoplastic disesease, Tumori1, 1996, 82: 450~452
[124] Shimma N, MedaI U, Metal A, The design and synthesis of a new tumor- selective fluoropyrimidine carbamate capecitabine, Bioorg Med Chem, 2000, 8 (7): 1697~706
[125]金小玲,张辅民,田瑄,等,新的4′-去甲表鬼臼衍生物的2DNMR研究,波谱学杂志,2002,19(3):259~264
[126]刘彦钦,张慧娟,韩士田,5-氟尿嘧啶-卟啉化合物的合成及抗癌活性,有机化学,2002,22(4):279~282
[127]杨秋青,刘彦钦,氯代苯基卟啉-5-氟尿嘧啶化合物的光谱研究,分析化学,2001,29(9):1016~1020
[128]邱红,刘彦钦,韩士田,双氯代苯基卟啉-5-氟尿嘧啶化合物的合成,化学试剂,2001,23(6):346~348
[129]胡泉源,黄素秋,5, 10, 15, 20-四[邻(5-氟尿嘧啶-1-)乙酰苯胺]苯基卟啉的合成,湖北医科大学学报,1998,9(4):305~307
[130]王昕,卟啉化合物合成的最新研究进展,湘潭师范学院学报(自然科学版),2001,23(3):52~59
[131]金晓敏,吴健,卟啉类光敏药物的研究进展,中国药物化学杂志,2002 ,12(1):52~56
[132]王杏乔,高爽,于连香,等,卟啉纳米材料的新法合成,高等学校化学学报,1998,19(6):854~857
[133]李屏英,林坤华,黄素秋,5, 10, 15-三对磺酰-5′-氟尿嘧啶苯基-20-对磺酸苯基卟啉的合成及抗肿瘤作用的研究,武汉大学学报(自然科学版),1985,31(20):111~116
[134]黄素秋,刘德伟,姜兆慈,等,卟啉胆甾酯及其金属络合物的合成、结构与光敏活性,药学学报,1989,24 (11):817~819
[135]何书美,刘彦钦,邱红,等,氯代5-氟脲嘧啶卟啉的红外光谱特性的研究,光谱学与光谱分析,2003,23 (1) :49~53
[136] Zhou R X,Ye D K, Liu G W, et al, Synthesis and biological activity of polycster containing 5-fluorourail in the main chain C// Preprint of 27th international symposium on macromolecules, France: Strasbourg, 1981, 1335~1339
[137]卓仁禧,陈衢生,刘高伟,等,主链含5-氟尿嘧啶聚酯的合成,高分子学报,1988,32(1):11~15
[138]卓仁禧,陈衢生,刘高伟,主链含5-氟尿嘧啶聚芳酯的合成,武汉大学学报:自然科学版,1983,29(3):114~118
[139]范昌烈,麦才淞,徐建军,等,1,3-羟烷基5-氟尿嘧啶与二氯磷酸酯缩聚物的合成,高分子学报,1985,29(1):77~80
[140]周念恩,陈衢生,卓仁禧,二羟烷基嘧啶与N,N′双-(二氯乙基)二氯磷酰胺缩聚物的合成及其抗肿瘤活性研究,高分子学报,1987,31(6):417 ~422
[141]陈衢生,卓仁禧,周念恩,5-氟尿嘧啶、腺嘧啶、胸腺嘧啶的N-羟烷基乙酰胺双取代衍生物的合成,武汉大学学报(自然科学版)1986,32(1):65~69
[142]朴爱植,孙树门,5-氟尿嘧啶齐聚物的合成,高分子学报,1983,27(1):74~77
[143]朴爱植,孙树门,含5-氟尿嘧啶的聚硅氧烷的合成,高分子学报,1984,28(1):21~26
[144]朱卡,汤谷平,陈启琪,等,5-氟尿嘧啶-聚α,β-(2-羟乙基)–DL-天冬酰胺的合成及体内释放的研究,药学学报,1998,33(12):906~909
[145]张静夏,潘仕荣,王琴梅,等,5-氟脲嘧啶-聚[(2-羟乙基)-L-谷酰胺]的合成及释药研究,中山医科大学学报,2002,23(5):19~21
[146]张静夏,潘仕荣,王琴梅,等,5-氟脲嘧啶-聚[N-(2-羟-乙基)–L-谷酰胺]的合成及缓释性能研究,广州化学,2002,27(2):1~5
[147]卓仁禧,范昌烈,赵儒林,含5-氟尿嘧啶的氨基酸衍生物的合成及其肿瘤活性研究高等学校化学学报,1986,7(6):508~512
[148]赵儒林,氨基酸5-氟尿嘧啶酯类衍生物的合成及其肿瘤活性研究,高等学校化学学报,1989,10(6): 60~608
[149]卓仁禧,刘高伟,彭普平,5-氟尿嘧啶-N-甲酰基氨基酸短肽的合成及抗肿瘤活性,高等学校化学学报,1991,12(4):555~559
[150]叶发青,合成5-氟尿嘧啶-N-甲酰基异亮氨酸的新方法,化学试剂,1996,18(5):308
[151]罗毅,卓仁禧,范昌烈:短肽5-氟尿嘧啶前体药物的合成及其抗肿瘤活性研究,高等学校化学学报,1994,15(4):545~547
[152]刘学军,陈茹玉,杨媛媛,5-氟尿嘧啶-1-基磷二肽化合物的合成及抗癌活性,天津大学学报,2001,34(6):745~748
[153]刘学军,陈茹玉,杨媛媛,5-氟尿嘧啶-1-基磷三肽化合物的合成及抗癌活性,高等学校化学学报,2002,23 (7):1299-1303
[154]胡喜钢,汪森明,张起兴,等:以磺胺嘧啶为载体的氟尿嘧啶导向药物的合成,2002,22(11):1402~1404
[155]石德清,魏佳,谭效松,新型含环状α-羟基膦酸酯的N1 -(四氢呋喃-2-基)-5-氟尿嘧啶衍生物的合成,有机化学,2005,25(12):1602~1605
[156]石德清,陈琦,李中华,含氨基酸席夫碱的5-氟尿嘧啶衍生物的合成及其抗肿瘤活性,有机化学,2005,25(5):549~553
[157] Wang W D, Hu M L, Synthesis and crystal structure of tetraaqua–copper(II)bis(5-fluorouracil-1-acetate)tetrahydrate, J Chin Struct Chem, 2006, 25 (5): 562~566
[158]宋之刚,张伏龙,5-氟尿嘧啶-1-乙酸锌单晶的合成、结构及抗菌活性研究,甘肃教育学院学报,2003,17(3):32~36
[159]李娟,李静,齐燕飞,等,12-钨硼酸5-氟尿嘧啶盐的合成及抗癌活性研究,高等学校化学学报,2004,25(6):1010~1012
[160]王彦广,田暄,李景新,等,具有抗癌活性氟脲嘧啶自旋标记衍生物的合成,高等学校化学学报,1992,13(12):1561~1563
[161]王彦广,田暄,李景新,等,5-氟脲嘧啶自旋标记衍生物的合成与抗肿瘤活性,高等学校化学学报,1993,14(10):1399~1401
[162]毛曼君,田暄,陈耀祖,5-氟脲嘧啶自旋标记衍生物的合成及其抗肿瘤活性研究,高等学校化学学报,1998,19(3):395~398
[163]孙昌俊,薛军,王义贵,等,5-氟脲嘧啶衍生物的合成及其抗肿瘤活性,中国药物化学杂志,1998,8(2):91~95
[164]孙昌俊,李洪祥,戚聿新,等,芳酰基氟脲嘧啶衍生物的合成及其抗肿瘤活性,中国药物化学杂志,2000,10(3):164~167
[165]匡永清,孙晓莉,何炜, 6-[N-(4-氨基丁基)-N-乙基]氨基-2,3-二氢-1,4-酞嗪二酮的合成,第四军医大学学报, 2002, 23(11):1037~1039
[166]匡永清,张生勇,蔚琳琳,N-(4-溴丁基)邻苯二甲酰亚胺的合成化学试剂, 2001,23(6):359~361
[167] Chong H S, Suzy V, Brechbiel T, et al, Synthesis and potent antitumor activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives, J Med Chem, 2004, 47: 5230~5234
[168] Jasys V J, Kelbaugh P R, Nason D M, et al, Novel quaternary ammonium salt-containing polyamines from the Agelenopsis aperta funnel-web spider, J Org Chem, 1992, 57: 1814~1820
[169] Kamal A, Reddy B S N, Reddy G S K, et al, Design and synthesis of C-8 linked pyrrolobenzodiazepine-naphthalimide hybrids as antitumour agents, Bioorganic & Medicinal Chemistry Letters, 2002, 12: 1933~1935
[170] Mosmann T, Rapid colorimetric assay for cellular growth and survival. Application to proliferation and cytotoxicity assays, J Immunol Meth, 1983, 65: 55~63
[171] Karigiannis G, Papaioannou D, Structure, biological activity and synthesis of polyamine analogues and conjugates, Eur J Org Chem, 2000, 10: 1841~1863
[172] Rodriguez L, Alves S, Lima J C, et al, Supramolecular interactions of hexacyanocobaltate(III) with polyamine receptors containing a terminal anthracene sensor, J Photochem And Photobiol, 2003, 159: 253~258
[173] Cullis P M, Green R E, Merson Davies L, et al, Probing the mechanism of transport and compartmentalisation of polyamines in mammalian cells, Chem Biol, 1999, 6: 717~729
[174] Xu J X, Wang C, Zhang Q H, Synthesis, structure and spectral properties of 1,5-benzothiazepines-alpha-phenyl-beta-lactams, Chin J Chem, 2004, 22 (9): 1012~1018
[175] [175a]方浩,夏霖,江振洲,等,化学学报,N-(取代苯基哌嗪基烷基)酰胺类α1-受体拮抗剂的设计、合成及生物活性研究,2002,60(4):725~731 [175b]Tahtaoui C, Parrot I, Klotz P, et al, Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor, J Med Chem, 2004, 47(18): 4300~4315 [175c]Ryckebusch A, Deprez-Poulain R, Maes L et al, Synthesis and in vitro and in vivo antimalarial activity of N1-(7-Chloro- 4-quinolyl)-1,4-bis(3-aminopropyl) pipera- zine Derivatives, J Med Chem, 2003, 46(4): 542~557 [175d]Cao J J, Kulkarni SS, Husbands M S et al, Dual Probes for the Dopamine transporter andδ1 receptors: Novel piperazinyl alkyl-bis(4'-fluoro-phenyl)amine analogues as potential cocaine-abuse therapeutic agents, J Med Chem, 2003, 46 (13): 2589~2598
[176] Basuroy U K, Gerner E W, Emerging concepts in targeting the polyamine metabolic pathway in epithelial cancer chemoprevention and chemotherapy, J Biochem, 2006,139: 27~33
[177] Eguchi Y, Srinnivasn A, Tomaselli KJ, et al, ATP-dependent steps in apoptotic signal transduction, Cancer Res, 1999, 59: 2174~81
[178] Gardner R A, Delcros J G, Konate F, et al, N1-substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2004, 47: 6055~6069
[179] Bra?a M F, Cacho M, Gradillas A, et al, Intercalators as anticancer drugs, Current Pharmaceutical Design, 2001, 7: 1745~1780
[180] Claus A M, Seidel A S, Markus H M, Nucleobase-specific quenching of fluorescent dyes. 1. Nucleobase one-electron redox potentials and their correlation with static and dynamic quenching efficiencies, J Phys Chem, 1996, 100: 5541~5553
[181] Reid G D, Whittaker D J, Day M A, et al, Ultra fast electron-transfer reactions between thionine and guanosine bases, J Am Chem Soc, 2001, 123 (28): 6953~6954
[182] Phanstiel O IV, Price H L, Wang L, et al, The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA- intercalator) conjugates, J Org Chem, 2000, 65: 5590~5599
[183] Zhu H, Huang M, Yang F, et al, R16, a novel amonafide analogue, induces apoptosis and G2/M arrest via poisoning topoisomerase II, Mol Cancer Ther, 2007, 6: 484~495
[184] Xie S Q, Cheng P F, Wang C J, Synthesis and bioevaluation of N-(arylalkyl)-homospermidine conjugates, Bioorg Med Chem Lett, 2007, 17: 4471~4475
[185] Xie S Q, Liu G C, Wang C J, Synergistic antitumor effects of anthracenylmethyl homospermidine and alpha-difluoromethylornithine on promyelocytic leukemia HL60 cells, Toxicity in vitro, 2008, 22 (3): 352~358
[186] Liu J, Li Y, Ren W, Apoptosis of HL-60 cells induced by extracts from narcissus tazetta var chinensis, Cancer Lett, 2006, 242: 133~140
[187] Eguchi Y, Srinnivasn A, Tomaselli KJ, et al, ATP-dependent steps in apoptotic signal transduction, Cancer Res, 1999, 59: 2174~81
[188]董永军,袁国峰,庞立营,合成邻苯二甲酰亚胺的工艺改进,辽宁化工,2006,35(10):574~576
[189] Alexandre L M, Lídia Lima M, Barreiro E J, et al, Design, synthesis and antiinflammatory activity of novelphthalimide derivatives, structurally related to thalidomide, Bioorg Med Chem Lett, 2005, 15:1169~1172
[190] Ragavendran J V, Sriram D, Yogeeswari P, et al, Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore, Eur J M Chem, 2007, 42: 146~151
[191] Gobec S, Plantan I, Mravljak J, et al, Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall, Eur J M Chem, 2007, 42: 54~63
[192] Alaa A M, Abdel A, Novel and versatile methodology for synthesis of cyclic imides and evaluation of their cytotoxic, DNA binding, apoptotic inducing activities and molecular modeling study, Eur J M Chem, 2007, 42: 614~626
[193] Hall I H, Wong O T, Scovill J P, The cytotoxicity of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide, Biomed & Pharmacother, 1995, 5: 251~258
[194] Yasumoto M, Yamawaki I, MarunaKa T, et al, Studies on antitumor agents. 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluoro- uracil and 1,3-bis(tetrahydro-2-furanyl) -5- fluorouracil, J Med Chem, 1978, 21 (8): 738~741
[195] Schoichiro O, Yoshimasa I, Haruo M, et al, 5-Fluorouracil, derivatives. I. The synthesis of 1-carbamoyl-5-fluorouracils, Bull Chem Soc Jpn, 1977, 50 (9): 2406~2412
[196] Chakravarty P K, Carl P L, Weber M J, et al, Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard, J Med Chem, 1983, 26 (5): 633~638
[197] Zhang C X, Chen R Y, Tang C C, et al, Synthesis of sulfur analogus of cyclic phospholipid conjugated with N1-(2-furanidyl)-N3-(2-hydroxyethyl)-5- fluorouracil, Phosphorus, Sulfur, and Silicon and the Related Elements, 1998, 132 (1): 155~161
[198]许新华,陈焕明,陈茹玉,N-3-羟烷基替加氟制备方法改良及其环甘油磷脂缀合物的合成与抗肿瘤活性,高等学校化学学报,2000,21(9):1410~1412
[199] Liu Z F, Stephen R, Synthesis and release of 5-fluorouracil from poly (N-vinylpyrrolidinone) bearing 5-fluorouracil derivatives, J Control Rel, 2002, 81: 91~99
[200]王玉霞,赵瑾,孙心奇,等,N-哌嗪烷基酰胺类化合物的合成与DNA相互作用及生理活性,有机化学,2006, 26: 1066~1072
[201] Bra?a M F, Castellano J M, Perron D, Maher C, et al, Chromophore-modified bis-naphthalimides: Synthesis and anti-tumor activity of bis-[de,h]isoquino- line-1,3-diones, J Med Chem, 1997, 40, 449~454
[202] Lee N J, Kim K H, Rhew H Y, et al, Synthesis and biological activity of medium molecular weight polymers containing 3,6-endo-methylene-1,2,3,6- tetrahydrophthalimido-butanoyl-5-fluorouracil, Polym Int, 2000, 49: 1702~ 1708
[203]周周冰,许新华,张秋林,等,磷脂核苷缀合物甘油结构修饰新方法及应用,有机化学, 2004,24(1):88~92
[204] Zhang C X, Zhang Z B, Chen R Y, et al, Synthesis of 1,2- and 1,3-cyclic phospholipid conjugates of N1-(2-Furanidyl)-N3-(2-hydroxyethyl)-5-fluoro- uracil, Heteroat Chem,1998, 9 (3): 295~298
[2] [2a]Saito I, Takayama M, Sugiyama H, et al, Photoinduced DNA cleavage via electron transfer: Demonstration that guanine residues located 5' to guanine are the most electron-donating sites, J Am Chem Soc, 1995, 117 (23): 6406~6407 [2b]曲宝源,含硫(氧)稠环萘酰亚胺DNA嵌入剂和光敏切断剂及其抗肿瘤应用,[硕士学位论文],上海;华东理工大学,2003
[3] Matsugo S, Nakana S, Adachi K, et al, 2-(3-methylthiopropyl)-1H-benz [d,e]isoquinoline-1,3-(2H)-dione derivatives as novel photo-induced DNA cleavers, J Chem Soc Chem Commun, 1995: 311~312
[4] Matsugo S, Kodaira K, Saito I, Transfecting activity of photo irradiatedφx 174 DNA in the presence of hydroperoxynaphthalimides, Bioorg Med Chem Lett, 1993, 3 (8): 1671~1674
[5] Saito I, Photogeneration of carbocation via intramolecular electron transfer: Photoinduced DNA alkylation, J Am Chem Soc, 1994, 116 (6): 2653~2654
[6] Sugiyama H, Saito I, Theoretical studies of GG-specific photocleavage of DNA via electron transfer: Significant lowering of ionization potential and 5, -localization of HOMO of stacked GG bases in B-form DNA, J Am Chem Soc, 1996, 118 (30): 7063~7068
[7] Waring W J, Gonzalez A, Jimenez A, Vazquez D, Intercalative binding to DNA of antitumor drugs derived from 3-nitro-1,8-naphthalic acid, Nucleic Acids Res, 1979, 7 (1): 217~230
[8] Mehrotra J, Misra R K, DNA intercalation and photoinduced cleavage by 4-nitro-N-(6-aminohexyl)-1,8-naphthalimide, Nucleosides Nucleotides, 1994, 13 (4): 963~978
[9] Tao Z F, Qian X H, Wei D Z, 1,8-Naphthalimide hydroperoxides as Novel intercalating DNA cleavers, Dyes and pigments, 1996, 31: 245~251
[10]姚伟,含萘酰亚胺型切断剂合成、性能研究,[博士学位论文],上海;华东理工大学,2000
[11]黄霞宇,含萘酰亚胺型切断剂研究,[硕士学位论文],上海;华东理工大学,2002
[12] [12a]Bra?a M F, Ramos A, Naphthalimides as anticancer agents: Synthesis and biological activity, Curr Med Chem-Anti-Cancer Agents, 2001, 1: 237~255 [12b]李志刚,新型萘系硫杂环类化合物的设计、合成及生物活性研究,[博士学位论文],大连;大连理工大学,2005
[13] Bra?a M F, Castellano J M, Roldan C M, et al, Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitro-1,8- naphthalic acid, Cancer Chem other Pharmaco1, 1980, 4: 61~66
[14] Rosell R, CarlesJ, Abad A, et al, Phase I study of mitonafide in 120 hour continuous infusion in non-small cell lung cancer, Invest NewDrugs, 1992, 10: 171~175
[15] Bra?a M F, Sanz A M, Castellano J M, et al, Syntehsis and cytostatic activity of benz[de]isoquinoline-1,3-diones, structure-activity relationships, Eur J Med Chem Chim Ther, 1981, 16: 207~212
[16] Llombart M, Poveda A, Forner E, et al, Phase I study of mitonafide in solid tumors, Invest New Drugs, 1992, 10: 177~181
[17] Diaz-Rubio E, Martin M, Lopez-Vege J M, et al, Phase I study of mitonafide with a 3-day administration schedule: early interruption due to severe central nervous system toxity, Invest New Drugs, 1994, 12: 277~281
[18] Malviya V K, Liu P Y, Alberts D S, et al, Evaluation of Amonafide in cervical cancer, phase II, Am J Clin Oncol, 1992, 15: 41~44
[19] Ratiain M J, Mick R, Berezin F, et al, Phase I study of amonafide dosing based on acetyl at orphenotype, Cancer Res, 1993, 53: 2304~2308
[20] Waring M J, Gonzalez A, Jimenez A, et al, Intercalative binding to DNA of antitumor drugs derived from 3-nitro-1,8-naphthalic acid, Nucleic Acids Res, 1979, 7: 217~230
[21] Feigon J, Deeny W A, Leupin W, et al, Interaction of antitumor drugs with natural DNA: H NMR study of binding mode and kinetics, J Med Chem, 1984, 27: 450~465
[22] Hsiang Y H, Jiang J B, Liu L F, Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs, Mol Pharmacol, 1989, 36: 371~376
[23] Bra?a M F, Castellano J M, Moran M, et al, Synthesis, structure and antitumor activity of new benz[d,e] isoquinoline-1,3-diones, Arzneim-Forsch, 1995, 45: 1311~1378
[24] Zee C R K Y, Cheng C C, N-(Aminoalkyl)imidea ntineoplastic agents. Synthesis and biological activity, J Med Chem, 1985, 28: 1216~1222
[25] Bra?a M F, Moran M, Perez de Vega M F, et al, Synthesis and cytostatic activity of enynes, enediynes and dienediynes linked to intercalators, Tetrahedron, 1995, 51: 9127-9138
[26] Sami S M, D or R T, Albert D S, et al, 2-Substituted 1,2-dihydro-3H-dibenz [de,h] isoquinoline-1,3-diones. A new class of antitumor agent, J Med Chem, 1993, 36: 765~770
[27] Sami S M, Dorr R T, Solyom A M, et al, Amino-substituted 2-[2'-(dimethyl- amino)ethyl 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Synthsis, anti- tumor activity, and quantitative structure-activity relation-ship, J Med Chem, 1995, 38: 983~993
[28] Sami S M, Dorr R T, Alberts D S, et al, Analogues of aminofide and azonafide with novel ring systems, J Med Chem, 2000, 43: 3067~3073
[29] Bra?a M F, Cacho M, Garcia M A, et al, Synthesis, antitumor activity, molecular modeling, and DNA binding properties of a new series of imidazo- naphthalimides, J Med Chem, 2002, 45: 5813~5816
[30] Quaquebeke E V, Mahieu T, Dumont P, et al, 2,2,2-Trichloro-N-({2-[2- (dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity, J Med Chem, 2007, 50: 4122~4134
[31] Denny W A, Dual topoisomerase I/II poisons as anticancer drugs, Exp Opin Invest Drugs, 1997, 6(12): 1845
[32] Bra?a M F, Castellano J M, Moran M, et al, Bisnaphthalimides: a new class of antitumor agents, Anticancer Drug Des, 1993, 8: 257~268
[33] Kaltenbach R F, Sun J H, Chmrney R, et al, Unsymmetrical mono-3-nitro- bis- naphthalimides as anticancer agents, US, 5376664, 1994-12-27
[34] Sun J H, Highly water soluble bisnaphthalimides useful as anticancer agents, US, 5488110, 1996-1-30
[35] Sun J H, Mates J R, Park C H, et al, Process for preparing for bisnaphthalimides containing amino-acid derived linkers, US, 5461176, 1995-10-24
[36] Sun J H, Bis-naphthalimides containing amino-acid derived linkers as anticancer agents, US, 5206249, 1993-4-27
[37] Weis A L, Chen S F, Reddy P S, et al, Diamine platinum naphthalimide complexes as antitumor agents, US, 5561042, 1996-10-1
[38] Sun J H, Highly water soluble bisnaphthalimides useful as anticancer agents, WO, 9312092, 1993-6-24
[39] Keihauer G, Romerdahl C, Bra?a M F, et al, New bisnaphthalimides for the treatment of cancer, WO, 9505365, 1995-2-23
[40] Weis A L, Chen S F, Reddy P S, et al, Bis-naphthalimide with linkers having heteroatoms and uses there of WO, 9603384, 1996-2-8
[41] Keihauer G, Romerdahl C, Bra?a M F, et al, Bisnaphthalimides for the treatment of cancer, US, 5616589, 1997-4-1
[42] Bra?a M F, Castellano J M, Moran M, et al, Bis-naphthalimides. 2. synthesis and biological activity of 5,6-acenaphthalimidoalkyl-1,8-naphthalimidoakyl amines, Eur J Med Chem, 1995, 30: 235~239
[43] Bra?a M F, Castellano J M, Moran M, et al, Bis-naphthalimides 3: Synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl]alkanedimines, Anticancer Drug Des, 1996, 11: 297~309
[44] Bra?a M F, Castellano J M, Perron D, et al, Chromophore-modified bis- naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]iso- quinoline-1,3- diones, J Med Chem, 1997, 40: 449~454
[45] Bousquet P F, Bra?a M F, Conlon D, et al, Preclinical Evaluation of LU-79553; a novel bisnaphthalimide with potent antitumor activity, Cancer Res, 1995, 55: 1176~1180
[46] [46a]Baily C, Bra?a M F, Waring M J, Sequence-selective intercalation of antitumor bisnaphthalimides into DNA evident for an approach via the major groove, Eur J Biochem, 1996, 240: 195~208 [46b]贺茜,李永刚,抗肿瘤药双萘酰亚胺的研究进展,广州化学,2002,27(2):48~52
[47] Chen S F, Behrens D L, Behrens C H, et al, XB596, a promising bisnaphthal- imide anticancer agent, Anti-Cancer Drugs, 1993, 4: 447~457
[48] Kirshenbaum M R, Chen S F, Behrens C H, et al, (R,R)-2,2'- [1,2-ethanediyl bis[imino(1-methyl-2,1-ethanediyl)]-bis[5-nitro-1H-benz[de]isoquino-line-1,3- (2H)-dione]dimethanesulfonate(DMP-840), a nove bisnaphthalimide with potent nonselective tumoricidal activity in vitro, Cancer Res, 1994, 54: 2199 ~2206
[49] McRipley R J, Burns-Horwitz P E, et al, Efficacy of DMP-840, a novel bisnaphthalimide cytotoxic agent with human solid tumor xenograft selectivity, Cancer Res, 1994, 54: 159~164
[50] Houghton P J, Cheshire P J, Hallman J C, et al, Evaluation of a novel bis- naphthalimide anticancer agent, DMP-840, against human xenograft derived from adult, juvenile and pediatric cancers, Cancer Chemother Pharmacol, 1994, 33 (4): 265 ~272
[51] Lai C M, Garner D M, Gray J E, et al, Determination of bisnafide, a novel bisnaphthalimide anticancer agent, in human plasma by high performance liquid chromatography with UV detection, J Pharm Biomed Anal, 1998, 17 (3): 427~434
[52] Kobb P W, Degen D R, Clark G M, et al, Activity of DMP-840, a new bis- naphthalimide, on primary human tumor colony-forming units, J Natl Cancer Inst, 1994, 86 (19): 1462~1465
[53] Nitiss J L, Zhou J F, Rose A, et al, The bis(naphthalimide)DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase II, Biochemistry, 1998, 37: 3078~3085
[54] Gallego J, Reid B R, Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale, Biochemistry, 1999, 38: 15104~15115
[55] Bra?a M F, Castellano J M, Sanz A M, et al, Synthesis and cytostatic activity of benz [d,e] isoquinolin-1.3-dione, structure-activity relationships, Eur J Med Chem, 1981, 16: 207~212
[56] McRipley R J, Burns-Horwitz P E, Czerniak P M, et al, Efficacy of DMP 840: a novel bisnaphthalimide cytotoxic agent with human solid tumor xenograft selectivity, Cancer Res, 1994, 54 (1): 159~164
[57] Bra?a M F,Cacho M, Garcia M A, et al, New analogues of amonafide and elinafide, containing aromatic heterocycles: synthesis,antitumor activity,molecular modeling, and DNA binding, J Med Chem, 2004, 47: 1391~1399
[58] Pavlov V, Lin Pl K T, Rodilla V, Cytotoxicity, DNA binding and localisation of novel bisnaphthalimidopropyl polyamine derivatives, Chemico-Biological Interactions, 2001, 137: 15~24
[59] McMasters S, Kelly L A,Ground-state Interactions of spermine- substituted naphthalimides with mononucleotides, J Phys Chem B, 2006, 110: 1046~1055
[60] Alison Rodger, Steven Taylor, Gareth Adlam, et al, Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine, Bioorg Med Chem, 1995, 3(6): 861~872
[61] Morris, D R, Marton, L J eds, Polyamines in Biology and Medicine, Marcel Dekker, New York (1981)
[62] Tabor C W, Tabor H, Polyamines in microorganisms, Microbiol Rev, 1985, 49 (1): 81~99
[63] Vassylyev D G, Tomitori H, Kashiwagi K, et al, Crystal structure and mutational analysis of the Escherichia coli putrescine receptor: structural basis for substrate specificity, J Biol Chem, 1998, 273: 17604~17609
[64] [64a]Tabor C W, Rabor H, 1,4-Diaminobutane (putrescine), spermidine, and spermine, Annu Rev Biochem, 1976, 45: 285~306 [64b]Marton L J, Pegg A E, Polyamines as targets for therapeutic intervention, Annu Rev Pharmacol Toxicol, 1995, 35: 55~91 [64c]Pegg A E, Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy, Cancer Res, 1988, 48: 759~774 [64d]Morgan D M L(Ed), Polyamine protocols in methods in molecular biology, (Series Ed: JM Walker), vol 79, Humana Press, Totowa, New Jersey, 1998
[65] [65a]Schipper R G, Penning L C,Verhofstad A A, Involvement of polyamines in apoptosis. Facts and controversies: effectors or protectors? Semi Cancer Biol, 2000, 10 (1): 55~68 [65b]Soulet D, Rivest S, Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system, J Cell Biol, 2003, 162 (2): 257~268
[66] Pieter smid, Hein K A C, Coolen, Hiskias G, et al, Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[ω-(1H-indol-3-yl) alkyl]piperazines, novel potential antipsychotics combining potent dopamineδ2 receptor antagonism with potent serotonin reuptake inhibition, J Med Chem, 2005, 48: 6855~6899
[67] Tabor H, Tabor C W, Biosynthesis and metablism of 1,4-diaminobutane, spermidine, spermine, and relatedamines Adv, Enzymol Relat Areas Mol Biol, 1972, 36: 203~268
[68]竺心影,邵以德,药理学[M](第二版),北京:人民卫生出版社,1986
[69] Cullis P M, Green R E, Merson Davies L, et al, Probing the mechanism of transport and compartmentalisation of polyamines in mammalian cells, Chem Biol, 1999, 6: 717~729
[70] Seiler N, Dezeure F, Polyamine transport in mammalian cells, Int J Biochem, 1990, 22 (3): 211~218
[71] Moulinoux J P, Darcel F, Quemener V, human glioblastoma in nude mice by polyamine deprivation, Anticancer-Res, 1991, 11 (1): 175~179
[72] Phanstiel O, IV, Price H L, Wang L, et al, The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA-intercalator) conjugates, J Org Chem, 2000, 65: 5590~5599
[73] Wang L, Price H L, Juusola J, et al, Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA- intercalator conjugates, J Med Chem, 2001, 44 (22): 3682~3691
[74] Wang C J, Delcros J G, Biggerstaff J, et al, Synthesis and biological evaluation of N1-(Anthracen-9-ylmethyl)triamines as molecular recognition elements for the polyamine transporter, J Med Chem, 2003, 46 (13): 2663~2671
[75] Wang C J, Delcros J G, Biggerstaff J, et al, Molecular requirements for targeting the polyamine transport system. Synthesis and biological evaluation of polyamine-anthracene conjugates, J Med Chem, 2003, 46 (13): 2672~2682
[76] Wang C J, Delcros J G, Cannon L, et al, Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2003, 46(24): 5129~5138
[77] Gardner R A, Delcros J G, Konate F, et al, N1-Substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2004, 47 (24): 6055~6069
[78] Horn Y, Beal S L, Walach N, et al, Further evidence for the use of polyamines as biochemical markers for malignant tumors, Tumors Cancer Res, 1982, 42: 3248~3251
[79] Xie S Q, Liu G C, Ma Y F, et al, Synergistic antitumor effects of anthracenylmethyl homospermidine and alpha-difluoromethylornithine on promyelocytic leukemia HL60 cells, Toxicology in Vitro, 2008, 22: 352~358
[80] Wang J H, Xie S Q, Li Y J, et al, Synthesis and evaluation of unsymmetrical polyamine derivatives as antitumor agents, Bioorg Med Chem, 2008, 16: 7005~7012
[81] Smith M K, Goral M A, Wright JH, et al, Ornithine decarboxylase overexpression leads to increased epithelial tumor invasiveness, Cancer Res, 1997, 57: 2104~2108
[82] Fujimoto S, Igarashi K, Shrestha R D, et al, Antitumor effects of two polyamine antimetabolites combined with mitomycin C on human stomach cancer cells xenotransplanted into nude mice, Int J Cancer, 1985, 35 (6): 821~825
[83] Volkov N, Goldman S S, Flamm E S, et al, Labeled putrescine as a probe in brain tumors, Science, 1983, 221: 673~675
[84] Robert A, Casero, J, Patrick M W, Terminally alkylated polyamine analogues as chemotherapeutic agents, J Med Chem, 2001, 44 (1): 1~26
[85] Marton LJ, Pegg A E, Polyamines as targets for therapeutic intervention, Ann Rev Pharmacol Toxicol, 1995, 35: 55~91
[86] [86a]Casero RA, Go B, Theiss HW, et al, Cytotoxic response of the relatively difluoromethylornithine-resistant human lung tumor cell line NCI H157 to the polyamine analogue N1,N8-Bis (ethyl) spermidine, Cancer Res, 1987, 47 (15): 3964~3967 [86b]Bergeron R J, Neims A H, McManis J S, et al, Synthetic polyamine analogs as antineoplastics, J Med Chem, 1988, 31 (6): 1183~1190 [86c]Edwards M L, Prakash N J, Stemerick D M, et al, Polyamine analogs with antitumor activity, J Med Chem, 1990, 33 (5): 1369~1375 [86d]Bergeron RJ, McManis JS, Weimar WR, Schreier KM, et al, The role of charge in polyamine analog recognition, J Med Chem, 1995, 38 (13): 2278~2285 [86e]Igarashi K, Koga K, He Y, et al, Inhibition of the growth of various human and mouse tumor cells by 1,15-bis(ethylamino)-4,8,12- triazapen- tadecane, Cancer Res, 1995, 55: 2615~2619 [86f] Bergeron R J, Feng Y, Weimar W R, et al, A comparison of structure-activity relationships between spermidine and spermine analogue antineoplastics, J Med Chem, 1997, 40 (10): 1475~1494
[87]刘晶华,王岩,刘俊亭,多胺合成和代谢中抗癌药作用新靶点的研究进展,中南药学,2005,3(2):113~115
[88] Gilad G M, Balakrishnan K, Gilad V H, The course of putrescine immunocytochemical appearance in neurons, astroglia and microglia in rat brain cultures, Neurosci Lett, 1999, 268(1): 33~36
[89] Soulet D, Rivest S, Polyamines play a critical role in the control of the innate immune response, J Cell Biol, 2003, 162 (2): 257~268
[90] Masuko T, Kusama E K, Sakata K, et al, J Polyamine transport, accumulation, and release in brain, NeuroChem, 2003, 84 (3): 610~617
[91] Adibhatla R M, Hatcher J F, Sailor K, et al, Polyamine and central nervous system injury: spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats, Brain Res, 2002, 938 (12): 81~86
[92] Gibson D A, Barton R H, Prendergast M A, et al, Polyamines contribute to ethanol withdrawal-induced neurotoxicity in rat hippocampal slice cultures through interactions with the NMDA Receptor, Alcohol Clin Exp Res, 2003, 27 (7): 1099~1106
[93]杨筱珍,陈耀星,佘锐萍,等,多胺与细胞凋亡,动物医学进展,2004,25(2):11~14
[94] Sriptiya V, Veena V, Akira S, et al, Antisense recognition of the HER-2 mRNA: Effects of phosphorothioate substitution and polyamines on DNA·RNA, RNA·RNA, and DNA·DNA duplex stability, Biochemistry, 2005, 44: 303~312
[95]梁峰,魏俊,李朝阳,等,含羟基环多胺金属配合体系切割DNA及其体外抗肿瘤活性研究,高等学校化学学报,2004,25(3):470~473
[96] Rodger A, Taylor S, Adlam G, et al, Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine, Bioorg Med Chem, 1995, 3(6): 861~872
[97] Dipanjan Sengupta, Andrei Blasko, Thomas B, A microgonotropen pentaaza pentabutylamine and its interactions with DNA, Bioorg Med Chem, 1996, 4 (6): 803~813
[98] [98a]Miguel F, Bra?a M C, Maro A, et al, New analogues of Amonafide and Elinafide, containing aromatic heterocycles: Synthesis, antitumor activity, molecular modeling, and DNA binding properties, J Med Chem, 2004, 47: 1391~1399 [98b]Dance A M, Ralton L , Fuller Z, et al, Synthesis and biological activities of bisnaphthalimido polyamines derivatives: cytotoxicity, DNA binding, DNA damage and drug localization in breast cancer MCF 7 cells Biochem, Pharmacology, 2005, 69: 19~27
[99] Heby O, Persson L, Molecular genetics of polyamine synthesis in eukaryotic cells trends in biochemical, Science, 1990, 15: 153~158
[100] Hu X, Washington S, Michael F, et al, Interaction between polyamines and the mitogen-activated protein kinase pathway in the regulation of cell cycle variables in breast cancer cells, Cancer Res, 2005, 65 (23): 11026~11033
[101] Bitonti A J, Dumont J A, Bush T L, et al, Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (plasmodium falciparum) in vitro and in combination withα-difluoromethylornithine cure murine, Malaria Proc, Natl Acad Sci, USA, Medical Sciences, 1989, 86 (2): 651~655
[102] Adina R, Rebecca D P, Louis M, et al, Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine derivatives, J Med Chem, 2003, 46: 542~557
[103] Birkholtz L M, Wrenger C, Joubert F, et al, Parasite- specific inserts in the bifunctional sadenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparu, Biochem J, 2004, 377: 439~448
[104] Piero S D, Ghezzi L, Melchior A, et al, Solvent role on cobalt(II) dioxygen carriers based on simple polyamine ligands, Helvetica Chemica Acta, 2005, 88: 839~853
[105]程鹏飞,多胺-药物缀合物的合成及其生理活性研究,[硕士学位论文],开封;河南大学,2006
[106] [106a]Duschinsky R, et al The synthesis of 5–fluoropyrimidenes, J Am Chem Soc, 1957, 79: 4559~4560 [106b]吴林艳,5-氟尿嘧啶衍生物的合成及抗癌活性研究,[硕士学位论文],成都;四川大学,2003 [106c]李小菊,5-氟尿嘧啶含磷衍生物的合成及其抗肿瘤活性研究,[硕士学位论文],武汉;华中师范大学,2004
[107] Hiller S A, Zhuk R A, Lidak M Y, et al, Analogs of pyrimidine, nucleoside 1-N-(ct-furanydyl)-derivatives of natural pyrimidine, bases and their antimetabolites, SSSR 1967, 176: 332~335
[108]张志义,孙燕,恶性肿瘤化学治疗学,第1版,上海:上海科学技术出版社,1981,11:36
[109] Cook P, Holman J K, Ramer J, et al, Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5'-deoxy-5-fluoropyrimidine nucleosides, J Med Chem, 1979, 22: 1330~1335
[110] Eda H, Tanaka Y, Shitsuka I, 5'-Deoxy-5-fluorouridine improves cachexia by a mechanism independent of its antiproliferative action in colon 26 adenocarcinoma-bearing mice, H Pharmacol, 1991, 29: 1~6
[111] Hoshi A, Ligo M, Yoshida M, et al, Antitumor actrvity of carbamoyl derivatives of 5-fluorouracil oral administration, Jpn J Cancer Res, 1975, 66: 673~674
[112] Hoshi A, Ligo M, Nakamura A, et al, Antitumor activity of 1-hexcarbamoyl -5- fluorouraeil in a variety of expermental tumors, Jpn J Cancer Res, 1976, 67: 725~731
[113] HCFU Clinical Study Group, Absorption and excretion of new oral antitumor drug, 1-hexylcarbamoyl-5-fluorouracil (HCFU), in cancer patients, Jpn J Clin Oncol, 1980, 10: 83~92
[114] Ligo M, Hoshi A, nakamura A, et al, Antiumor activity of L-alkylcarbamoyl derivatives of 5-fluorouracil in a variety of mouse tumors, Cancer Chemother Pharmacol, 1978, 1: 203~208
[115] Ligo M, Hoshi A, nakamura A, et al, Absorption and excretion of a new oral antitumor drug, J Pharm Dyn, 1978, 1: 49~54
[116] Koyama Y, 1-Hexylcarbamoyl-5-fluorouracil (HCFU) a masked 5-fluorinated pyrimidine, Cancer Treat Rev, 1981, 8: 147~156
[117]靳清泉,赵媞萍,卡莫氟的III期临床实验总结报告,中国肿瘤临床,2002,29(7):501~503
[118] Bajetta E, Camaghi C, SommaL, et al, A pilot safety study of ca picetabine, a new oral fluoropyrimidine, inpatients with adcanced neoplastic disesease, Tumori, 1996, 82: 450~452
[119] [119a]郭宗儒编著,药物化学总论,北京:中国医药科技出版社,1994, 304~311 [119b]王卫东,谭祥中,胡茂林,5-氟尿嘧啶衍生物的研究进展,化学试剂,2006,28(11):653~656 [119c]扈靖,刘彦钦,韩士田,等,5-氟尿嘧啶衍生物的合成及其抗癌活性研究进展,河北师范大学学报(自然科学版),2006,30(5):580~584
[120]海俐,吴林艳,黄娟,等,N1-(芳)烷氧酰基烷酰基-5-氟尿嘧啶的合成,四川大学学报(医学版),2004,35(4):552~554
[121] Fredric M M, Michael J, Rourk Synthesis and Reactivity of 5-Fluorou- racil /Cytarabine Mutual Prodrugs, J Org Chem, 1997, 62: 9083~9088
[122] Chung I D, Jung E Y, Lee Y W, et al, Syntheses, antitumor activities, and antiangiogenesis of exo-3,6-Epoxy-1,2,3,6–tetrahydro-phthalimidoethanoyl 5- fluorouracil and its polymers, Journal of Polymer Science: Part A: Polymer Chemistry, 2000, 38: 4272~4281
[123] Bajetta E, Camaghi C, SommaL, et al, A pilot safety study of ca picetabine, a new oral fluoropyrimidine, inpatients with adcanced neoplastic disesease, Tumori1, 1996, 82: 450~452
[124] Shimma N, MedaI U, Metal A, The design and synthesis of a new tumor- selective fluoropyrimidine carbamate capecitabine, Bioorg Med Chem, 2000, 8 (7): 1697~706
[125]金小玲,张辅民,田瑄,等,新的4′-去甲表鬼臼衍生物的2DNMR研究,波谱学杂志,2002,19(3):259~264
[126]刘彦钦,张慧娟,韩士田,5-氟尿嘧啶-卟啉化合物的合成及抗癌活性,有机化学,2002,22(4):279~282
[127]杨秋青,刘彦钦,氯代苯基卟啉-5-氟尿嘧啶化合物的光谱研究,分析化学,2001,29(9):1016~1020
[128]邱红,刘彦钦,韩士田,双氯代苯基卟啉-5-氟尿嘧啶化合物的合成,化学试剂,2001,23(6):346~348
[129]胡泉源,黄素秋,5, 10, 15, 20-四[邻(5-氟尿嘧啶-1-)乙酰苯胺]苯基卟啉的合成,湖北医科大学学报,1998,9(4):305~307
[130]王昕,卟啉化合物合成的最新研究进展,湘潭师范学院学报(自然科学版),2001,23(3):52~59
[131]金晓敏,吴健,卟啉类光敏药物的研究进展,中国药物化学杂志,2002 ,12(1):52~56
[132]王杏乔,高爽,于连香,等,卟啉纳米材料的新法合成,高等学校化学学报,1998,19(6):854~857
[133]李屏英,林坤华,黄素秋,5, 10, 15-三对磺酰-5′-氟尿嘧啶苯基-20-对磺酸苯基卟啉的合成及抗肿瘤作用的研究,武汉大学学报(自然科学版),1985,31(20):111~116
[134]黄素秋,刘德伟,姜兆慈,等,卟啉胆甾酯及其金属络合物的合成、结构与光敏活性,药学学报,1989,24 (11):817~819
[135]何书美,刘彦钦,邱红,等,氯代5-氟脲嘧啶卟啉的红外光谱特性的研究,光谱学与光谱分析,2003,23 (1) :49~53
[136] Zhou R X,Ye D K, Liu G W, et al, Synthesis and biological activity of polycster containing 5-fluorourail in the main chain C// Preprint of 27th international symposium on macromolecules, France: Strasbourg, 1981, 1335~1339
[137]卓仁禧,陈衢生,刘高伟,等,主链含5-氟尿嘧啶聚酯的合成,高分子学报,1988,32(1):11~15
[138]卓仁禧,陈衢生,刘高伟,主链含5-氟尿嘧啶聚芳酯的合成,武汉大学学报:自然科学版,1983,29(3):114~118
[139]范昌烈,麦才淞,徐建军,等,1,3-羟烷基5-氟尿嘧啶与二氯磷酸酯缩聚物的合成,高分子学报,1985,29(1):77~80
[140]周念恩,陈衢生,卓仁禧,二羟烷基嘧啶与N,N′双-(二氯乙基)二氯磷酰胺缩聚物的合成及其抗肿瘤活性研究,高分子学报,1987,31(6):417 ~422
[141]陈衢生,卓仁禧,周念恩,5-氟尿嘧啶、腺嘧啶、胸腺嘧啶的N-羟烷基乙酰胺双取代衍生物的合成,武汉大学学报(自然科学版)1986,32(1):65~69
[142]朴爱植,孙树门,5-氟尿嘧啶齐聚物的合成,高分子学报,1983,27(1):74~77
[143]朴爱植,孙树门,含5-氟尿嘧啶的聚硅氧烷的合成,高分子学报,1984,28(1):21~26
[144]朱卡,汤谷平,陈启琪,等,5-氟尿嘧啶-聚α,β-(2-羟乙基)–DL-天冬酰胺的合成及体内释放的研究,药学学报,1998,33(12):906~909
[145]张静夏,潘仕荣,王琴梅,等,5-氟脲嘧啶-聚[(2-羟乙基)-L-谷酰胺]的合成及释药研究,中山医科大学学报,2002,23(5):19~21
[146]张静夏,潘仕荣,王琴梅,等,5-氟脲嘧啶-聚[N-(2-羟-乙基)–L-谷酰胺]的合成及缓释性能研究,广州化学,2002,27(2):1~5
[147]卓仁禧,范昌烈,赵儒林,含5-氟尿嘧啶的氨基酸衍生物的合成及其肿瘤活性研究高等学校化学学报,1986,7(6):508~512
[148]赵儒林,氨基酸5-氟尿嘧啶酯类衍生物的合成及其肿瘤活性研究,高等学校化学学报,1989,10(6): 60~608
[149]卓仁禧,刘高伟,彭普平,5-氟尿嘧啶-N-甲酰基氨基酸短肽的合成及抗肿瘤活性,高等学校化学学报,1991,12(4):555~559
[150]叶发青,合成5-氟尿嘧啶-N-甲酰基异亮氨酸的新方法,化学试剂,1996,18(5):308
[151]罗毅,卓仁禧,范昌烈:短肽5-氟尿嘧啶前体药物的合成及其抗肿瘤活性研究,高等学校化学学报,1994,15(4):545~547
[152]刘学军,陈茹玉,杨媛媛,5-氟尿嘧啶-1-基磷二肽化合物的合成及抗癌活性,天津大学学报,2001,34(6):745~748
[153]刘学军,陈茹玉,杨媛媛,5-氟尿嘧啶-1-基磷三肽化合物的合成及抗癌活性,高等学校化学学报,2002,23 (7):1299-1303
[154]胡喜钢,汪森明,张起兴,等:以磺胺嘧啶为载体的氟尿嘧啶导向药物的合成,2002,22(11):1402~1404
[155]石德清,魏佳,谭效松,新型含环状α-羟基膦酸酯的N1 -(四氢呋喃-2-基)-5-氟尿嘧啶衍生物的合成,有机化学,2005,25(12):1602~1605
[156]石德清,陈琦,李中华,含氨基酸席夫碱的5-氟尿嘧啶衍生物的合成及其抗肿瘤活性,有机化学,2005,25(5):549~553
[157] Wang W D, Hu M L, Synthesis and crystal structure of tetraaqua–copper(II)bis(5-fluorouracil-1-acetate)tetrahydrate, J Chin Struct Chem, 2006, 25 (5): 562~566
[158]宋之刚,张伏龙,5-氟尿嘧啶-1-乙酸锌单晶的合成、结构及抗菌活性研究,甘肃教育学院学报,2003,17(3):32~36
[159]李娟,李静,齐燕飞,等,12-钨硼酸5-氟尿嘧啶盐的合成及抗癌活性研究,高等学校化学学报,2004,25(6):1010~1012
[160]王彦广,田暄,李景新,等,具有抗癌活性氟脲嘧啶自旋标记衍生物的合成,高等学校化学学报,1992,13(12):1561~1563
[161]王彦广,田暄,李景新,等,5-氟脲嘧啶自旋标记衍生物的合成与抗肿瘤活性,高等学校化学学报,1993,14(10):1399~1401
[162]毛曼君,田暄,陈耀祖,5-氟脲嘧啶自旋标记衍生物的合成及其抗肿瘤活性研究,高等学校化学学报,1998,19(3):395~398
[163]孙昌俊,薛军,王义贵,等,5-氟脲嘧啶衍生物的合成及其抗肿瘤活性,中国药物化学杂志,1998,8(2):91~95
[164]孙昌俊,李洪祥,戚聿新,等,芳酰基氟脲嘧啶衍生物的合成及其抗肿瘤活性,中国药物化学杂志,2000,10(3):164~167
[165]匡永清,孙晓莉,何炜, 6-[N-(4-氨基丁基)-N-乙基]氨基-2,3-二氢-1,4-酞嗪二酮的合成,第四军医大学学报, 2002, 23(11):1037~1039
[166]匡永清,张生勇,蔚琳琳,N-(4-溴丁基)邻苯二甲酰亚胺的合成化学试剂, 2001,23(6):359~361
[167] Chong H S, Suzy V, Brechbiel T, et al, Synthesis and potent antitumor activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives, J Med Chem, 2004, 47: 5230~5234
[168] Jasys V J, Kelbaugh P R, Nason D M, et al, Novel quaternary ammonium salt-containing polyamines from the Agelenopsis aperta funnel-web spider, J Org Chem, 1992, 57: 1814~1820
[169] Kamal A, Reddy B S N, Reddy G S K, et al, Design and synthesis of C-8 linked pyrrolobenzodiazepine-naphthalimide hybrids as antitumour agents, Bioorganic & Medicinal Chemistry Letters, 2002, 12: 1933~1935
[170] Mosmann T, Rapid colorimetric assay for cellular growth and survival. Application to proliferation and cytotoxicity assays, J Immunol Meth, 1983, 65: 55~63
[171] Karigiannis G, Papaioannou D, Structure, biological activity and synthesis of polyamine analogues and conjugates, Eur J Org Chem, 2000, 10: 1841~1863
[172] Rodriguez L, Alves S, Lima J C, et al, Supramolecular interactions of hexacyanocobaltate(III) with polyamine receptors containing a terminal anthracene sensor, J Photochem And Photobiol, 2003, 159: 253~258
[173] Cullis P M, Green R E, Merson Davies L, et al, Probing the mechanism of transport and compartmentalisation of polyamines in mammalian cells, Chem Biol, 1999, 6: 717~729
[174] Xu J X, Wang C, Zhang Q H, Synthesis, structure and spectral properties of 1,5-benzothiazepines-alpha-phenyl-beta-lactams, Chin J Chem, 2004, 22 (9): 1012~1018
[175] [175a]方浩,夏霖,江振洲,等,化学学报,N-(取代苯基哌嗪基烷基)酰胺类α1-受体拮抗剂的设计、合成及生物活性研究,2002,60(4):725~731 [175b]Tahtaoui C, Parrot I, Klotz P, et al, Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor, J Med Chem, 2004, 47(18): 4300~4315 [175c]Ryckebusch A, Deprez-Poulain R, Maes L et al, Synthesis and in vitro and in vivo antimalarial activity of N1-(7-Chloro- 4-quinolyl)-1,4-bis(3-aminopropyl) pipera- zine Derivatives, J Med Chem, 2003, 46(4): 542~557 [175d]Cao J J, Kulkarni SS, Husbands M S et al, Dual Probes for the Dopamine transporter andδ1 receptors: Novel piperazinyl alkyl-bis(4'-fluoro-phenyl)amine analogues as potential cocaine-abuse therapeutic agents, J Med Chem, 2003, 46 (13): 2589~2598
[176] Basuroy U K, Gerner E W, Emerging concepts in targeting the polyamine metabolic pathway in epithelial cancer chemoprevention and chemotherapy, J Biochem, 2006,139: 27~33
[177] Eguchi Y, Srinnivasn A, Tomaselli KJ, et al, ATP-dependent steps in apoptotic signal transduction, Cancer Res, 1999, 59: 2174~81
[178] Gardner R A, Delcros J G, Konate F, et al, N1-substituent effects in the selective delivery of polyamine conjugates into cells containing active polyamine transporters, J Med Chem, 2004, 47: 6055~6069
[179] Bra?a M F, Cacho M, Gradillas A, et al, Intercalators as anticancer drugs, Current Pharmaceutical Design, 2001, 7: 1745~1780
[180] Claus A M, Seidel A S, Markus H M, Nucleobase-specific quenching of fluorescent dyes. 1. Nucleobase one-electron redox potentials and their correlation with static and dynamic quenching efficiencies, J Phys Chem, 1996, 100: 5541~5553
[181] Reid G D, Whittaker D J, Day M A, et al, Ultra fast electron-transfer reactions between thionine and guanosine bases, J Am Chem Soc, 2001, 123 (28): 6953~6954
[182] Phanstiel O IV, Price H L, Wang L, et al, The effect of polyamine homologation on the transport and cytotoxicity properties of polyamine-(DNA- intercalator) conjugates, J Org Chem, 2000, 65: 5590~5599
[183] Zhu H, Huang M, Yang F, et al, R16, a novel amonafide analogue, induces apoptosis and G2/M arrest via poisoning topoisomerase II, Mol Cancer Ther, 2007, 6: 484~495
[184] Xie S Q, Cheng P F, Wang C J, Synthesis and bioevaluation of N-(arylalkyl)-homospermidine conjugates, Bioorg Med Chem Lett, 2007, 17: 4471~4475
[185] Xie S Q, Liu G C, Wang C J, Synergistic antitumor effects of anthracenylmethyl homospermidine and alpha-difluoromethylornithine on promyelocytic leukemia HL60 cells, Toxicity in vitro, 2008, 22 (3): 352~358
[186] Liu J, Li Y, Ren W, Apoptosis of HL-60 cells induced by extracts from narcissus tazetta var chinensis, Cancer Lett, 2006, 242: 133~140
[187] Eguchi Y, Srinnivasn A, Tomaselli KJ, et al, ATP-dependent steps in apoptotic signal transduction, Cancer Res, 1999, 59: 2174~81
[188]董永军,袁国峰,庞立营,合成邻苯二甲酰亚胺的工艺改进,辽宁化工,2006,35(10):574~576
[189] Alexandre L M, Lídia Lima M, Barreiro E J, et al, Design, synthesis and antiinflammatory activity of novelphthalimide derivatives, structurally related to thalidomide, Bioorg Med Chem Lett, 2005, 15:1169~1172
[190] Ragavendran J V, Sriram D, Yogeeswari P, et al, Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore, Eur J M Chem, 2007, 42: 146~151
[191] Gobec S, Plantan I, Mravljak J, et al, Design, synthesis, biochemical evaluation and antimycobacterial action of phosphonate inhibitors of antigen 85C, a crucial enzyme involved in biosynthesis of the mycobacterial cell wall, Eur J M Chem, 2007, 42: 54~63
[192] Alaa A M, Abdel A, Novel and versatile methodology for synthesis of cyclic imides and evaluation of their cytotoxic, DNA binding, apoptotic inducing activities and molecular modeling study, Eur J M Chem, 2007, 42: 614~626
[193] Hall I H, Wong O T, Scovill J P, The cytotoxicity of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide, Biomed & Pharmacother, 1995, 5: 251~258
[194] Yasumoto M, Yamawaki I, MarunaKa T, et al, Studies on antitumor agents. 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluoro- uracil and 1,3-bis(tetrahydro-2-furanyl) -5- fluorouracil, J Med Chem, 1978, 21 (8): 738~741
[195] Schoichiro O, Yoshimasa I, Haruo M, et al, 5-Fluorouracil, derivatives. I. The synthesis of 1-carbamoyl-5-fluorouracils, Bull Chem Soc Jpn, 1977, 50 (9): 2406~2412
[196] Chakravarty P K, Carl P L, Weber M J, et al, Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard, J Med Chem, 1983, 26 (5): 633~638
[197] Zhang C X, Chen R Y, Tang C C, et al, Synthesis of sulfur analogus of cyclic phospholipid conjugated with N1-(2-furanidyl)-N3-(2-hydroxyethyl)-5- fluorouracil, Phosphorus, Sulfur, and Silicon and the Related Elements, 1998, 132 (1): 155~161
[198]许新华,陈焕明,陈茹玉,N-3-羟烷基替加氟制备方法改良及其环甘油磷脂缀合物的合成与抗肿瘤活性,高等学校化学学报,2000,21(9):1410~1412
[199] Liu Z F, Stephen R, Synthesis and release of 5-fluorouracil from poly (N-vinylpyrrolidinone) bearing 5-fluorouracil derivatives, J Control Rel, 2002, 81: 91~99
[200]王玉霞,赵瑾,孙心奇,等,N-哌嗪烷基酰胺类化合物的合成与DNA相互作用及生理活性,有机化学,2006, 26: 1066~1072
[201] Bra?a M F, Castellano J M, Perron D, Maher C, et al, Chromophore-modified bis-naphthalimides: Synthesis and anti-tumor activity of bis-[de,h]isoquino- line-1,3-diones, J Med Chem, 1997, 40, 449~454
[202] Lee N J, Kim K H, Rhew H Y, et al, Synthesis and biological activity of medium molecular weight polymers containing 3,6-endo-methylene-1,2,3,6- tetrahydrophthalimido-butanoyl-5-fluorouracil, Polym Int, 2000, 49: 1702~ 1708
[203]周周冰,许新华,张秋林,等,磷脂核苷缀合物甘油结构修饰新方法及应用,有机化学, 2004,24(1):88~92
[204] Zhang C X, Zhang Z B, Chen R Y, et al, Synthesis of 1,2- and 1,3-cyclic phospholipid conjugates of N1-(2-Furanidyl)-N3-(2-hydroxyethyl)-5-fluoro- uracil, Heteroat Chem,1998, 9 (3): 295~298