新型苯并磺内酰胺类微管蛋白抑制剂的设计、合成及活性研究
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摘要
肿瘤是严重威胁人类生命的常见病和多发病,其死亡率仅次于心血管疾病而列居第二。肿瘤细胞具有快速增殖能力,其有丝分裂过程频繁且细胞周期明显短于正常细胞。微管是细胞有丝分裂过程中重要的细胞骨架之一,为动态不稳定结构,在细胞有丝分裂过程中具有促使姐妹染色单体分离的重要作用。这一重要作用使微管成为抗肿瘤治疗的重要靶点。
抗有丝分裂药物在肿瘤治疗中发挥着重要的作用。它们主要通过破坏微管蛋白/微管之间的动态循环(聚合和解聚)来治疗各种实体肿瘤。根据对微管作用的不同将药物分为两类:抑制微管蛋白聚合的药物,如长春碱类;稳定微管的药物,如紫杉烷类和埃坡霉素类。抑制微管蛋白聚合的药物通过与β微管蛋白结合使细胞分裂停止于G_2/M期;稳定微管的药物有两个不同的结合位点:秋水仙碱位点和长春碱位点,但作用机制相似,即可逆地与β微管蛋白结合形成“药物-蛋白”复合物,阻止其他蛋白单体的继续添加而抑制微管的聚合,同时还通过诱导微管的解聚抑制纺锤体的形成,使细胞的有丝分裂停止于M期。紫杉醇与多西他赛是最早用于治疗实体瘤的微管蛋白抑制剂,但由于耐药性的出现,使其应用受到局限。近年来,小分子微管蛋白抑制剂研究方面取得了很大的进展。其中,磺胺类药物ABT-751可以口服给药,生物利用度高。它通过与秋水仙碱结合位点β微管蛋白结合,抑制微管的聚合,现已进行临床研究。
另一方面,秋水仙碱、鬼臼毒素、Combretastatin A-4(CA-4)等天然抗肿瘤药物分子中的多酚醚类结构是抑制微管蛋白聚合的主要药效团之一。
基于片断的药物设计(Fragment based drug design)是近年来发展、成熟起来的寻找先导化合物的有效方法。本文基于微管蛋白秋水仙碱结合腔的特点,以微管蛋白抑制剂ABT-751分子中的苯磺酰胺结构片段和作用于微管蛋白同一靶点的天然产物鬼臼毒素等分子中的多酚醚结构片段为基础,利用基于片断的药物设计方法并结合计算机辅助药物设计,设计结构新颖的五元环苯并磺内酰胺类小分子微管蛋白抑制剂。
合成反应分别以苯磺酰氯和1,2-亚甲二氧基苯为原料,通过磺化、氨解、亲核加成及环合等反应得到目标产物。通过优化环合反应条件,开辟了合成3位单取代苯并磺内酰胺的新途径,并合成了两个系列共23个全新结构的化合物。所合成化合物的化学结构由IR、MS以及~1H-NMR光谱分析确证。
将设计合成的化合物进行了初步的抑制微管蛋白聚合、细胞生长抑制活性筛选。结果显示,化合物虽然对微管蛋白聚合及细胞生长有一定的抑制作用,但是活性不高。这可能是由以下原因造成的:首先,由于目标化合物溶解性不是很好,导致测试溶液中有效浓度的降低而使得活性丧失;其次,目标化合物为消旋体,计算机对接结果显示S型与秋水仙碱结合腔匹配性较好,R型则匹配较差。
总之,我们以微管蛋白为靶点,采用基于片段的药物设计新理念,以微管蛋白抑制剂ABT-751分子中的苯磺酰胺结构片段和作用于微管蛋白同一靶点的天然产物鬼臼毒素等分子中的多酚醚结构片段为基础,结合计算机辅助药物设计,设计并合成两个系列全新结构的五元环3位单取代苯并磺内酰胺衍生物,并对部分化合物进行了体外微管蛋白聚合抑制和细胞生长抑制活性筛选。这为进一步设计新型微管蛋白抑制剂奠定了基础。
Cancer is a common and frequently-occurring disease that threatens the human life seriously and causes mortality only second to cardiovascular vessel diseases. Tumor cells proliferate rapidly, and the cell cycle is obviously shorter than normal cell. The tubulin/microtubule system is an integral component of the cytoskeleton. Microtubules are highly dynamic structures that play a critical role in orchestrating the separation and segregation of chromosomes during mitosis. This makes microtubules highly valued as anticancer drug targets.
Antimitotic agents that target the dynamic equilibrium between the microtubule polymer and tubulin heterodimers are key components of chemotherapeutic regimens for various solid tumors. These agents can be divided into two major classes based on their effect on microtubule polymerization and the mass of microtubule polymers: those that inhibit polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The agents that inhibit tubulin polymerization bind toβ-tubulin, and make cells in G_2/M arrest. The microtubule-stabilizing agents bind to two classes of sites on tubulin: the colchicine, and Vinca domains. But their mechanism of action are similar. They bind toβ-tubulin to form "drug-proteinum" complex reversibly, so they can prevent other protein to bind, resulting in inhibition of tubulin polymerization. At the same time they inhibit the formation of spindles through inducing the depolymerization of microtubule. These actions make cells in M arrest. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use in solid tumors, but their usefulness is often limited by development of drug resistance. In recent years, small-molecule antimitotic agents have been a focus in the development of effective anticancer drugs. Among them, ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization and currently undergoing clinical evaluation for the treatment of many kinds of tumors.
On the other hand, the polyphenolic pharmacophore are widely existed in the molecules of many antimitotic agents like colchicines, podophyllotoxin, Combretastatin A4, among others.
Fragment-based drug design has become an important and powerful tool for the discovery and optimization of new drug leads. Base on the binding models of colchicine site in tubulin, making use of the fragment-based drug design approach, with the help of computer-assisted drug design, we designed a series of five-membered benzosultams in order to discover novel antimitotic agents. These compounds have the key features that combine the sulfonamide fragment and the important polyphenolic pharmacophore in one molecule.
We have developed a novel method for the synthesis of 3-monosubstitued five-membered benzosultams. Based on our new method, 23 compounds with different substituens at A-ring or C-ring have been synthesized. All of them have been characterized by IR, MS and ~1H-NMR spectral analysis.
Some of the synthesized benzosultam analogues have been analyzed for tubulin destabilization activity using commercial reagents with fluorescence detection. The preliminary results showed that these analogs appears capable of inhibiting tubulin polymerization to some extent, but the levels of activity measured in these assays does not appear to demonstrate meaningful activity that can be expected to significantly impact cancer cell proliferation. Some of the synthesized benzosultams have also been analyzed for growth inhibition activity using breast cancer cells. The results indicate these compounds have much lower growth inhibition activity than podophyllotoxin or colchicine. The poor solubility in water and the racemic properties may attribute, in part, to the low activities in the bioassay tests.
In summary, based on the sulfonamide fragment and the polyphenolic pharmacophore, with the aid of computer-assisted drug design, we have designed and synthesized novel benzosultams as antimitotic agents. The tubulin destabilization activity and the cell growth inhibition activity have been also studied. Our researches may provide useful information for further design of small-molecule antimitotic drugs.
抗有丝分裂药物在肿瘤治疗中发挥着重要的作用。它们主要通过破坏微管蛋白/微管之间的动态循环(聚合和解聚)来治疗各种实体肿瘤。根据对微管作用的不同将药物分为两类:抑制微管蛋白聚合的药物,如长春碱类;稳定微管的药物,如紫杉烷类和埃坡霉素类。抑制微管蛋白聚合的药物通过与β微管蛋白结合使细胞分裂停止于G_2/M期;稳定微管的药物有两个不同的结合位点:秋水仙碱位点和长春碱位点,但作用机制相似,即可逆地与β微管蛋白结合形成“药物-蛋白”复合物,阻止其他蛋白单体的继续添加而抑制微管的聚合,同时还通过诱导微管的解聚抑制纺锤体的形成,使细胞的有丝分裂停止于M期。紫杉醇与多西他赛是最早用于治疗实体瘤的微管蛋白抑制剂,但由于耐药性的出现,使其应用受到局限。近年来,小分子微管蛋白抑制剂研究方面取得了很大的进展。其中,磺胺类药物ABT-751可以口服给药,生物利用度高。它通过与秋水仙碱结合位点β微管蛋白结合,抑制微管的聚合,现已进行临床研究。
另一方面,秋水仙碱、鬼臼毒素、Combretastatin A-4(CA-4)等天然抗肿瘤药物分子中的多酚醚类结构是抑制微管蛋白聚合的主要药效团之一。
基于片断的药物设计(Fragment based drug design)是近年来发展、成熟起来的寻找先导化合物的有效方法。本文基于微管蛋白秋水仙碱结合腔的特点,以微管蛋白抑制剂ABT-751分子中的苯磺酰胺结构片段和作用于微管蛋白同一靶点的天然产物鬼臼毒素等分子中的多酚醚结构片段为基础,利用基于片断的药物设计方法并结合计算机辅助药物设计,设计结构新颖的五元环苯并磺内酰胺类小分子微管蛋白抑制剂。
合成反应分别以苯磺酰氯和1,2-亚甲二氧基苯为原料,通过磺化、氨解、亲核加成及环合等反应得到目标产物。通过优化环合反应条件,开辟了合成3位单取代苯并磺内酰胺的新途径,并合成了两个系列共23个全新结构的化合物。所合成化合物的化学结构由IR、MS以及~1H-NMR光谱分析确证。
将设计合成的化合物进行了初步的抑制微管蛋白聚合、细胞生长抑制活性筛选。结果显示,化合物虽然对微管蛋白聚合及细胞生长有一定的抑制作用,但是活性不高。这可能是由以下原因造成的:首先,由于目标化合物溶解性不是很好,导致测试溶液中有效浓度的降低而使得活性丧失;其次,目标化合物为消旋体,计算机对接结果显示S型与秋水仙碱结合腔匹配性较好,R型则匹配较差。
总之,我们以微管蛋白为靶点,采用基于片段的药物设计新理念,以微管蛋白抑制剂ABT-751分子中的苯磺酰胺结构片段和作用于微管蛋白同一靶点的天然产物鬼臼毒素等分子中的多酚醚结构片段为基础,结合计算机辅助药物设计,设计并合成两个系列全新结构的五元环3位单取代苯并磺内酰胺衍生物,并对部分化合物进行了体外微管蛋白聚合抑制和细胞生长抑制活性筛选。这为进一步设计新型微管蛋白抑制剂奠定了基础。
Cancer is a common and frequently-occurring disease that threatens the human life seriously and causes mortality only second to cardiovascular vessel diseases. Tumor cells proliferate rapidly, and the cell cycle is obviously shorter than normal cell. The tubulin/microtubule system is an integral component of the cytoskeleton. Microtubules are highly dynamic structures that play a critical role in orchestrating the separation and segregation of chromosomes during mitosis. This makes microtubules highly valued as anticancer drug targets.
Antimitotic agents that target the dynamic equilibrium between the microtubule polymer and tubulin heterodimers are key components of chemotherapeutic regimens for various solid tumors. These agents can be divided into two major classes based on their effect on microtubule polymerization and the mass of microtubule polymers: those that inhibit polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The agents that inhibit tubulin polymerization bind toβ-tubulin, and make cells in G_2/M arrest. The microtubule-stabilizing agents bind to two classes of sites on tubulin: the colchicine, and Vinca domains. But their mechanism of action are similar. They bind toβ-tubulin to form "drug-proteinum" complex reversibly, so they can prevent other protein to bind, resulting in inhibition of tubulin polymerization. At the same time they inhibit the formation of spindles through inducing the depolymerization of microtubule. These actions make cells in M arrest. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use in solid tumors, but their usefulness is often limited by development of drug resistance. In recent years, small-molecule antimitotic agents have been a focus in the development of effective anticancer drugs. Among them, ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization and currently undergoing clinical evaluation for the treatment of many kinds of tumors.
On the other hand, the polyphenolic pharmacophore are widely existed in the molecules of many antimitotic agents like colchicines, podophyllotoxin, Combretastatin A4, among others.
Fragment-based drug design has become an important and powerful tool for the discovery and optimization of new drug leads. Base on the binding models of colchicine site in tubulin, making use of the fragment-based drug design approach, with the help of computer-assisted drug design, we designed a series of five-membered benzosultams in order to discover novel antimitotic agents. These compounds have the key features that combine the sulfonamide fragment and the important polyphenolic pharmacophore in one molecule.
We have developed a novel method for the synthesis of 3-monosubstitued five-membered benzosultams. Based on our new method, 23 compounds with different substituens at A-ring or C-ring have been synthesized. All of them have been characterized by IR, MS and ~1H-NMR spectral analysis.
Some of the synthesized benzosultam analogues have been analyzed for tubulin destabilization activity using commercial reagents with fluorescence detection. The preliminary results showed that these analogs appears capable of inhibiting tubulin polymerization to some extent, but the levels of activity measured in these assays does not appear to demonstrate meaningful activity that can be expected to significantly impact cancer cell proliferation. Some of the synthesized benzosultams have also been analyzed for growth inhibition activity using breast cancer cells. The results indicate these compounds have much lower growth inhibition activity than podophyllotoxin or colchicine. The poor solubility in water and the racemic properties may attribute, in part, to the low activities in the bioassay tests.
In summary, based on the sulfonamide fragment and the polyphenolic pharmacophore, with the aid of computer-assisted drug design, we have designed and synthesized novel benzosultams as antimitotic agents. The tubulin destabilization activity and the cell growth inhibition activity have been also studied. Our researches may provide useful information for further design of small-molecule antimitotic drugs.
引文
[1]Benson JD,Chen Y-NP,Comell-Kennon SA,et al.Validating Cancer Drug Targets[J].Nature 2006,441:451-456.
[2]Narayanan BA.Chemopreventive Agents Alters Global Gene Expression Pattern:Predicting Their Mode of Action and Targets[J].Curr Cancer Drug Targets 2006,6(8):711-727.
[3]Jordan MA,Wilson L.Microtubules as a Target for Anticancer Drugs[J].Nat.Rev.Cancer 2004,4(4):253-265.
[4]任萱,孙启明,林莉萍等.肿瘤血管靶向药物的研究进展[J].生命科学 2007,19(4):427-433.
[5]李耀武,周有骏,朱驹.作用于微管的抗肿瘤药物研究进展[J].国外医学药学分册,2005,32(1):1-5.
[6]韩贻仁.分子细胞生物学(第二版)[M].北京:科学出版社,2001:244-245.
[7]罗深秋.医用细胞生物学[M].第二军医大学出版社,2004:140-143.
[8]凌诒萍.细胞生物学[M].北京:人民卫生出版社,119-121.
[9]Wam MC,Tayor HL,Wall ME,et al.Plant antitumor agents.VI.The isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxus brevifolia[J].J Am Chem Soc,1971,93(9):2325-2327.
[10]Haar ET,Kowalski RJ,Hamel E,et al.Discodermolide,a cytotoxic marine agent that stabilizes microtubules more potently than taxol[J].Biochemistry,1996,35:243-250.
[11]Bollag DM.,McQueney PA,Zhu J,et al.Epothilones,a new class of microtubule-stabilizing agents with a taxol-like mechanism of action[J].Cancer Res,1995,55:2325-2333.
[12]徐志南,郑建明.新型天然抗肿瘤药物埃坡霉素研究进展[J].中国药学杂志,2003,38(9):648-651.
[13]Medrano FJ,Andreu JM,Gorbunoff MJ,et al.Roles of colchicine tings B and C in the binding process to tubulin[J].Biochemistry,1989,28(13):5589-5599.
[14]南京药学院主编.药物化学[M].北京:人民卫生出版社,1918:513.
[15]Rosner M,Capraro HG,Jacobson AE,et al.Biological effects of modified colchicines.Improved preparation of 2-demethylcolchicine,3-demethylcolchicine,and(+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines[J].J Med Chem,1981,24(3):257-261.
[16]Cersosimo RJ,Bromer R,Licciardello JT,et al.Pharmacology,clinical efficacy and adverse effects of vindesine sulfate,a new vinca alkaloid[J].Pharmacotherapy,1983,3(5):259-274.
[17]Goa KL,Faulds D.A review of its pharmacological properties and clinical use in cancer chemotherapy[J].Drugs Aging,1994,5(3):200-234.
[18]王瑾,王宫.长春碱类化合物的研究概况[J].福建中医学院学报,2005,15(增刊):88-89.
[19]Fahy J,Duflos A,Ribet J-P,et al.Vinca alkaloids in superacidic media:a method for creating a new family of antitumor derivatives[J].J Am Chem Soc,1997,119:8576-8577.
[20]肖亮,全海天,徐永平等.长春氟宁抗肿瘤作用的研究[J].中国药理学通报,2007,23(4):507-511.
[21]Stahelin HF,Wartburg AV.The chemical and biological route from podophyllotoxin glucoside to etoposide:ninth cain memorial award lecture[J].Cancer Res,1991,51(1):5-15.
[22]Gordaliza M,Garcia PA,Corral JMM,et al.Podophyllotoxin:distribution,sources,applications and new cytotoxic derivatives[J].Toxicon,2004,44(4):441-459.
[23]Pei-nan Z,Zhao-feng L,Chang-qi Z.Podophyllotoxin and its derivatives[J].Natural Product Research and Development,2004,16(1):80-83.
[24]Edwards ML,Stemerick DM,Sunkara PS.Chalcones:a new class of antimitotic agents[J].J Med Chem,1990,33(7):1948-1954.
[25]Silence K,D'Hoore A,Englborghs Y,et al.Fluorescence stopped-flow study of the interaction of tubulin with the antimitotic drug MDL27048[J].Biochemistry,1992,31(45):11133-11137.
[26]Wheeler GP,Bowdon BJ,Temple C,et al.Biological effects and structure-activity relationships of 1,2-dihydropyrido[3,4-b]pyrazines[J].Cancer Res,1983,43(8):3567-3575.
[27]de Ines C,Leynadier D,Barasoain I,et al.Inhibition of microtubules and cell cycle arrest by a new 1-deaza-7,8-dihydropteridine antitumour drug,CI-980,and by its chiral isomer,NSC 613863[J].Cancer Res,1994,54(1):75-84.
[28]Jiang JD,Roboz J,Weisz I,et al.Synthesis,cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas[J].Anticancer Drug Des,1998,13(7):735-747.
[29]Li JN,Song DQ,Lin YH,et al.Inhibition of microtubule polymerization by 3-bromopropionylamino benzoylurea(JIMB01),a new cancericidal tubulin ligand[J].Biochem Pharmacol,2003,65(10):1691-1699.
[30]Okada H,Koyanagi T,Yamada N,et al.Synthesis and antitumor activities of novel benzoylphenylurea derivatives[J].Chem Pham Bull(Tokyo),1991,39(9):2308-2315.
[32]Navia MA.A chicken in every pot,thanks to sulfonamide drug[J].Science,2000,288(5474):2132-2133.
[33]Drews J.Drug discovery:a historical perspective[J].Science,2000,287(5460):1960-1964.
[34]郑虎.药物化学[M].北京:人民卫生出版社,2001,348-353.
[35]Winum JY,Scozzafava A,Montero JL,et al.Therapeutic potential of sulfamides as enzyme inhibitors[J].Med.Res.Rev.2006,26(6):767-792.
[36]Winum JY,Scozzafava A,Montero JL,et al.Sulfamates and their therapeutic potential[J].Med.Res.Rev.2005,25(2):186-228.
[37]Nicolas C,Veiny M,Giraud I,et al.New quaternary ammonium oxicam derivatives targeted toward cartilage:synthesis,pharmacokinetic studies,and antiinflammatory potentcy[J].J Med Chem,1999,42(25):5235-5240.
[38]Novello FC,Sprague JM.Benzothiadiazine dioxides as novel diuretics[J].J Am Chem Soc,1957,79(8):2028-2029.
[39]Cohen E,Klarberg B,Vaughan JR.Quinazolinone sulfonamides as diuretic agents[J].J Am Chem Soc,1959,81(20):5508-5509.
[40] Yoshino H, Ueda N, Niijima J, et al. Novol sulfonamides as potential, systemically active antitumor agents[J]. J Med Chem, 1992,35(13): 2496-2497.
[41] Yoshimatsu K, Yamaguchi A, Yoshino H, et al. Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin[J]. Cancer Res, 1997, 57: 3208-3213.
[42] Yee KWL, Hagey A, Verstovsek S, et al. Phase I study of ABT-751, a novol microtubule inhibitor, in patents with refractory Hematologic Malignancies[J]. Clin Cancer Res, 2005, 11: 6615-6624.
[43] Siemann DW, Bibby MC, Dark GG, et al. Differentiation and definition of vascular-targeted therapies[J]. Clin Cancer Res, 2005, 11:461-420.
[44] Mohan R, Banerjee M, Ray A, et al. Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation[J]. Biochemistry, 2006, 45(17),5440-5449.
[45] Mohan R, Banerjee M, Ray A, et al. Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation[J]. Biochemistry, 2006, 45(17),5440-5449.
[46] Lebegue N, Gallet S, Flouquet N, et al. Novel benzopyridothiadiazepines as potential active antitumor agents[J]. J Med Chem, 2005, 48(23): 7363-7373.
[47] Chang JY, Hsieh HP, Chang CY, et al. 7-Aroyl-aminoindoline-1 -sulfonamides as a novel class of potent antitubulin agents[J]. J Med Chem, 2006, 49(23): 6656-6659.
[48] Lambert JD, Hong J, Yang G, et al. Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations[J]. Am J Clin Nutr, 2005, 81(suppl): 284s-291s.
[49] Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57(10):1829-1834.
[50] Lin CM, Ho HH, Pettit GR, et al. Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin[J]. Biochemistry, 1989, 28(17): 6984-6991.
[51]任萱,林莉萍,丁健.Combretastatin A4的抗肿瘤作用研究进展[J].中国新药杂志,2007,16(7):1336-1341.
[52]Zhang Q,Peng Y,Wang XI,et al.Highly potent triazole-based tubulin polymerization inhibitors[J].J Med Chem,2007,50(4):749-754.
[53]Pirali T,Busacca S,Beltrami L,et al.Synthesis and cytotoxic evaluation of combretafurans,potential scaffolds for dual-action antitumoral agents[J].J Med Chem,2006,49(17):5372-5376.
[54]Simoni D,Romagnoli R,Baruchello R,et al.Novel combretastatin analogues endowed with antitumor activity[J].J Med Chem,2006,49(11):3143-3152.
[55]Chang JY,Yang MF,Chang CY,et al.2-Amino and 2'-aminocombretastatin derivatives as potent antitumor agents[J].J Med Chem,2006,49(21):6412-6415.
[56]Romagnoli R,Baraldi PG,Remusat V,et al.Synthesis and biological evaluation of 2-(3',4',5'-trimethoxybenzoyl)-3-amino 5-aryl thiophenes as a new class of tubulin inhibitors[J].J Med Chem,2006,49(21):6425-6428.
[57]Mahmoudian M,Mehrpour M,Benaissa F,et al.Apreliminary report on the application of noscapine in the treatment of stoke[J].Eur J Clin Pharmacol,2003,59(8-9):579-581.
[58]Ke Y,Ye K,Grossniklaus HE,et al.Noscapine inhibits tumor growth with little toxicity to normal tissues or inhibition of immune responses[J].Cancer Immunol Immunother,2000,49(4-5):217-225.
[59]Ye K,Ke Y,Keshava N,et al.Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells[J].Proc Natl Acad Sci USA,1998,95(4):1601-1606.
[60]Anderson JT,Ting AE,Boozer S,et al.Discovery of S-phase arresting agents derived from noscapine[J].J Med Chem,2005,48(8):2756-2758.
[61]Zhou J,Gupta K,Aggarwal S,et al.Brominated derivatives of noscapine are potent microtubule-interfering agents that perturb mitosis and inhibit cell proliferation[J].Mol Pharmacol,2003,63(4):799-807.
[62]Zhou J,Liu M,Luthra R,et al.EM012,a microtubule-interfering agent,inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice[J].Cancer Chemother Pharmacol,2005,55(5):461-465.
[63]Hajduke PJ,Greer J.A decade of fragment-based drug design:strategic advances and lessons learned[J].Nat Rev Drug Discov,2007,6(3):211-219.
[64]Erlanson DA,McDowell RS,O'Brien T.Fragment-based drug discovery[J].J Med Chem,2004,47(14):3463-3481.
[65]Nguyen TL,McGrath C,Hermone AR,et al.A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach[J].J Med Chem,2005,48(19):6107-6116.
[66]李耀武,周有骏,朱驹等.秋水仙碱位点抑制剂的结构特征研究[J].药学实践杂志,2007,25(6):372-375.
[67]Kim DY,Kim KH,Kim ND,et al.Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin[J].J Med Chem,2006,49(19):5664-5670.
[68]Lane C,Snieckus V.Combined directed ortho metalation-Grubbs metathesis tactics.Synthesis of benzazepine,benzazocine,and benzannulated 7-,8-,9-,and 15-membered ring sulfonamide heterocycles[J].Synlett,2000,9:1294-1296.
[69]Ahn KH,Ham C,Kim SK,et al.Practical synthesis of chiral sultam auxiliaries:3-substituted-1,2-benzisothiazolinel,1-dioxides[J].J Org Chem,1997,62(20):7047-7048.
[70]Dauban P,Dodd RH.Synthesis of cyclic sulfonamides via intramolecular copper-catalyzed reaction of unsaturated iminoiodinanes[J].Org.Lett,2000,2(15),2327-2329.
[71]Olay GA,Narano SC.Iodotrimethylsilane—a versatile synthetic reagent[J].Tetrahedron,1982,38(15):2225-2277.
[72]Liu ZP,Shibata N,Takeuchi Y.Facile synthesis of disubstituted and spiro five-membered benzosultams mediated by TMSCl-NaI-MeCN reagent[J].J Chem Soc,Perkins Trans 1,2002:302-303.
[73]Liu ZP,Shibata N,Takeuchi Y.Novel methods for the facile construction of 3,3-disubstituted and 3,3-spiro-2H,4H-benzo[e]1,2-thiazine-1,1-diones:synthesis of(11S,12R,14R)-2-fluoro-14-methyl-11-(methylethyl)spiro[4H-benzo[e]-1,2-thi azine-3,2'-cyclohexane]-1,1-dione,an agent for the electrophilic asymmetric fluorination of aryl ketone enolates[J].J Org Chem,2000,65(22):7583-7587.
[74]Togo H,Iida S.Synthetic use of molecular iodine for organic synthesis[J].Synlett,2006,14:2159-2175.
[75]Olah GA,Nearing SC,Salem GF,et al.Synthetic methods and reactions;90.Iodotrimethylsilane-mediated mild and neutral transesterification of esters[J].Synthesis,1981:142-143.
[76]Lombardino JG.Preparation of substituted 1,2-benzoisothiazolin-3-one 1,1-dioxides(o-benzoic sulfimides)[J].J Org Chem,1971,36(13):1843-1845.
[77]MacNeil SL,Familoni OB,Snieckus V.Selective Ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides.Ipso-bromo desilylation and Suzuki cross-coupling reactions[J].J Org Chem,2001,66:3662-3670.
[78]Snieckus V.Directed ortho metalation.Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics[J].Chem Rev,1990,90(6):879-933.
[79]Watanabe H,Gay RL,Hauser CR.Ortho metalation of N-substituted benzenesulfonamides by excess N-butyllithium.Condensation with carbonyl compounds[J].J Org Chem,1968,33(2):900-903.
[80]Jung ME,Lyster MA.Quantitative dealkylation of alkyl ethers via treatment with trimethylsilyl iodide.A new method for ether hydrolysis[J].J Org Chem,1977,42(23):3761-3764.
[81]李英奇,彭雨春.三甲基氯硅烷在有机合成中的应用进展[J].精细化工中间体,2005,35(3):1-4.
[82]Shibata N,Liu ZP,Takeuchi Y.Novel enantioselective fluorinating agents,(R)-and(S)-N-fluoro-3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]thiazine1,2-dioxides[J].Chem Pham Bull,48(12):1954-1958.
[83]Inagaki M,Tsuri T,Jyoyama H,et al.Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide(γ-sultam)skeleton:cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase[J].J Med Chem,2000,43(10):2040-2048.
[2]Narayanan BA.Chemopreventive Agents Alters Global Gene Expression Pattern:Predicting Their Mode of Action and Targets[J].Curr Cancer Drug Targets 2006,6(8):711-727.
[3]Jordan MA,Wilson L.Microtubules as a Target for Anticancer Drugs[J].Nat.Rev.Cancer 2004,4(4):253-265.
[4]任萱,孙启明,林莉萍等.肿瘤血管靶向药物的研究进展[J].生命科学 2007,19(4):427-433.
[5]李耀武,周有骏,朱驹.作用于微管的抗肿瘤药物研究进展[J].国外医学药学分册,2005,32(1):1-5.
[6]韩贻仁.分子细胞生物学(第二版)[M].北京:科学出版社,2001:244-245.
[7]罗深秋.医用细胞生物学[M].第二军医大学出版社,2004:140-143.
[8]凌诒萍.细胞生物学[M].北京:人民卫生出版社,119-121.
[9]Wam MC,Tayor HL,Wall ME,et al.Plant antitumor agents.VI.The isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxus brevifolia[J].J Am Chem Soc,1971,93(9):2325-2327.
[10]Haar ET,Kowalski RJ,Hamel E,et al.Discodermolide,a cytotoxic marine agent that stabilizes microtubules more potently than taxol[J].Biochemistry,1996,35:243-250.
[11]Bollag DM.,McQueney PA,Zhu J,et al.Epothilones,a new class of microtubule-stabilizing agents with a taxol-like mechanism of action[J].Cancer Res,1995,55:2325-2333.
[12]徐志南,郑建明.新型天然抗肿瘤药物埃坡霉素研究进展[J].中国药学杂志,2003,38(9):648-651.
[13]Medrano FJ,Andreu JM,Gorbunoff MJ,et al.Roles of colchicine tings B and C in the binding process to tubulin[J].Biochemistry,1989,28(13):5589-5599.
[14]南京药学院主编.药物化学[M].北京:人民卫生出版社,1918:513.
[15]Rosner M,Capraro HG,Jacobson AE,et al.Biological effects of modified colchicines.Improved preparation of 2-demethylcolchicine,3-demethylcolchicine,and(+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines[J].J Med Chem,1981,24(3):257-261.
[16]Cersosimo RJ,Bromer R,Licciardello JT,et al.Pharmacology,clinical efficacy and adverse effects of vindesine sulfate,a new vinca alkaloid[J].Pharmacotherapy,1983,3(5):259-274.
[17]Goa KL,Faulds D.A review of its pharmacological properties and clinical use in cancer chemotherapy[J].Drugs Aging,1994,5(3):200-234.
[18]王瑾,王宫.长春碱类化合物的研究概况[J].福建中医学院学报,2005,15(增刊):88-89.
[19]Fahy J,Duflos A,Ribet J-P,et al.Vinca alkaloids in superacidic media:a method for creating a new family of antitumor derivatives[J].J Am Chem Soc,1997,119:8576-8577.
[20]肖亮,全海天,徐永平等.长春氟宁抗肿瘤作用的研究[J].中国药理学通报,2007,23(4):507-511.
[21]Stahelin HF,Wartburg AV.The chemical and biological route from podophyllotoxin glucoside to etoposide:ninth cain memorial award lecture[J].Cancer Res,1991,51(1):5-15.
[22]Gordaliza M,Garcia PA,Corral JMM,et al.Podophyllotoxin:distribution,sources,applications and new cytotoxic derivatives[J].Toxicon,2004,44(4):441-459.
[23]Pei-nan Z,Zhao-feng L,Chang-qi Z.Podophyllotoxin and its derivatives[J].Natural Product Research and Development,2004,16(1):80-83.
[24]Edwards ML,Stemerick DM,Sunkara PS.Chalcones:a new class of antimitotic agents[J].J Med Chem,1990,33(7):1948-1954.
[25]Silence K,D'Hoore A,Englborghs Y,et al.Fluorescence stopped-flow study of the interaction of tubulin with the antimitotic drug MDL27048[J].Biochemistry,1992,31(45):11133-11137.
[26]Wheeler GP,Bowdon BJ,Temple C,et al.Biological effects and structure-activity relationships of 1,2-dihydropyrido[3,4-b]pyrazines[J].Cancer Res,1983,43(8):3567-3575.
[27]de Ines C,Leynadier D,Barasoain I,et al.Inhibition of microtubules and cell cycle arrest by a new 1-deaza-7,8-dihydropteridine antitumour drug,CI-980,and by its chiral isomer,NSC 613863[J].Cancer Res,1994,54(1):75-84.
[28]Jiang JD,Roboz J,Weisz I,et al.Synthesis,cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas[J].Anticancer Drug Des,1998,13(7):735-747.
[29]Li JN,Song DQ,Lin YH,et al.Inhibition of microtubule polymerization by 3-bromopropionylamino benzoylurea(JIMB01),a new cancericidal tubulin ligand[J].Biochem Pharmacol,2003,65(10):1691-1699.
[30]Okada H,Koyanagi T,Yamada N,et al.Synthesis and antitumor activities of novel benzoylphenylurea derivatives[J].Chem Pham Bull(Tokyo),1991,39(9):2308-2315.
[32]Navia MA.A chicken in every pot,thanks to sulfonamide drug[J].Science,2000,288(5474):2132-2133.
[33]Drews J.Drug discovery:a historical perspective[J].Science,2000,287(5460):1960-1964.
[34]郑虎.药物化学[M].北京:人民卫生出版社,2001,348-353.
[35]Winum JY,Scozzafava A,Montero JL,et al.Therapeutic potential of sulfamides as enzyme inhibitors[J].Med.Res.Rev.2006,26(6):767-792.
[36]Winum JY,Scozzafava A,Montero JL,et al.Sulfamates and their therapeutic potential[J].Med.Res.Rev.2005,25(2):186-228.
[37]Nicolas C,Veiny M,Giraud I,et al.New quaternary ammonium oxicam derivatives targeted toward cartilage:synthesis,pharmacokinetic studies,and antiinflammatory potentcy[J].J Med Chem,1999,42(25):5235-5240.
[38]Novello FC,Sprague JM.Benzothiadiazine dioxides as novel diuretics[J].J Am Chem Soc,1957,79(8):2028-2029.
[39]Cohen E,Klarberg B,Vaughan JR.Quinazolinone sulfonamides as diuretic agents[J].J Am Chem Soc,1959,81(20):5508-5509.
[40] Yoshino H, Ueda N, Niijima J, et al. Novol sulfonamides as potential, systemically active antitumor agents[J]. J Med Chem, 1992,35(13): 2496-2497.
[41] Yoshimatsu K, Yamaguchi A, Yoshino H, et al. Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin[J]. Cancer Res, 1997, 57: 3208-3213.
[42] Yee KWL, Hagey A, Verstovsek S, et al. Phase I study of ABT-751, a novol microtubule inhibitor, in patents with refractory Hematologic Malignancies[J]. Clin Cancer Res, 2005, 11: 6615-6624.
[43] Siemann DW, Bibby MC, Dark GG, et al. Differentiation and definition of vascular-targeted therapies[J]. Clin Cancer Res, 2005, 11:461-420.
[44] Mohan R, Banerjee M, Ray A, et al. Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation[J]. Biochemistry, 2006, 45(17),5440-5449.
[45] Mohan R, Banerjee M, Ray A, et al. Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation[J]. Biochemistry, 2006, 45(17),5440-5449.
[46] Lebegue N, Gallet S, Flouquet N, et al. Novel benzopyridothiadiazepines as potential active antitumor agents[J]. J Med Chem, 2005, 48(23): 7363-7373.
[47] Chang JY, Hsieh HP, Chang CY, et al. 7-Aroyl-aminoindoline-1 -sulfonamides as a novel class of potent antitubulin agents[J]. J Med Chem, 2006, 49(23): 6656-6659.
[48] Lambert JD, Hong J, Yang G, et al. Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations[J]. Am J Clin Nutr, 2005, 81(suppl): 284s-291s.
[49] Dark GG, Hill SA, Prise VE, et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature[J]. Cancer Res, 1997, 57(10):1829-1834.
[50] Lin CM, Ho HH, Pettit GR, et al. Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin[J]. Biochemistry, 1989, 28(17): 6984-6991.
[51]任萱,林莉萍,丁健.Combretastatin A4的抗肿瘤作用研究进展[J].中国新药杂志,2007,16(7):1336-1341.
[52]Zhang Q,Peng Y,Wang XI,et al.Highly potent triazole-based tubulin polymerization inhibitors[J].J Med Chem,2007,50(4):749-754.
[53]Pirali T,Busacca S,Beltrami L,et al.Synthesis and cytotoxic evaluation of combretafurans,potential scaffolds for dual-action antitumoral agents[J].J Med Chem,2006,49(17):5372-5376.
[54]Simoni D,Romagnoli R,Baruchello R,et al.Novel combretastatin analogues endowed with antitumor activity[J].J Med Chem,2006,49(11):3143-3152.
[55]Chang JY,Yang MF,Chang CY,et al.2-Amino and 2'-aminocombretastatin derivatives as potent antitumor agents[J].J Med Chem,2006,49(21):6412-6415.
[56]Romagnoli R,Baraldi PG,Remusat V,et al.Synthesis and biological evaluation of 2-(3',4',5'-trimethoxybenzoyl)-3-amino 5-aryl thiophenes as a new class of tubulin inhibitors[J].J Med Chem,2006,49(21):6425-6428.
[57]Mahmoudian M,Mehrpour M,Benaissa F,et al.Apreliminary report on the application of noscapine in the treatment of stoke[J].Eur J Clin Pharmacol,2003,59(8-9):579-581.
[58]Ke Y,Ye K,Grossniklaus HE,et al.Noscapine inhibits tumor growth with little toxicity to normal tissues or inhibition of immune responses[J].Cancer Immunol Immunother,2000,49(4-5):217-225.
[59]Ye K,Ke Y,Keshava N,et al.Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells[J].Proc Natl Acad Sci USA,1998,95(4):1601-1606.
[60]Anderson JT,Ting AE,Boozer S,et al.Discovery of S-phase arresting agents derived from noscapine[J].J Med Chem,2005,48(8):2756-2758.
[61]Zhou J,Gupta K,Aggarwal S,et al.Brominated derivatives of noscapine are potent microtubule-interfering agents that perturb mitosis and inhibit cell proliferation[J].Mol Pharmacol,2003,63(4):799-807.
[62]Zhou J,Liu M,Luthra R,et al.EM012,a microtubule-interfering agent,inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice[J].Cancer Chemother Pharmacol,2005,55(5):461-465.
[63]Hajduke PJ,Greer J.A decade of fragment-based drug design:strategic advances and lessons learned[J].Nat Rev Drug Discov,2007,6(3):211-219.
[64]Erlanson DA,McDowell RS,O'Brien T.Fragment-based drug discovery[J].J Med Chem,2004,47(14):3463-3481.
[65]Nguyen TL,McGrath C,Hermone AR,et al.A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach[J].J Med Chem,2005,48(19):6107-6116.
[66]李耀武,周有骏,朱驹等.秋水仙碱位点抑制剂的结构特征研究[J].药学实践杂志,2007,25(6):372-375.
[67]Kim DY,Kim KH,Kim ND,et al.Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin[J].J Med Chem,2006,49(19):5664-5670.
[68]Lane C,Snieckus V.Combined directed ortho metalation-Grubbs metathesis tactics.Synthesis of benzazepine,benzazocine,and benzannulated 7-,8-,9-,and 15-membered ring sulfonamide heterocycles[J].Synlett,2000,9:1294-1296.
[69]Ahn KH,Ham C,Kim SK,et al.Practical synthesis of chiral sultam auxiliaries:3-substituted-1,2-benzisothiazolinel,1-dioxides[J].J Org Chem,1997,62(20):7047-7048.
[70]Dauban P,Dodd RH.Synthesis of cyclic sulfonamides via intramolecular copper-catalyzed reaction of unsaturated iminoiodinanes[J].Org.Lett,2000,2(15),2327-2329.
[71]Olay GA,Narano SC.Iodotrimethylsilane—a versatile synthetic reagent[J].Tetrahedron,1982,38(15):2225-2277.
[72]Liu ZP,Shibata N,Takeuchi Y.Facile synthesis of disubstituted and spiro five-membered benzosultams mediated by TMSCl-NaI-MeCN reagent[J].J Chem Soc,Perkins Trans 1,2002:302-303.
[73]Liu ZP,Shibata N,Takeuchi Y.Novel methods for the facile construction of 3,3-disubstituted and 3,3-spiro-2H,4H-benzo[e]1,2-thiazine-1,1-diones:synthesis of(11S,12R,14R)-2-fluoro-14-methyl-11-(methylethyl)spiro[4H-benzo[e]-1,2-thi azine-3,2'-cyclohexane]-1,1-dione,an agent for the electrophilic asymmetric fluorination of aryl ketone enolates[J].J Org Chem,2000,65(22):7583-7587.
[74]Togo H,Iida S.Synthetic use of molecular iodine for organic synthesis[J].Synlett,2006,14:2159-2175.
[75]Olah GA,Nearing SC,Salem GF,et al.Synthetic methods and reactions;90.Iodotrimethylsilane-mediated mild and neutral transesterification of esters[J].Synthesis,1981:142-143.
[76]Lombardino JG.Preparation of substituted 1,2-benzoisothiazolin-3-one 1,1-dioxides(o-benzoic sulfimides)[J].J Org Chem,1971,36(13):1843-1845.
[77]MacNeil SL,Familoni OB,Snieckus V.Selective Ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides.Ipso-bromo desilylation and Suzuki cross-coupling reactions[J].J Org Chem,2001,66:3662-3670.
[78]Snieckus V.Directed ortho metalation.Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics[J].Chem Rev,1990,90(6):879-933.
[79]Watanabe H,Gay RL,Hauser CR.Ortho metalation of N-substituted benzenesulfonamides by excess N-butyllithium.Condensation with carbonyl compounds[J].J Org Chem,1968,33(2):900-903.
[80]Jung ME,Lyster MA.Quantitative dealkylation of alkyl ethers via treatment with trimethylsilyl iodide.A new method for ether hydrolysis[J].J Org Chem,1977,42(23):3761-3764.
[81]李英奇,彭雨春.三甲基氯硅烷在有机合成中的应用进展[J].精细化工中间体,2005,35(3):1-4.
[82]Shibata N,Liu ZP,Takeuchi Y.Novel enantioselective fluorinating agents,(R)-and(S)-N-fluoro-3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]thiazine1,2-dioxides[J].Chem Pham Bull,48(12):1954-1958.
[83]Inagaki M,Tsuri T,Jyoyama H,et al.Novel antiarthritic agents with 1,2-isothiazolidine-1,1-dioxide(γ-sultam)skeleton:cytokine suppressive dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase[J].J Med Chem,2000,43(10):2040-2048.