Synthesis and cytotoxicity of 2,5-dihydroxychalcones and related compounds

A series of 2, 5-dihydroxychalcones and related compounds were synthesized, and their cytotoxicities against tumor cell lines and human umbilical venous endothelial cells (HUVEC) evaluated. It was found that chalcones, with electron-withdrawing substituents on an A ring, exhibited significant cytotoxicities. Among the synthesized compounds, 2'-chloro-2, 5-dihydroxychalcone (9) was most potent, with an IC50 value as low as 0.31 microg/mL. This compound also exhibited a significant cytotoxic selectivity toward HUVEC.     

Synthesis and cytotoxicity of some rigid derivatives of methyl 2,5-Dihydroxycinnamate

Eight rigid compounds designed as esterase-stable analogues of methyl 2,5-dihydroxycinnamate (1) were synthesized. These derivatives include 2-(2',5'-dihydroxybenzylidene)cyclopentenone (3a), 2-(2',5'-dihydroxybenzylidene)cyclohexanone (3b), 2,6-bis(2',5'-dihydroxybenzylidene)cyclohexanone (4b), 2,6-bis(2',5'-dihydroxybenzylidene)cyclopentenone (4a), (E)-3-(2',5'-dihydroxybenzylidene)pyrrolidin-2-one (5), (E)-5-(2',5'-dihydroxybenzylidene)-1,2-isothiazolidine-1,1-dioxide (6), 4-(2',5'-dihydroxyphenyl)-5H-furan-2-one (7), and 3-(2',5'-dihydroxyphenyl)cyclopent-2-ene-1-one (8). Among the eight compounds, the furanone 7 and cyclopentenone 8 showed the most potent cytotoxicity with IC50 values of 0.39-0.98 microg/mL. Compound 8 was further brominated, phenylated and methylated at the alpha position to give three corresponding analogues, including 2-bromo-3-(2',5'-dihydroxyphenyl)cyclopent-2-ene-1-one (24), 3-(2',5'-dihydroxyphenyl)-2-phenylcyclopent-2-ene-1-one (27), and 3-(2',5'-dihydroxyphenyl)-2-methylcyclopent-2-ene-1-one (28). Among the three, the most enhanced activity was observed with the phenylated compound 27.     

2-(1-Hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones: Synthesis and evaluation of cytotoxicity

A series of 2-(1-hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones (oximes) was synthesized and evaluated for cytotoxicity against L1210 cells and A549 cells. These oximes showed a greater cytotoxic activity compared to those of 2-(1-hydroxyalkyl)-1,4-dimethoxy-9,10-anthraquinones as the hydroxyalkyl bioisosteres. The enhanced cytotoxicity assumed to be due to the improved water solubility of the hydroxyimino group. Moreover, it was found that the cytotoxicity of the oximes decreased with elongation of alkyl groups at the side chain. All of the synthesized compounds showed higher cytotoxicity against L1210 cells than A549 cells.     

Structure-activity relationships of gagaminine and its derivatives on the inhibition of hepatic aldehyde oxidase activity and lipid peroxidation

In order to determine the structure-activity relationships for antioxidative effects of gagaminine, a steroidal alkaloid isolated from the roots ofCynanchum wilfordi (Asclepiadaceae), two derivatives identified as sarcostin and penupogenin were prepared from gagaminine by hydrolysis and reduction. These compounds were evaluated for the inhibitory effects on the aldehyde oxidase activity and on lipid peroxidationin vitro. Furthermore, their effects were compared with those of gagaminine and the related compounds, cinnamic acid and nicotinic acid. The results of this study prove that the cinnamoyl group in the structure of gagaminine is critical in inhibition of the aldehyde oxidase activity while the nicotinoyl group may be necessary for anti-lipid peroxidation of the compound.     

Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity

Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.     

Pentacyclic triterpenoids and their cytotoxicity from the stem bark of<Emphasis Type="Italic">Styrax japonica</Emphasis> S. et Z

The methylene chloride soluble fraction of MeOH extract from the stem bark of Styrax japonica S. et Z. (Styracaceae) showed significant cytotoxicity by SRB method against five human tumor cell lines. Four known pentacyclic triterpenoids, oleanolic aldehyde acetate (1), erythrodiol-3-acetate (2), euphorginol (3), and anhydrosophoradiol-3-acetate (4) were isolated by activity-guided fractionation. Their structures were determined by chemical and spectral analysis. Compounds 1-4 were isolated from S. japonica for the first time.     

半边旗5种成分体外细胞毒活性比较及构效关系分析

用多种人癌细胞株以MTT试验,体外筛选半边旗抗肿瘤活性成分。结果显示:化合物5F,6F,A及半边旗乙醇提取物PSE对5种人癌细胞均有不同程度的杀伤作用,且呈明显的剂量依赖关系。其中6F的活性最强,其次是A,5F,而化合物4F和B对5种细胞均无细胞毒活性。分析它们的构效关系可以推测,α-β-亚甲基环戊酮结构是其活性部位,结构中羟基数目和位置的不同可以影响化合物的活性强度。     

A pair of isomeric saponins with cytotoxicity from Albizzia julibrissin

Two new saponins have been isolated from the stem barks of Albizzia julibrissin Durazz, and their structures identified as 3-O-[β-d-xylopyranosyl-(1 → 2)-β-d-fucopyranosyl-(1 → 6)-β-d-2-deoxy-2-acetoamidoglucopyranosyl]-21-O-{(6S)-2- trans -2-hydroxymethyl-6-methyl-6-O-[4-O-((6S )-2- trans -2-hydroxymethyl-6-hydroxy-6-methyl-2,7-octadienoyl)-β-d-quinovopyranosyl]-2,7-octadienoyl}-acacic acid-28-O-β-d-glucopyranosyl-(1 → 3)-[α-l-arabinofuranosyl-(1 → 4)]-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl ester (1) and 3-O-[β-d-xylopyranosyl-(1 → 2)-β-d-fucopyranosyl-(1 → 6)-β-d-2-deoxy-2-acetoamidoglucopyranosyl]-21-O-{(6S)-2-trans-2-hydroxymethyl-6-methyl-6-O-[3-O-((6S)-2-trans-2-hydroxymethyl-6-hydroxy-6-methyl-2,7-octadienoyl)-β-d-quinovopyranosyl]-2,7-octadienoyl}acacic acid 28-O-β-d-glucopyranosyl-(1 → 3)-[α-l-arabinofuranosyl-(1 → 4)]-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl ester (2), based on chemical and spectral evidences, named as julibroside J₁₉ and julibroside J₁₈, respectively. Both compounds show significant inhibition action against HeLa, Bel-7402 and MDA-MB-435 cancer cell lines in vitro.     

Inhibition of nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells by synthetic flavones: Structure-activity relationship and action mechanism

Recent investigations have shown that certain flavonoids, especially flavone derivatives, inhibit nitric oxide (NO) production by inducible NO synthase (iNOS) in macrophages, which contribute their anti-inflammatory action. For the purpose of finding the optimized chemical structures of flavonoids that inhibit NO production, various A- and B-ring substituted flavones were synthesized and evaluated for their inhibitory activity using lipopolysaccharide-treated RAW 264.7 cells. It was found that the optimal chemical structures were A-ring 5,7-dihydroxyflavones having the B-ring 2',3'-dihydroxy or 3',4'-dihydroxy or 3',4'-hydroxy/methoxy (methoxy/hydroxy) groups. These structurally optimized compounds were revealed to be down-regulators of iNOS induction, but not direct iNOS inhibitors. Of these derivatives that were evaluated, 2',3',5,7-tetrahydroxyflavone and 3',4',5,7-tetrahydroxyflavone (luteolin) showed the strongest inhibition. The IC50 values for these compounds were 19.7 and 17.1 microM, respectively. Therefore, these compounds may have a potential as new anti-inflammatory agents.     

Structure of three new terpenoids,spiciformisins a and b,and monocyclosqualene,isolated from the herbs of Ligularia fischeri var. spiciformis and cytotoxicity

The diethylether fraction from the leaves extract of Ligularia fischeri var. spiciformis (Compositae) was subjected to silica gel column chromatography and yielded three new terpenoids named spiciformisin a (1), spiciformisin b (3), and monocyclosqualene (2). Acyclic diterpenes, spiciformisin a and -b, were established as 3,7,11,15-tetramethyl-1,3(20)-hexadecadiene and 3,7,11,15-tetramethyl-1,3,6,10,14-hexadecapentaene (IUPAC), respectively. A monocyclic triterpene, monocyclosqualene, were determined as [3,8,12,16,16-pentamethyl-(3,7,11,15-hexadecatetraenyl)]-3,3,5-trimethyl-1-cyclohexene. The structures were determined on the basis of NMR and MS analysis. Spiciformicin b showed potent cytotoxicity (IC50, <9.7 microg/ml against HL-60) in contrast to no cytotoxicity (IC50, >200 microg/ml against HL-60 cells) of spiciformicin a with a cis-conjugated dienyl diexomethylene.     

A new triterpenoid from <Emphasis Type="Italic">Panax ginseng</Emphasis> exhibits cytotoxicity through p53 and the caspase signaling pathway in the HepG2 cell line

A new triterpenoid, 20(R),22(ξ),24(S)-dammar-25(26)-ene-3β,6α,12β,20,22,24-hexanol (1), and three known triterpenoids, β-D-glucopyranoside,(3β,12β)-12,20-dihydroxydammar-24-en-3-yl,6-acetate (2), 20(R)-ginsenoside Rg₃ (3), and 20(R)-ginsenoside Rh₂ (4), were isolated from the leaves of Panax ginseng. Their structures were determined by chemical analysis and spectral methods (IR, 1D and 2D NMR, HR-ESI-MS). Compounds 1–4 were exhibited various degrees of cytotoxicity in the human hepatoma cell line, HepG2. Compound 1 had the highest cytotoxic potency, with an IC₅₀ value of 20.1 μM, by stimulating p53-mediated cell cycle arrest at the G1 to S phase transition, leading to apoptosis via activation of the caspase signaling pathway.     

黄芩素衍生物构效关系研究进展

综述近年来有关黄芩素衍生物的合成及其生物活性和构效关系的研究进展。黄芩素是具有抗氧化、抗菌、抗病毒、抗过敏、降压、利尿、利胆等多种药理活性的一种天然产物，但溶解性差、生物利用度低，限制了其临床应用。因此，运用化学、生物学等方法合成黄芩素衍生物，改善其溶解性及生物利用度，开发出专一性强、活性高、更具有临床应用价值的相关药物，已成为人们关注的研究方向。     

Cytotoxic terpenes and lignans from the roots ofAinsliaea acerifolia

The chromatographic separation of the MeOH extract of the roots of Ainsliaea acerifolia (Compositae) led to the isolation of six known terpenes and two known lignans. Their structures were identified by spectroscopic methods as mokko lactone (1), betulonic acid (2), betulinic acid (3), zaluzanin C (4), 1beta-hydroperoxygermacra-4(15),5,10(14)-triene (5), pluviatilol (6), (+)-syringaresinol (7), and glucozaluzanin C (8). Compounds 1 approximately 4 and 8 showed non-specific significant cytotoxicity against five human tumor cell lines with ED50 values ranging from 0.36 approximately 5.54 microg/mL.     

Bioactive triterpenoids from Callistemon lanceolatus

A new triterpenoid, 30-hydroxyalphitolic acid 1, and eight known triterpenoids, alphitolic acid 2, lupenol 3, 3-acetoxy-olean-18-en-28-oic acid 4, betulinic acid 5, ursolic acid 6, betulinic acid 3-O-caffeate 7, morolic acid 3-O-caffeate 8, and ursolic acid 3-O-caffeate 9, were isolated from Callistemon lanceolatus. Their structures were determined using spectroscopic techniques, which included 1D- and 2D-NMR. All compounds were evaluated for the inhibition of LPS-induced nitric oxide production in murine macrophage RAW264.7 cells. Betulinic acid 3-O-caffeate 7 showed a moderate inhibitory effect on nitric oxide production with IC50 value of 15.4 μM.     

甲状旁腺激素生理作用和构效关系研究

对甲状旁腺激素的生理作用及机制、分子结构、受体结合和构效关系等方面的研究作一综述，以期为开发新型骨质疏松症治疗药物提供理论依据。甲状旁腺激素是一种生理活性多肽，体内独特的成骨作用使其作为治疗骨质疏松症药物的研究日益深入。     

流感病毒神经氨酸酶抑制剂构效关系研究

神经氨酸酶在流感病毒的感染和传播过程中起着重要作用。针对酶活性位点进行基于结构的合理药物设计，开发各类流感病毒神经氨酸酶抑制剂，业已成为药物研究的热点之一。根据化学结构的不同，综述各类神经氨酸酶抑制剂的作用机制及构效关系。     

Acute toxicity and cytotoxicity of Bacillus thuringiensis and Bacillus sphaericus strains on fish and mouse bone marrow

The insecticidal properties of delta-endotoxins from Bacillus thuringiensis (Bt) serotypes kurstaki and israelensis and crystal proteins of Bacillus sphaericus (Bs) serotype H5 have been used in insect control for decades. The availability of microbial toxins in biopesticides as well as in plants with incorporated protection has been increasing the concerns about biosafety. Acute toxicity to Danio rerio and cytotoxicity on mouse bone marrow cells and peripheral erythrocytes of Oreochromis niloticus were tested with Bt israelensis, Bt kurstaki and Bs H5 strains. The concentration and dose tested were 10⁶ and 10⁸ spores/ml, respectively. Neither lethality nor effects on mouse bone marrow were promoted by any strain. In necrosis–apoptosis study on peripheral erythrocytes of O. niloticus an increased frequency of necrotic cells caused by exposure to strains of B. thuringiensis was found. Exposure to B. sphaericus did not show cytotoxic effects in either tested system. None of the strains studied induced apoptosis in contrast with the chemical controls.     

酪氨酸蛋白磷酸酯酶1B抑制剂的构效关系

介绍了最近几年来关于酪氨酸蛋白磷酸酯酶1B作用的机制以及通过各种途径发现的结构新颖的小分子抑制剂的构效关系研究进展。酪氨酸蛋白磷酸酯酶1B在胰岛素依赖的信号传导途径中发挥着非常重要的作用,并作为一个潜在的治疗2型糖尿病和肥胖的作用靶点日益受到广泛的关注。在其晶体结构被报道后,强效和选择性好的抑制剂更成为研制开发新药的焦点。     

A new indole alkaloid, 7-hydroxyspeciociliatine, from the fruits of Malaysian Mitragyna speciosa and its opioid agonistic activity

A new indole alkaloid, 7-hydroxyspeciociliatine (1), was isolated from the fruits of Malaysian Mitragyna speciosa Korth., together with 11 known indole and oxindole alkaloids (3–13). The structure of the new compound was determined by spectroscopic analysis and chemical conversion. The opioid agonistic activity of the new alkaloid was investigated in guinea-pig ileum experiments. The compound was found to have a weak stimulatory effect on -opioid receptors.     

Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes

The Clock gene is a core clock factor that plays an essential role in generating circadian rhythms. In the present study, it was investigated whether the Clock gene affects the response to diethylnitrosamine (DEN)-induced cytotoxicity using mouse primary hepatocytes. DEN-induced cytotoxicity, after 24h exposure, was caused by apoptosis in hepatocytes isolated from wild-type mouse. On the other hand, Clock mutant mouse (Clk/Clk) hepatocytes showed resistance to apoptosis. Because apoptosis is an important pathway for suppressing carcinogenesis after genomic DNA damage, the mechanisms that underlie resistance to DEN-induced apoptosis were examined in Clk/Clk mouse hepatocytes. The mRNA levels of metabolic enzymes bioactivating DEN and apoptosis-inducing factors before DEN exposure were lower in Clk/Clk cells than in wild-type cells. The accumulation of p53 and Ser15 phosphorylated p53 after 8h DEN exposure was seen in wild-type cells but not in Clk/Clk cells. Caspase-3/7 activity was elevated during 24h DEN exposure in wild-type cells but not in Clk/Clk cells. In addition, resistance to DEN-induced apoptosis in Clk/Clk cells affected the cell viability. These studies suggested that the lower expression levels of metabolic enzymes bioactivating DEN and apoptosis inducing factors affected the resistance to DEN-induced apoptosis in Clk/Clk cells, and the Clock gene plays an important role in cytotoxicity induced by DEN.