白杨素衍生物的合成及其抗癌活性研究

目的　合成一系列白杨素衍生物并研究其体外抗肿瘤活性。方法　以白杨素为起始原料,通过醚化反应引入5- 溴水杨酸酯,合成6 个白杨素衍生物。然后采用MTT 法检测白杨素衍生物对人胃癌MGC-803 细胞、人肝癌HepG2 细胞的体外抗肿瘤活性。结果　化合物3a、3b、4b 抑制HepG2 的IC50 值高于白杨素,化合物2a、2b、4a 抑制HepG2 的IC50 值低于白杨素,其中化合物2a、4a 的IC50 值低于阳性对照药5- 氟尿嘧啶。化合物3a 抑制MGC-803 细胞的IC50 值低于白杨素和阳性对照药5- 氟尿嘧啶。结论　合成的白杨素衍生物均经过1H NMR,MS 确证。目标化合物2a 对HepG2 细胞具有较强抑制作用,化合物3a 对MGC-803 细胞具有较好的抑制作用,抑制作用均较阳性对照药物5- 氟尿嘧啶强。     

白杨素抗肿瘤衍生物的合成及其构效关系

目的合成一系列白杨素衍生物并结合体外实验探讨白杨素衍生物抗肿瘤作用的构效关系。方法以5,7-二羟基黄酮为原料,通过取代、水解、酰胺缩合等化学反应引入一些极性不同的小分子化合物,合成一系列白杨素的衍生物,然后采用MTT比色法检测白杨素及其衍生物对食管癌EC109细胞、肝癌HepG2细胞、宫颈癌Hela细胞的增殖抑制作用。结果化合物Ⅲa、Ⅲb、Ⅲc、Ⅲd、Ⅲf对抑制EC109增殖表现出的抗癌活性较白杨素有明显的提高,化合物Ⅲa、Ⅲd、Ⅲe、Ⅲf对抑制HepG2增殖表现出的抗癌活性较白杨素有明显的提高,其中Ⅲd和Ⅲf的抗肿瘤作用显著;白杨素及其衍生物对抑制Hela细胞的增殖均较高,但其衍生物抗肿瘤作用与白杨素相比没有提高。结论引入极性基团对白杨素的抗肿瘤活性有明显的提高,经过极性基团修饰后的白杨素衍生物能明显提高对EC109、HepG2细胞增殖抑制作用。     

黄酮乙酸类衍生物肿瘤血管破坏剂的设计、合成及其抗肿瘤活性的初步评价

目的设计、合成一系列黄酮乙酸类衍生物肿瘤血管破坏剂,并测定其体外抗肿瘤活性。方法以邻羟基苯乙酮为起始原料,通过氯甲基化、氰基取代、水解以及缩合等反应得到相应的目标化合物;以5,6-二甲基呫吨酮-4-乙酸(DMXAA)为阳性对照药,通过3种模型对目标化合物的抗肿瘤活性进行评价,包括采用Alpha LISA法检测目标化合物对RAW 264.7细胞的促TNF-α分泌作用、采用MTS法测定化合物的细胞毒作用,以及采用鸡胚绒毛尿囊膜模型测定化合物对鸡胚血管生成的影响。结果与结论合成的18个化合物均未见文献报道,其结果经1H-NMR、MS谱确证;活性评价结果表明有3个目标化合物在抗肿瘤测试中表现出较好的体外抗肿瘤活性。     

黄酮衍生物的合成及其抗炎活性研究

目的 设计合成一系列黄酮衍生物,并考察其抗炎活性。方法 采用Baker-Venkataraman反应合成单羟基取代的黄酮,进而经Williamson反应合成黄酮衍生物;以布洛芬为阳性对照药,采用巴豆油致小鼠耳肿胀实验对5个目标化合物（1a、1c、1d、2a、2c）的抗炎活性进行了评价。结果与结论 以2’,5’-二羟基苯乙酮或2’,4’-二羟基苯乙酮为原料,合成了12个未见文献报道的新化合物,其结构经核磁共振氢谱、高分辨质谱及红外光谱确证。初步的药理筛选结果表明化合物6-[2-(4-吗啉基)乙氧基]黄酮(1a)和2’-氟-7-(2-二甲氨基甲酰甲氧基)黄酮(2c)具有潜在的抗炎活性。     

1,2,3-三氮唑类苦参碱衍生物的合成及其体外抗肿瘤活性研究

目的设计并合成了1,2,3-三氮唑类苦参碱衍生物,并对其进行体外抗肿瘤活性研究。方法以苦参碱为起始原料,通过水解反应、N-烷基化反应、click反应等反应得到目标化合物。采用噻唑蓝(MTT)法考察所合成目标化合物对HeLa、MCF-7和HepG23种肿瘤细胞的体外抗增殖活性。结果合成了9个1,2,3-三氮唑类苦参碱衍生物,其结构经~1H-NMR,~(13)C-NMR及HR-MS确定,抗肿瘤活性测试结果表明该类化合物具有一定的抗肿瘤活性,其中化合物5h对MCF-7肿瘤细胞表现出良好的活性,且活性优于母体化合物苦参碱。结论部分目标化合物具有较好的抗肿瘤活性,为该类抗肿瘤化合物的进一步优化提供思路。     

沙利度胺衍生物的设计合成及其抗肿瘤活性研究

目的设计合成1，3-二氢-1，3-二氧代．2H-异吲哚-N-取代沙利度胺衍生物。并对其进行体外抗肿瘤活性测试。方法以2．氨基-β-D-吡喃葡萄糖盐酸盐为原料，经过6步反应得到化合物N-（3’，4’，6＇-三乙酰-1’-溴代吡喃葡萄糖）-1,3-二氢-1，3-二氧代-2H-异吲哚，该化合物经过溴代、取代反应得到目标化合物。通过对4T1细胞存活率的测试测定20个目标化合物体外抗肿瘤活性。结果设计合成的20个目标化合物均未见文献报道。所有化合物均经过1H-NMR谱确证，部分化合物经IR、MS谱确证。结论所有目标化合物对4T1细胞均具有-定的抑制生长作用。表明所合成的沙利度胺衍生物均有-定的抗肿瘤活性。     

薯蓣皂苷元衍生物的制备及其抗肿瘤活性

目的 设计、合成薯蓣皂苷元衍生物并研究其体外抗肿瘤活性.方法 以薯蓣皂苷元为原料,与不同的L-氨基酸缩合,合成了6个化合物(Ⅰ～Ⅵ);与1,2,3-三氮唑和1,2,4-三氮唑偶联合成了2个中间体(Ⅶ,Ⅷ);再分别与不同的苄溴化合物反应得到一系列的盐(Ⅸ～Ⅻ).结果 合成的化合物中,除化合物Ⅴ外,其余11个是新化合物.结论 所合成的化合物结构经1HNMR、13CNMR确证.采用噻唑蓝(MTT)法测定了部分化合物的体外抗肿瘤活性.所测化合物都有良好的抗肿瘤活性,其中,化合物Ⅵ的抗肿瘤活性与阳性对照1-(3β-薯蓣皂苷元)-3-苄基咪唑溴盐相当.     

咔啉类衍生物的合成及抗肿瘤活性研究

目的合成咔啉类衍生物并研究其抗肿瘤活性。方法以α-咔啉、β-咔啉以及1,2,3,4-四氢-β-咔啉-3-羧酸为原料,经过多步反应分别得到6-取代α-咔啉类、6-取代β-咔啉类以及3-取代β-咔啉类衍生物,用MTT法考察目标化合物对肿瘤细胞的抑制作用。结果合成了15个新的咔啉类衍生物,结构经过1H NMR和ESI-M S确证。结论 MTT法测试所得的目标化合物对2种受试细胞株均具有一定的抗肿瘤活性,部分化合物显示出与阳性对照紫杉醇相当或更佳的肿瘤细胞抑制活性。     

2-(4-三氟甲基苯基)-4-乙基-呋喃-3-酰胺衍生物的设计、合成及其抗肿瘤活性研究

目的 设计、合成新型抗肿瘤的2-（4-三氟甲基苯基）-4-乙基-呋喃-3-酰胺衍生物.方法 以对三氟甲基苯甲醛和丙二酸二乙酯为起始原料,经缩合、环合、酰氯化及胺解等4步反应,合成系列目标化合物.结果 设计合成了15个目标化合物,并对其进行了4种肿瘤细胞A549、QGY、HeLa和SW480的活性测试.结论 显示出较好的抗肿瘤活性,化合物5b显示出最优的高效、广谱抗肿瘤活性,值得深入研究.     

白杨素Mannich碱衍生物的合成及抗高尿酸血症活性

目的设计并合成新型具有抗高尿酸活性的白杨素Mannich碱衍生物。方法以天然产物白杨素为起始原料,与不同含氟有机物进行胺甲基化反应,合成系列白杨素Mannich碱衍生物。采用氯化硝基四氮唑蓝比色法测定目标化合物在体外对黄嘌呤氧化酶的抑制活性,并研究其在昆明种小鼠的体内抗高尿酸活性。结果与结论合成了10个未见文献报道的新化合物,目标化合物的结构经核磁共振氢谱和碳谱、电子轰击质谱(EI-MS)确证。体外活性实验显示,大多数含氟白杨素衍生物都具有较好的黄嘌呤氧化酶抑制作用,且体内抗高尿酸作用显著,在40 mg·kg~(-1)剂量时白杨素衍生物1a、1b、1c、1e、1f、1i和1j抗高尿酸效果最好,可使昆明种小鼠的血清尿酸值接近正常水平。     

Synthetic derivatives of chrysin and their biological activities

Chrysin is one of flavones constituents of Orocylumineicum vent. It has been a hot spot as a potential chemopreventive agent and as a natural molecule with numerous biological activities such as antioxidant, antitumor, antiviral, anti-hypertension, anti-diabetic, antibacterial, and so on in recent years. Because of its poor solubility, small intestinal absorption, and the rapid metabolism of glycosylation, a large number of efforts had been made by domestic and foreign researchers on designing its analogs and conjugates to obtain compounds with improved efficacy and selectivity for developing more active drugs for clinic. This article reviews the current research of studying on chrysin derivatives including their properties and possible applications. Additionally, this article also presents the basic information concerning chemical reactivity of chrysin, relevant to the synthesis of its derivatives.     

C-Isoprenylation of flavonoids enhances binding affinity toward P-glycoprotein and modulation of cancer cell chemoresistance

Previous studies have shown that flavones bind to P-glycoprotein (Pgp) with higher affinity than isoflavones, flavanones, and glycosylated derivatives. In the present work, a series of C- or O-substituted hydrophobic derivatives of chrysin were synthesized to further investigate structural requirements of the A ring toward Pgp modulation. Increasing hydrophobicity at either position 6, 8, or 7 increased the affinity of in vitro binding to a purified cytosolic domain of Pgp, but only benzyl and 3,3-dimethylallyl C-substitution produced a high maximal quenching of the protein intrinsic fluorescence. Inhibition of membrane Pgp within leukemic cells, characterized by intracellular drug accumulation, was specifically produced by isoprenylated derivatives, with 8-(3,3-dimethylallyl)chrysin being even more efficient than the commonly used cyclosporin A.     

白杨素Mannich碱衍生物的合成及其抗癌活性

目的设计合成新型白杨素Mannich碱衍生物,并寻求具有抗癌活性的新化合物。方法利用Baker-Venkataraman重排法完成白杨素的全合成,再与甲醛、胺类进行Mannich缩合反应得到目标化合物。采用MTT法,以5-氟尿嘧啶为阳性对照,评价目标化合物对人宫颈癌细胞(Hela)、人肺腺癌细胞(A549)、人胃癌细胞(SGC-901)、人结肠癌细胞(HCT-116)、人白血病细胞(K562)5种肿瘤细胞的抗癌活性。结果与结论合成了10个未见文献报道的新化合物,其结构经1H-NMR、IR和MS确证。体外抗癌活性实验表明,部分化合物显示出较好的抗癌活性。     

Cancer chemopreventive properties of orally bioavailable flavonoids--methylated versus unmethylated flavones

Poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemopreventive agents. In this study, we examined fully methylated flavones as promising improved agents. In the human oral SCC-9 cancer cells, 5,7-dimethoxyflavone and 5,7,4'-trimethoxyflavone were both 10 times more potent inhibitors of cell proliferation (IC(50) values 5-8 microM) than the corresponding unmethylated analogs chrysin and apigenin. Flow cytometry indicated that both methylated flavones arrested the SCC-9 cells in the G1 phase with a concomitant decrease in the S phase, dramatically different from the unmethylated analogs, which promoted G2/M phase arrest. Both methylated compounds inhibited the proliferation of two other cancer cell lines with very little effect on two immortalized normal cell lines. Examination of additional flavone structures indicated that methylated flavones in general have antiproliferative properties. Finally, we demonstrated that 5,7-dimethoxyflavone, in contrast to its unmethylated analog chrysin, was well absorbed and had high oral bioavailability as well as tissue accumulation in vivo in the rat. Thus, fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents, in particular in oral cancer.     

Nitrogen-containing flavonoid and their analogs with diverse B-ring in acetylcholinesterase and butyrylcholinesterase inhibition

In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone, 2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing 6 or 7-substituted tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results indicated that the alteration of aromatic ring connecting to chromone scaffold brings about a significant impact on biological activity. Compared with flavones, the inhibitory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE significantly decreased, while that of 2-biphenyl chromone derivatives with 7-substituted tertiary amine side chain is better than relative flavones derivatives. For all new synthesized compounds, the position of tertiary amine side chain obviously influenced the activity of inhibiting AChE. The results above provide great worthy information for the further development of new AChE inhibitors. Among the newly synthesized compounds, compound 5a is potent in AChE inhibition (IC₅₀ = 1.29 ± 0.10 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a mixed-type inhibitory effect against AChE.     

Flavone modulators of rat hepatic aryl hydrocarbon hydroxylase

The cytochrome P-450-dependent aryl hydrocarbon hydroxylase (AHH) metabolizes a wide variety of endogenous and exogenous compounds to nontoxic metabolites and/or toxic products. We have utilized a series of 18 flavone modulators of AHH to distinguish and probe for different cytochrome P-450 isozymes in liver microsomes from control and 3-methylcholanthrene (MC)-injected rats. some flavones (maackiain acetate, flavanone, mollisacacidin, embinin, sciadopitysin) activated, while most of the tested compounds inhibited the MC-induced type of AHH. Although all flavones either inhibited or had little effect on the constitutive AHH in microsomes from control rats, the degree of inhibition varied greatly: some flavones (chrysin, chrysoeriol, baicalein, maackiain acetate, isoliquiritigenin, sciadopitysin) inhibited over 75% of the AHH. The various flavones we screened may prove useful in defining the cytochrome P-450 content of tissues and for probing the active sites of individual isozymes. The modulatory effects of the naturally occurring flavones assume additional importance in that they may be factors in animal and human responsiveness to cytochrome P-450 substrates.     

2H-1-苯并吡喃衍生物的合成及其体外抗癌活性的初步评价

目的设计并合成2H-1-苯并吡喃衍生物化合库并对其体外抗癌活性进行评价。方法以2＇-羟基查耳酮为原料通过微波促进合成得到黄酮衍生物中间体，此中间体与POCl，反应得到4-氯-2H-色原烯-3-醛，通过微波辅助液相平行合成的方法，此醛与ROCONHNH2反应得到2H-1-苯并吡喃衍生物化合库。利用HL-60细胞系评价该化合物库的体外抗癌活性。结果与结论合成了含有32个化合物的2H-1-苯并吡喃衍生物库，体外活性评价表明。部分化合物对HL-60细胞的增殖有一定的抑制作用，其中。化合物9e在浓度为30μmol·L^-1的抑制率为70．8％。     

Inhibition of ethoxy- and pentoxy-resorufin dealkylases of rat liver by flavones and flavonols: structure-activity relationship

The inhibitory effects of 17 flavones and flavonols on ethoxy- and pentoxy-resorufin dealkylases of rat liver were investigated. Several findings concerning the relationship between structure and activity can be pointed out. The presence or lack of hydroxyl groups on the flavane nucleus has no influence on the efficiency of inhibition. Flavone and quercetin result in the same degree of inhibition. For polyhydroxylated moleculse, the position of hydroxyl groups on A and B rings was an important factor. The more powerful inhibitors were the flavones having hydroxyl groups only on the A ring (e.g. chrysin) and the inhibitory effect was decreased by addition of hydroxyl substituents on the B group (e.g. quercetin). EROD activities were more responsive than PROD activities. Flavone and quercetin were competitive inhibitors of EROD activity whereas chrysin and morin were mixed type inhibitors. In the case of PROD activity, all four flavones were of the mixed type inhibitors.     

Qualitative and Quantitative Analysis of the Phenolic Constituents from Orthosiphon aristatus

ORTHOSIPHON ARISTATUS (Orthosiphonis folium DAB 9) was studied with regard to its phenolic constituents. Twenty compounds were isolated and identified on the basis of their spectral characteristics. The compounds included nine lipophilic flavones, two flavonol glycosides, and nine caffeic acid derivatives. The presence of the recently reported methylripariochromene A could not be confirmed. All compounds identified were quantified by HPLC. The caffeic acid derivatives including the major compounds rosmarinic acid and 2,3-dicaffeoyltartaric acid (67% of total identified phenolics) predominated over the flavones (33%) in an aqueous MeOH extract. The predominance of the caffeic acid derivatives was even more pronounced in a hot water extract (94.5% of total identified phenolics) that was comparable to a herbal tea.