氟代香豆素的合成与抗肿瘤活性研究

目的 合成具有抗肿瘤活性的氟代香豆素.方法 以四氯化锡(摩尔分数为5%) 为催化剂,取代酚与三氟乙酰乙酸乙酯(物质的量比1∶1.2),通过Pechmann缩合反应,合成氟代香豆素衍生物,以MTT法检测其抗肿瘤活性.结果 合成得到6种氟代香豆素,其中化合物1、3、4具有较好的抗肿瘤活性.结论 6种氟代香豆素中的化合物1、3、4具有开发成为抗肿瘤药物的前景.     

大黄酚的分离纯化及其在兔体内药动学及组织分布

目的建立一种利用制备型高效液相色谱(PHPLC)法纯化大黄酚的方法,并研究大黄酚在兔体内的药动学及组织分布规律。方法大黄经石油醚脱脂后,稀硫酸水解总蒽醌苷,氯仿提取苷元,去除杂质,用氢氧化钠萃取氯仿提取液中的大黄酚,酸化后,沉淀析出并真空干燥,得到大黄酚粗品。在色谱柱为ZORBAX SB-C18(21.2 mm×250 mm,7μm)、流动相为甲醇-0.1%磷酸溶液(85∶15,V/V)、流速为20 mL.min-1、检测波长为254 nm、柱温为30℃、进样量为8 mL的条件下,对大黄酚粗品进行纯化得到大黄酚单体。利用高效液相色谱研究单体大黄酚静脉注射、肌内注射、腹腔给药在兔体内的药动学及静脉给药后组织分布。结果大黄酚纯度达到98.8%,经1H-NMR鉴定,制备得到的大黄酚单体化学位移值与标准品大黄酚化学位移值一致。大黄酚静脉给药药动学符合二室开放模型,消除半衰期(155.73±0.87)min,AUC为(103.05±3.78)μg.min.mL-1,大黄酚主要分布在兔的心、肺、肝等组织中。兔腹腔注射大黄酚后,其血药浓度在150 min达峰值,浓度为0.78μg.mL-1。兔肌内注射大黄酚15和30 mg.kg-1,血浆中均不能明确测得大黄酚浓度,未发现达峰时间。结论利用PHPLC法提取高纯度大黄酚,制备工艺稳定,适用于实验室大规模制备。静脉注射大黄酚的药动学符合二室模型,药物在兔体内分布快,以消除过程为主。     

1,8-二乙酰基大黄酸-(2-溴)-乙酯的合成及对骨肉瘤MG-63细胞的作用研究

目的设计并合成新的大黄酸衍生物1,8-二乙酰基大黄酸-(2-溴)-乙酯(大黄酸衍生物B),探讨其对骨肉瘤MG-63细胞的作用和机制。方法以大黄酸为原料合成了1,8-二乙酰基大黄酸-(2-溴)-乙酯,经UV、IR、NMR确定合成产物的结构,并利用HPLC测定其纯度。采用MTT法测定大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的体外生长抑制作用;流式细胞仪检测细胞凋亡和细胞周期分布。结果经UV、IR、~1H NMR、¹³C NMR进行分子结构表征,确证合成的目标化合物为1,8-二乙酰基大黄酸-(2-溴)-乙酯,纯度>98%。MTT结果表明,大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的IC₅₀值分别为110.60、25.78μmol·L^-1。流式细胞仪检测细胞凋亡和周期结果表明,80μmol·L^-1的大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的凋亡率分别为(6.87±0.53)%、(48.84±2.20)%,且主要将细胞周期阻滞在S期。结论合成化合物1,8-二乙酰基大黄酸-(2-溴)-乙酯的体外抗肿瘤活性明显优于大黄酸,且具有阻滞骨肉瘤MG-63细胞周期进程和促进其凋亡的作用。     

3种大黄酚制剂在兔血浆中的药动学研究

目的研究大黄酚脂质体(chrysophanol liposomes)、大黄酚聚氰基丙烯酸丁酯纳米囊(chrysophanol loaded polybu-tylcyanoacrylate,Chry-PBCA-NC)、大黄酚羟丙基-β-环糊精包合物(chrysophanol-hydroxypropyl-β-cyclodextrin inclusion com-plex,Chry-HP-β-CD)在兔血浆内的药动学特征,为优选最佳的大黄酚制剂提供依据。方法将3种制剂各分为高、中、低(9、3、1 mg.kg-1)3个剂量组,分别静脉注射于家兔体内,采用高效液相色谱法测定给药后不同时间点血浆中大黄酚的浓度并计算药动学参数。结果 3种大黄酚制剂的药时曲线下面积随着剂量的增加而增加。在中、高剂量下,大黄酚聚氰基丙烯酸丁酯纳米囊相对于另两种制剂其消除相半衰期差异有显著性。结论 3种大黄酚制剂静注后的血药浓度-时间曲线均符合二室模型,在血浆中消除过程较快,大黄酚聚氰基丙烯酸丁酯纳米囊的消除最为缓慢。     

鬼臼毒素衍生物的合成及其体外抗肿瘤活性

目的 获得更高活性且具有抗多药耐药活性的抗肿瘤新化合物。方法 将4β-氨基-4-脱氧鬼臼毒素与醇类化合物以丁二酸为桥连接合成了7个鬼臼毒素衍生物,其结构经1H-NMR、TOF-MS证实。用K562和K562/AO2细胞经MTT法筛选了这些衍生物的体外抗肿瘤活性。结果 7个化合物均为新化合物,其中5b、5d的抗肿瘤活性显著高于VP-16, 并且5b、5c、5d、5e的抗多药耐药活性显著高于VP-16。结论 这些鬼臼毒素衍生物可提高抗肿瘤活性。     

大黄酸及其衍生物药理作用研究新进展

摘 要：大黄酸是中药芦荟、大黄的主要成分之一,临床上用于治疗骨关节炎、糖尿病肾病等多种疾病,且具有协同抗肿瘤的作用。鉴于其较广泛的药理作用及低毒性、低成本等特点,大黄酸有望得到进一步开发与应用。综述近几年来对大黄酸及其衍生物在抗肿瘤、抗氧化、抗炎和对消化系统、肾脏、心血管系统、骨以及调脂等方面的药理作用研究进展。     

鸦胆子根化学成分的研究

从鸦胆子〔Brucea javanica(L.)Merr.〕根的乙醇提取物中分离得到十二个单体。经理化常数及光谱分析,鉴定了其中的六个化合物:鸦胆苦醇(Brusatol)、没食子酸乙酯(Ethylgallate)、大黄素(Emodin)、大黄酚(Chrysophanol)、大黄酚葡萄糖甙(Chrysophanein)和β-谷甾醇(β-sitosterol)。该六个化合物均系首次从鸦胆子根中得到。     

HPLC法测定不同产地决明子中大黄酚含量

决明子为豆科植物决明Cassia obtusifolia L或小决明Cas-sia tora L的干燥成熟种子.具有清热明目,润肠通便的功效.主治目赤涩痛,羞明多泪,头痛眩晕,目暗不明,大便秘结[1].全国大部分地区均有栽培.主产河南、安徽、广西等地.决明子中含较多羟基蒽醌衍生物,经酸水解后变为大黄酚、大黄素甲醚、决明素等.其中大黄酚是决明子有效成分之一.目前文献报道对决明子中大黄酚测定方法有HPLC法和薄层扫描法,但对不同产地决明子中大黄酚含量测定尚未见报道,为此,本文采用HPLC法测定不同产地决明子中大黄酚含量,从而为决明子的质量研究提供依据.     

丹皮酚衍生物的合成及其抗肿瘤细胞增殖研究

以间苯二酚为原料, 经过酰化、醚化反应合成了15个丹皮酚及其衍生物, 以HeLa、MCF-7细胞为靶细胞, 采用MTT法进行了初步的体外抗肿瘤活性研究。结果表明, 4-位甲氧基是丹皮酚抗肿瘤活性的增效官能 团, 酮羰基侧链为丹皮酚抗肿瘤活性的必需官能团, 与羰基相连侧链的碳原子数小于4时, 随着侧链的延长其抗肿瘤细胞增殖活性会不断加强, 优选出的化合物2d对HeLa和MCF-7细胞株具有较显著的抗增殖活性, IC₅₀值分别为2.67和4.74 μmol·L⁻¹, 这为丹皮酚抗肿瘤活性构效关系的研究打下了基础, 值得进一步研究。     

大黄酚在兔体内药动学的研究

目的研究大黄酚静脉注射在兔体内的药动学.方法应用高效液相色谱法,以甲醇-0.1%磷酸(8020)为流动相,测定兔血浆中大黄酚(iv,10 mg·kg-1含量),采用3P87程序计算药动学参数.结果大黄酚iv药动学符合二房室开放模型,t1/2α=9.60 min,t/2β=139.27 min,K21=0.016 min-1,K12=0.039 min-1,K10=0.023min-1,AUC=73.05 mg·L-1·min,CL=0.16 L·min-1·kg-1,VC=9.60 L·kg-1.结论大黄酚在兔体内分布快,药物起效迅速,在体内主要以消除过程为主,药物在体内滞留时间较长.     

苯并吡喃-4-酮衍生物的合成及其趋骨性探讨

目的 根据具有趋骨性的化合物的共同特征，设计并合成苯并吡喃-4-酮类化合物，检测它们的趋骨性。方法 以苯并吡喃-4-酮为核心，设计并合成了6个在其3位、5位、6位有酚羟基、甲氧基、羧基、酯基、甲氧羰甲氧基等基团的衍生物，用羟基磷灰石吸附实验检测其趋骨性。结果 所有合成的目标化合物的结构均经过IR，^1H—NMR和MS确认。结论 部分设计的苯并吡喃-4-酮衍生物具有比四环紊更好的趋骨性。     

1-(5-取代糠基)吲哚啉-2-酮衍生物的合成和初步抗肿瘤活性

为了寻找具有较好抗肿瘤活性的新型吲哚啉-2-酮类化合物，本研究以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯与5位不同取代的吲哚啉-2-酮(2a～2d)为原料，首先经缩合得3-吡咯亚甲基-吲哚啉-2-酮(3a～3d)，再经N烃化反应得到1-(5-甲酰基糠基)-3-(吡咯亚甲基)-吲哚啉-2-酮(4a～4d)，然后与吲哚啉-2-酮缩合得到以5-亚甲基糠基连接的双吲哚啉-2-酮化合物(5a～5d)。所合成的12个新型吲哚啉-2-酮类化合物的结构经核磁共振谱、质谱和元素分析确认。采用四氮唑盐(MTT)还原法测试所合成化合物的体外抗肿瘤活性，结果表明所合成的化合物均有一定的抗肿瘤作用，其中6个化合物对SPC-A1肺癌肿瘤株体外抑制活性优于舒尼替尼，特别是化合物5a～5d， IC₅₀值均小于5 μmol·L^-1，值得作为抗肿瘤药物先导化合物。     

2-位取代苯并呋喃类化合物的生物活性及合成研究进展

苯并呋喃衍生物是当前研究杂环芳香族化合物的热点之一。据文献报道该类化合物具有抗肿瘤,抗氧化,钙内流阻滞,血管紧张素II受体拮抗,腺苷A1受体拮抗,抗真菌、抗菌活性和血小板聚集拮抗等药理作用。由于苯并呋喃具有广泛活性,因此吸引很多学者对其进行研究。为了更好地研究该类化合物的合成和生物活性,本文对近几年来文献报道的具有良好生物活性的2-位取代苯并呋喃衍生物进行综述,并对它们的合成方法进行概括,为开发新型2-取代苯并呋喃类化合物提供参考。     

Synthesis of mono- and bisdihydrodipyridopyrazines and assessment of their DNA binding and cytotoxic properties

Aminoalkyl-substituted monomeric and dimeric dihydrodipyridopyrazines have been synthesized and evaluated as antitumor agents. Potent cytotoxic compounds were identified in both series. Biochemical and biophysical studies indicated that all these compounds strongly stabilized the duplex structure of DNA and some of them elicited a selectivity for GC-rich sequences. Sequence recognition by of the dimeric dihydrodipyridopyrazines is reminiscent of that of certain antitumor bisnaphthalimides. Compared to monomers, corresponding dimeric derivatives showed higher affinity for DNA. This property was attributed to a bisintercalative binding to DNA. This assumption was indirectly probed by electric linear dichroism and DNA relaxation experiments. DNA provides a bioreceptor for these dihydrodipyridopyrazine derivatives, but no poisoning of human topoisomerases I or II was detected. Most of the compounds efficiently inhibited the growth of L1210 murine leukemia cells and perturbed the cell cycle progression (with a G2/M block in most cases). A weak but noticeable in vivo antitumor activity was observed with one of the dimeric compounds. This studies identifies monomeric and dimeric dihydrodipyridopyrazines as a new class of DNA-targeted antitumor agents.     

Sorafenib硫脲衍生物的合成及活性研究

在已上市的多靶点小分子靶向抗肿瘤药sorafenib的基础上,设计合成了16个4-[4-(2-甲胺酰基吡啶)]氧苯基芳香硫脲衍生物。16个目标化合物的结构经1H NMR、MS及元素分析确证。采用四氮唑盐(MTT)法测试了所合成化合物的体外抗肿瘤活性,结果表明所合成的化合物均具有一定的抗肿瘤活性,其中化合物1a、1d、1i及1j的抗肿瘤活性优于或相当于阳性对照sorafenib。     

Novel benzoylurea derivatives as potential antitumor agents; synthesis,activities and structure-activity relationships

A series of pyrazoloxyphenyl benzoyl urea derivatives was designed and synthesized for cytotoxic evaluation as potential antitumor agents. The synthetic compounds were evaluated for in vitro cytotoxicity against five human tumor cell lines, including A-549, SKOV-3, SK-MEL-2, XF-498 and HCT-15. Among others, compound 11 exhibited 50-100 times greater antitumor activities than the commercial product, Cisplatin.     

Synthesis and biological activity of new class of dioxygenated anticancer agents

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against beta-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.     

苯并吡喃酮酯衍生物的合成及其趋骨性初探

目的 设计并合成苯并吡喃酮酯衍生物并探索其趋骨性。方法 以3-乙酰基-4-羟基苯甲酸甲酯为原料，经酯化、分子内酰化、环合反应得目标物，并用羟基磷灰石吸附实验检测目标物的趋骨性。结果 合成的目标化物(2a，2b，2c)的结构均经IR，^1H NMR，MS及EA确认。结论 目标物(2c)具有比四环素更强的趋骨性。     

A new series of ellipticine derivatives (1-(alkylamino)-9-methoxyellipticine). Synthesis, DNA binding, and biological properties

A new series of ellipticine derivatives, 1-(alkylamino)-5,11-dimethyl-9-methoxy-6H-pyrido[4,3-b]carbazoles, were synthesized as potential DNA intercalating antitumor drugs. The structure of these compounds were confirmed by 1H NMR spectroscopy and mass spectrometry. These compounds are able to bind to DNA with an affinity of about 10(6) M-1, and their intercalating characteristics (lengthening and unwinding of DNA) depend upon the length of the chain in position 1. The cytotoxicities of these compounds on L1210 and NIH-3T3 cells are quite similar, and fluorescence techniques showed that the compounds are localized mainly in the cytoplasmic granules of the cells. One of these compounds appears to show a very high antitumor activity (equivalent to the more active known ellipticine analogues: 10-[[gamma-(diethylamino)propyl]amino]-6-methyl-5H- pyrido[3',4':4,5]pyrollo[2,3-g]isoquinoleine (BD40), 1-[[gamma-(diethylamino)propyl]amino]-9-methoxyellipticine (BD84) and 2-[beta-(diethylamino)ethyl]-9-hydroxyellipticinium chloride (DEAE).     

4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives as anti-tumor agents

A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.