番荔枝内酯类化合物体外抗肿瘤活性研究

目的研究不同结构类型的番荔枝内酯对多种人肿瘤细胞的体外抗肿瘤活性,探讨其构效关系。方法选取代表不同结构类型的番荔枝内酯单体,以人宫颈癌细胞株(Hela)、人肺癌细胞株(A-5408)、人乳腺癌细胞株(MCF-7)、人胃癌细胞株(SGC-790 1)和人肝癌细胞株(SMMC-75 41)为瘤株,用MTT法筛选各番荔枝内酯单体的抗肿瘤活性。结果邻双四氢呋喃番荔枝内酯(1~5)的抗肿瘤活性大于间位双四氢呋喃番荔枝内酯(6~10)和单四氢呋喃番荔枝内酯(11~12);间位双四氢呋喃番荔枝内酯对部分肿瘤细胞的抗癌活性比单四氢呋喃番荔枝内酯强;赤式双四氢呋喃环番荔枝内酯(6)比苏式构型(7)活性更强;顺式番荔枝内酯(12)有时显示更显著的抗癌选择活性;S构型比R构型的番荔枝内酯具有更好的选择活性。结论通过体外抗肿瘤活性研究,进一步揭示了番荔枝内酯的构效关系。     

番荔枝内酯抗肿瘤作用研究进展

番荔枝内酯是一类很有希望的新抗癌药物 ,被喻为“明日抗癌之星” ,它也是一类具有多种生物活性的物质 ,已经从多种番荔枝科植物的不同部位中分离提得。现就其抗癌作用、逆转肿瘤多药耐药作用、作用机制、构效关系等方面作简单的回顾     

Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice

Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7?nm, a zeta potential of –23.0?mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483?μg/mL vs. 0.915?μg/mL, p?In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p?相似文献   

番荔素亚微乳的制备及其抗肿瘤作用研究

目的制备番荔素亚微乳,并进行体内外抗肿瘤作用研究,为番荔素的口服给药提供可行方案。方法以离心稳定常数(Ke)为指标,采用正交试验对注射用大豆油的用量、混合乳化剂总量和混合乳化剂的质量比进行考察,优化最佳处方配比。考察纳米乳匀机的运转压力和运转次数对番荔素亚微乳的粒径大小和分布的影响,优化工艺参数。透射电镜观察最佳工艺所得番荔素亚微乳,考察其在生物介质中的稳定性。采用噻唑蓝(MTT)比色法评价番荔素亚微乳对鼠乳腺癌4T1、人黑色素瘤A875细胞和人肝癌细胞Hep G2的细胞毒性。建立鼠源肝癌H22细胞实体瘤模型,小鼠ig番荔素亚微乳、番荔素油溶液,计算抑瘤率。结果番荔素亚微乳的最佳处方配比和制备工艺为:注射用大豆油用量为10%,乳化剂总量为3%,其中精制蛋黄卵磷脂与聚山梨酯80质量比为8∶2;均质压力为1 500 bar,均质次数为9次。番荔素亚微乳在人工胃肠液中稳定,呈球形,粒径较小,主要在100 nm左右。番荔素亚微乳对4T1、A875、Hep G2细胞IC50值分别为3.082、2.001、1.762μg/m L;ig给药1 mg/kg番荔素亚微乳与4 mg/kg油溶液对H22荷瘤鼠的抑瘤效果相当(65.0%vs 56.5%)。结论番荔素亚微乳可以解决番荔素难溶于水、难于给药的问题,能在不降低疗效的同时将用药剂量降低到传统油溶液的1/4,在一定程度上具有增效减毒作用。     

Systematic synthesis of antitumor annonaceous acetogenins

Systematic synthesis of mono- and bis-THF ring cores, synthetic intermediates of antitumor annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation as key steps. The asymmetric alkynylation of alpha-oxyaldehyde and alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yield with very high diastereoselectivity. These adducts were converted into mono- and bis-THF cores via two kinds of one-pot THF ring formation, respectively. In addition, the total synthesis of murisolin, which shows cytotoxic activity against human tumor cell lines with potency from 10(5) to 10(6) times that of adriamycin, was also achieved.     

Annomocherin, annonacin and annomontacin: a novel and two known bioactive mono-tetrahydrofuran annonaceous acetogenins from Annona cherimolia seeds

A novel and two known bioactive mono-tetrahydrofuran (THF) annonaceous acetogenins, annomocherin (1), annonacin (2) and annomontacin (3), have been isolated from the fractionated ethanolic extracts of the seeds of Annona cherimolia, guided by the brine shrimp lethality test (BST). Their structures were elucidated on the basis of spectroscopic and chemical methods. All compounds have a relative stereochemistry of threo/trans/threo for the mono-THF ring with two flanking hydroxyls. Compound 1 has a double bond at C-23/24 of aliphatic chain. Compound 1 was isolated from natural sources for the first time, and was named annomocherin. Two known Compounds 2 and 3 which have never been isolated from this species before, were obtained. Compound 1 exhibited potent and selective cytotoxicities against the breast carcinoma (MCF-7) and kidney carcinoma (A-498) cell lines with 100 to 1,000 times the potency of adriamycin. In brine shrimp lethality test (BST), 1-3 exhibited cytotoxicity.     

New cytotoxic analogues of annonaceous acetogenins

A series of new acetogenin analogues incorporating a central catechol moiety instead of the tetrahydrofuran ring(s) have been prepared and tested against L1210 leukemia cells. Although less potent than bullatacinone, which has the same terminal lactone, these compounds display interesting cell cycle effects.     

番荔素纳米混悬剂的制备及其抗肿瘤作用研究

目的 制备高载药量番荔素纳米混悬剂（ACGs-NSPs）,并研究其对小鼠乳腺癌4T1移植肿瘤的生长抑制作用,为强效抗肿瘤药物ACGs的临床应用提供可用注射剂型。方法 番荔素、TPGS、SPC（质量比7:5:2）采用超声-沉淀法制备ACGs-NSPs,并用动态光散射法测定ACGs-NSPs的粒径,透射电镜观察其形态;稳定剂TPGS、SPC组成比例对ACGs-NSPs的溶血性考察;透析法考察其体外释放;采用MTT比色法评价ACGs-NSPs对4T1细胞细胞毒性;建立4T1乳腺癌皮下小鼠肿瘤模型,以紫杉醇注射液（PTX）为阳性对照,考察不同剂量ACGs-NSps静脉注射给药对4T1肿瘤的抗肿瘤药效。结果 ACGs-NSPs为表面光滑的球形,平均粒径为(129.03±1.03）nm,多分散指数PDI为0.134±0.03,zeta为（-17.7±0.16）mV,HPLC法测得番荔素线性回归方程为Y=0.157 2 X-0.363 2（R²=0.999）,在5~200 μg/mL范围内显性关系良好,载药量高达（45.03±0.72）%;体外释放较为缓慢;MTT试验中,ACGs-NSPs对4T1乳腺癌的细胞毒性显著强于游离药物（IC⁵⁰,3.221 μg/mL vs 4.464 μg/mL,P<0.05）;4T1荷瘤小鼠的药效学实验中,ACGs-NSPs表现出剂量相关性的抑瘤作用,高、中、低剂量组（0.4、0.2、0.1 mg/kg）抑瘤率分别为76.09%、74.34%、42.03%;但高剂量组小鼠有死亡（3/10）。结论 成功制备高载药量的ACGs-NSPs,且其对4T1乳腺癌有显著的抑制作用;从药效和小鼠存活率来看,0.2 mg/kg为合适的给药剂量。     

cis-Annonacin and (2,4)-cis-andtrans-isoannonacins: Cytotoxic monotetrahydrofuran annonaceous acetogenins from the seeds ofAnnona cherimolia

cis-Annonacin (1) and the mixture of (2,4)-cis-and trans-isoannonacins (2 and 3), three known mono-tetrahydrofuran annonaceous acetogenins, have been isolated from the seeds of Annona cherimolia by the use of the brine shrimp lethality test (BST) for bioactivity directed fractionation. Their structures were elucidated based on spectroscopic and chemical methods. 1 showed potent cytotoxicities in the brine shrimp lethality test (BST) and among six human solid tumor cell lines with notable selectivity for the pancreatic cell line (PaCa-2) at about 1,000 times the potency of adriamycin. The mixture of 2 and 3 is over 10,000 times cytotoxic as adriamycin in the pancreatic cell line (PaCa-2). All of the compounds are about 10 to 100 times as cytotoxic as adriamycin in the prostate cell line (PC-3).     

Polyether mimics of naturally occurring cytotoxic annonaceous acetogenins

On the basis of the ionophore model, polyether analogues 4 and 6 were designed and synthesized to mimic the naturally occurring annonaceous acetogenins corossolin (2) and bullatin (5), which were discovered as members of a large family of novel polyketides with cytotoxicity, antitumoral, and other biological activities since 1982. The preliminary screening shows that they have compatible cytotoxicity with the corresponding natural annonaceous acetogenins. These results open a potential way to find more active antitumor agents with simplified structures based on natural annonaceous acetogenins.     

Atemoyacin E, a bis-tetrahydrofuran annonaceous acetogenin from Annona atemoya seeds

Atemoyacin E (1), a new adjacent bis-tetrahydrofuran annonaceous acetogenin was isolated and characterized from the seeds of Annona atemoya.     

Callus cultures of Annona squamosa for the production of annonaceous acetogenins

Callus cultures of Annona squamosa were induced using different explants including petals, seed contents (megagametophyte and embryo) and fruits (mesocarp). Growth of the calli induced from the explants was found to be influenced by the type, concentration and ratio of auxin vs. cytokinin. The content of squamocin (67.8 w g g m 1 dry weight) in calli cultured on Gamborg B-5 medium containing 5.0 mg l m 1 naphthalene acetic acid and 4.0 mg l m 1 zeatin was nearly seven times higher than that in intact fruits.     

铂类抗肿瘤药物的研究现状

自从顺铂作为第一代抗肿瘤药物被开发利用以来，人们一直在寻找广谱、高活性、低毒性和无交叉耐药性的铂类抗肿瘤药物，合成和筛选出各种铂络合物。分别介绍根据不同设计思路合成的四价铂络合物、具有活性配体的铂络合物、生物载体为配体的靶向铂络合物、反式铂络合物和具有立体位阻效应的铂络合物及其抗肿瘤活性，综述当前铂类抗肿瘤药物的研究现状。     

Callus cultures of Annona squamosa for the production of annonaceous acetogenins

Callus cultures of Annona squamosa were induced using different explants including petals, seed contents (megagametophyte and embryo) and fruits (mesocarp). Growth of the calli induced from the explants was found to be influenced by the type, concentration and ratio of auxin vs. cytokinin. The content of squamocin (67.8 μg g -1 dry weight) in calli cultured on Gamborg B-5 medium containing 5.0 mg l -1 naphthalene acetic acid and 4.0 mg l -1 zeatin was nearly seven times higher than that in intact fruits.     

A new epimeric pair of mono-THF annonaceous acetogenins from Goniothalamus gardneri

From the roots of Goniothalamus gardneri Hook f. et. Thoms (Annonaceae), we have isolated a novel epimeric pair, gardnerinin ( 1) and 34- EPI-gardnerinin ( 1'), characterized by the presence of a gamma-hydroxymethyl-gamma-lactone moiety. These compounds represent an unusual type of mono-THF Annonaceous acetogenins, bearing one flanking hydroxy group on the hydrocarbon side, and another hydroxy group on the lactone side, that is only one carbon away from the THF ring.     

菲并咪唑衍生物的体外抗肿瘤活性及其对斑马鱼胚胎发育的毒性效应研究

目的 设计合成菲并咪唑衍生物L271,并研究其外抗肿瘤活性,及其对斑马鱼胚胎发育的毒性效应.方法 以1,10-邻菲啰啉-5,6-二酮和2-甲基苯甲醛为原料,运用微波辅助合成技术制备了菲并咪唑衍生L271.采用噻唑蓝(MTT)比色法研究菲并咪唑衍生物L271对人宫颈癌细胞Hela和人肺腺癌细胞A549在体外生长的抑制作用.以斑马鱼为模型,研究L271对斑马鱼胚胎发育的形态、孵化率、死亡率和畸形率的影响,评价L271对斑马鱼胚胎发育的毒性效应.结果 经电喷雾质谱技术(ESI-MS)表征确证成功合成了目标化合物L271.新合成的菲并咪唑衍生物L271对人宫颈癌细胞Hela和人肺腺癌细胞A549均有增殖抑制作用,尤其对人宫颈癌细胞Hela的IC50值达到(8.38±0.09)μmol/L,与同等条件下吡柔比星的抗肿瘤活性相当[IC50=(6.97±0.07)μmol/L].与对照组相比,L271浓度≥15μmol/L暴露组能够引起斑马鱼出现尾鳍萎缩、脊柱弯曲、卵黄囊水肿和心包囊水肿等畸形现象;L271浓度≥30μmol/L可显著降低斑马鱼的孵化率和提高死亡率(P＜0.05);在48、72、96 hpf时,L271对斑马鱼胚胎半致死浓度LC5o分别是37.331μmol/L(95％CI:35.535-39.301)、34.911μmol/L(95％CI:33.213-36.729)、30.283μmol/L(95％CI:29.590-30.980);在L271浓度≥15μmol/L时,随着L271浓度的逐渐增加,各暴露组正常胚胎百分率渐下降,胚胎死亡率逐渐上升,而胚胎畸形率先升后降.结论 L271对人宫颈癌细胞Hela具有良好的抗肿瘤活性,且与吡柔比星的相当;L271浓度≤10μmol/L对斑马鱼胚胎发育无明显毒性效应.     

Two epimeric pairs of C-4-acetyl annonaceous acetogenins from Goniothalamus donnaiensis

Further studies on the roots of Goniothalamus donnaiensis Finet et Gagnap (Annonaceae) led to the isolation of two pairs of Annonaceous acetogenins, donnaienin C ( 1) and 34- EPI-donnaienin C ( 1'), donnaienin D ( 2) and 34- EPI-donnaienin D ( 2'), containing a rare gamma-hydroxymethyl-gamma-lactone moiety and a C-4-acetoxy group. Their structures were elucidated by spectral data and chemical derivatization. Preliminary pharmacological tests showed that the mixture of donnaienin C( 1) and 34- EPI-donnaienin C ( 1') inhibited human hepatoma (Bel) cell lines in vitro (IC (50), 7.1 microg/ml).     

Current topics of organic and biological chemistry of annonaceous acetogenins and their synthetic mimics

Annonaceous acetogenins are a large family of natural polyketides. So far, more than 430 compounds have been isolated. Biologically, they are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Herein, we would like to conduct an overview on the progress of the total synthesis, structural revisions, structure activity relationship for the inhibition of complex I, and action mechanism.     

Antitumor activity of polysaccharides isolated from Patrinia heterophylla

The research investigated the effect of Patrinia heterophylla Bunge (Valerianaceae) polysaccharides (PHB-P1) on U14-bearing mice. The tumor weight of mice treated with PHB-P1 (30, 60?mg/kg body weight) was significantly lower than that of the control group, a decrease of serum lactate dehydrogenase (LDH) activity was observed, and the serum alkaline phosphatase (AKP) level was increased slightly. The number of apoptotic tumor cells was significantly increased in the mice by treatment of PHB-P1 (30, 60?mg/kgbw). Cell cycle analysis showed the accumulation of tumor cells in the G2/M phase and a relative decrease of the S phase. By the immunohistochemical analysis, PHB-P1 (30, 60?mg/kgbw) might up-regulate the expression of p53 and Bax, and significantly inhibited the expression of Bcl-2 in tumor tissues. In conclusion, PHB-P1 could inhibit tumor growth and induce tumor cell apoptosis.     

Antitumor activity and toxicity of novel nitroheterocyclic phosphoramidates

A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions were observed in the MX-1 breast cancer xenograft model. All compounds exhibited some degree of toxicity to granulocyte/macrophage progenitors in the bone marrow of mice. Two drugs were selected for further toxicologic, histopathologic, and pharmacokinetic evaluations. Toxicity of potential clinical significance was observed only in the bone marrow at the highest drug dose; otherwise no significant abnormalities in blood chemistries or organ histopathology were noted. The bone marrow lesions consisted of reduced numbers of progenitor cells in the myeloid and erythroid series; platelets were not affected. The compounds were eliminated rapidly by first-order kinetics, with half-lives in the 4-12 min range. The best of these compounds exhibits excellent antitumor activity and minimal toxicity at therapeutically effective doses in mice.