Preparation of 1,8-di-O-alkylaloe-emodins and 15-amino-, 15-thiocyano-, and 15-selenocyanochrysophanol derivatives from aloe-emodin and studying their cytotoxic effects

1,8-di-O-alkylaloe-emodin derivatives (namely, methyl-, propyl-, hexyl-, dodecyl-, and octadecyl) were synthesized from naturally occurring aloe-emodin. Further, derivatives having various substituents such as diethylamino, pyrrolidinyl, piperidinyl, methylpiperazinyl, imidazolyl, thiocyano and selenocyano groups at the 15 position of chrysophanol and 1,8-di-O-hexylchrysophanol from aloe-emodin were synthesized. The cytotoxic effects of these derivatives on less P-glycoprotein (P-gp)-expressing HCT 116 cells and stably P-gp-expressing Hep G2 cells were evaluated by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among these products, several of them exhibited markedly higher potent cytotoxic effects not only on HCT116 cells but also Hep G2 cancer cells as compared to aloe-emodin.     

Functional monomers and polymers. LXXI. Conformation and interaction studies of poly-L-lysine derivatives with pendant nucleic acid bases

Copolymers of L -lysine and L -lysine derivatives which contained nucleic acid bases substituted on the N^ε position were synthesized by grafting nucleic acid derivatives onto poly-L -lysine. The conformation and interaction of these copolymers in solution were studied by using spectroscopic measurements. They existed in helical conformation at neutral pH values, and the polymer complex formation among them was examined by ultraviolet (UV) measurements in organic solvents. A decrease in the nucleic acid base content of the copolymers resulted in a decrease in helical structures and also in interactions with the polymer-containing complementary bases.     

Reactions of 26-iodopseudodiosgenin and 26-iodopseudodiosgenone with various nucleophiles and pharmacological activities of the products

26-Iodopseudodiosgenin (8) and 26-iodopseudodiosgenone (9) were reacted with various nucleophiles (KSCN, KOCN, NaCN, NaN(3) and various amines) to give pseudodiosgenin derivatives (4, 12, 16-20, 26) and pseudodiosgenone derivatives (5, 13, 21-25, 27), respectively. The reactions of 8 and 9 with KOCN gave the elimination products (10) and (11), respectively. The reaction of 9 with NaCN gave 5alpha,26- (14) and 5beta,26-dicyanocholestan-3-one (15). The reaction of 8 with NaN3 gave triazepine derivative (30), while that of 9 gave 26-azidopseudodiosgenone (31). Compound 31 was converted into triazepine derivative (32) by heating at 120 degrees C. The cytotoxicity of the pseudodiosgenins and pseudodiosgenones on P-gp-underexpressing HCT 116 cells and P-gp-overexpressing Hep G2 cells was examined by MTT assay. Pseudodiosgenins 2, 4, 12 and 30 showed strong cytotoxic activity (IC50 values: 2.6+/-0.3-6.7+/-1.4 microM), as did pseudodiosgenones 3, 5, 11, 13, 21-25 and 27 (IC50 values: 1.3+/-0.3-6.4+/-0.3 microM) toward HCT 116 cells. Pseudodiosgenins 12, 16 and 30 (IC50 values: 1.2+/-0.7-2.2+/-0.6 microM) and pseudodiosgenones 22, 23, 25 and 27 (IC50 values: 0.6+/-0.1-2.5+/-0.3 microM) were highly cytotoxic to Hep G2 cells. Compounds 3 and 27 showed efficient antibacterial activity (MIC: 15.6, 10.4 microg/ml) and (MIC: 7.8, 15.6 microg/ml) against Bacillus subtilis and Staphylococcus aureus, respectively.     

Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives

New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells.     

Synthesis of Novel Amide Derivatives with In Vitro Antiproliferative and Cytotoxic Activity

Some amide derivatives are highly valuable products with antiproliferative and cytotoxic bioactivity. In this paper, 12 novel amide compounds were synthesized correspondingly by boc‐protection glycine, deprotection, and condensation reactions. The antiproliferative and cytotoxic activity of these compounds was also evaluated by human cervical cancer (Hela) and hepatoma carcinoma (SK‐Hep‐1) cancer cell lines. The assay revealed that eight compounds ( 5a–d , 6a–d ) exhibited activity against Hela cancer cells. Four of them ( 5a–d ) also showed activity against SK‐Hep‐1 cancer cells. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:9–17, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21057     

Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Colorectal cancer (CRC) is a malignancy of the colon or rectum. It is ranked as the third most common cancer in both men and women worldwide. Early resection permitted by early detection is the best treatment, and chemotherapy is another main treatment, particularly for patients with advanced CRC. A well-known thymidylate synthase (TS) inhibitor, 5-fluorouracil (5-FU), is frequently prescribed to CRC patients; however, drug resistance is a critical limitation of its clinical application. Based on the hypothesis that Coptidis Rhizoma extract (CRE) can abolish this 5-FU resistance, we explored the efficacy and underlying mechanisms of CRE in 5-FU-resistant (HCT116/R) and parental HCT116 (HCT116/WT) cells. Compared to treatment with 5-FU alone, combination treatment with CRE and 5-FU drastically reduced the viability of HCT116/R cells. The cell cycle distribution assay showed significant induction of the G0/G1 phase arrest by co-treatment with CRE and 5-FU. In addition, the combination of CRE and 5-FU notably suppressed the activity of TS, which was overexpressed in HCT116/R cells, as compared to HCT116/WT cells. Our findings support the potential of CRE as an adjuvant agent against 5-FU-resistant colorectal cancers and indicate that the underlying mechanisms might involve inhibition of TS expression.     

One-pot multicomponent synthesis of novel 1-thiazolyl-5-coumarin-3-yl-pyrazole derivatives and evaluation of their cytotoxic activity

A series of novel 1-thiazolyl-5-coumarin-3-yl-pyrazole derivatives (4a–l) were synthesized via one-pot multicomponent reaction of 5-substituted salicylaldehydes (1a–c), 4-hydroxy-6-methyl-2H-pyran-2-one (2) and 2-hydrazinyl-4-arylthiazoles (3a–d) in acetonitrile using a catalytic amount of piperidine under reflux conditions. This multicomponent approach has advantages such as reduced reaction time and a high product yield percentage when compared with corresponding multistep approaches. All the synthesized compounds were evaluated for their cytotoxic activity against Hep G2 (hepatocellular liver carcinoma) and MCF-7 (breast cancer) cell lines and compared with the standard drug Doxorubicin. Among all the compounds, compounds 4d against Hep G2, 4k against MCF-7 and 4e against both Hep G2 & MCF-7 showed excellent cytotoxic activity.     

Synthesis and characterization of phosphorylated polystyrene derivatives for use in chromatography: DNA-like and phospholipid-like behavior

New functional crosslinked polystyrene derivatives have been synthesized. These polymers are substituted with chemical groups such as phosphate, purine, and pyrimidine bases, choline, serine, and nucleotides in order to mimic DNA and phospholipids. For this purpose, hydroxylated polystyrene beads were prepared, where monomer units were substituted via spacers. Then, phosphomonoester groups at various substitution ratios were grafted onto hydroxylated resins by using a phosphorus oxychloride method. Nucleosides and nucleic acid bases derivatives were coupled with dicyclohexylcarbodiimide on phosphorylated polymers whereas nucleotides, phosphorylcholine, and phosphorylserine were grafted on to hydroxylated polystyrene. The synthesis and characterization of these DNA-like and phospholipid-like polystyrene resins are described here extensively.     

新型芳基修饰的藤黄酸衍生物的合成及其抗肿瘤活性

以取代酚或羟基吡啶为原料,在无水碳酸钾存在下,与溴代醇发生威廉姆森醚合反应制得中间体--芳（杂环）氧基醇(2a~2k); 2a~2k分别与藤黄酸通过光延反应合成了藤黄酸衍生物（3a~3k）。以DDC/HOSu为偶联剂,芳酸与3-氨基-1-丙醇经偶联反应制得中间体--芳酰氨基醇（5a~5h）; 5a~5h分别与藤黄酸通过光延反应合成了藤黄酸衍生物（6a~6h）。 2, 3, 5和6为新化合物,其结构经¹H NMR, ESI-MS和HR-MS表征。采用MTT法测定了3和6对肺腺癌细胞(A549)、肝癌细胞(HepG-2)和乳腺癌细胞(SK-BR-3)的体外抗肿瘤活性。结果表明：部分化合物对肿瘤细胞的抑制活性明显高于藤黄酸。     

Asymmetric Hydrogenation of Furans and Benzofurans with Iridium–Pyridine–Phosphinite Catalysts

Enantioselective hydrogenation of furans and benzofurans remains a challenging task. We report the hydrogenation of 2‐ and 3‐substituted furans by using iridium catalysts that bear bicyclic pyridine–phosphinite ligands. Excellent enantioselectivities and high conversions were obtained for monosubstituted furans with a 3‐alkyl or 3‐aryl group. Furans substituted at the 2‐position and 2,4‐disubstituted furans proved to be more difficult substrates. The best results (80–97 % conversion, 65–82 % enantiomeric excess) were obtained with monosubstituted 2‐alkylfurans and 2‐[4‐(trifluoromethyl)phenyl]furan. Benzofurans with an alkyl substituent at the 2‐ or 3‐position also gave high conversions and enantioselectivity, whereas 2‐aryl derivatives showed essentially no reactivity. The asymmetric hydrogenation of a 3‐methylbenzofuran derivative was used as a key step in the formal total synthesis of the cytotoxic naphthoquinone natural product (?)‐thespesone.     

Synthesis and in vitro biological evaluation of farnesylthiosalicylic acid derivatives as anti-tumor carcinoma agents

Novel farnesylthiosahcylic acid(FTA) derivatives 5a-m with different substituted 1,3,4-thiadiazoles were synthesized. Compounds 5b,5c,5e and 5f displayed anti-tumor activities superior to FTA in most cancer cells tested.Furthermore,5e induced tumor cell apoptosis,which was accompanied by lower Bcl-2 expression,but with higher Bax and caspase 3 expression activities in cancer cells.     

Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and related prodrugs have been considered first-line chemotherapy agents for the treatment of colorectal cancer. However, poor specificity and tumor cell resistance remain major limiting bottlenecks. G-quadruplexes, have been suggested as preferred nanostructures for enhancing cellular uptake mediated by G-quadruplex binding proteins which are abundant at the membranes of some tumor cells. In the current study, we propose a new strategy to deliver 5-fluoro-2′-deoxyuridine (5-FdU) monophosphate, the main active drug from 5-FU derivatives that may circumvent the cellular mechanisms of FU-resistant cancer cells. Two G-quadruplexes delivery systems containing four and six G-tetrads ((TG₄T) and (TG₆T)) linked to a FdU oligonucleotide were synthesized. Biophysical studies show that the G-quadruplex parallel structures are not affected by the incorporation of the 5 units of FdU at the 5’-end. Internalization studies confirmed the ability of such G-quadruplex nanostructures to facilitate the transport of the FdU pentamer and increase its cytotoxic effect relative to conventional FU drug in FU-resistant colorectal cancer cells. These results suggest that FdU oligomers linked to G-quadruplex parallel sequences may be a promising strategy to deliver fluoropyrimidines to cancer cells.     

Synthesis and Properties of Hydrophilic Copolymers Containing 5-Fluorouracil,Thymine, or Adenine

Hydrophilic copolymers containing 5-fluorouracil (5-FU), thymine, or adenine were prepared by the free-radical copolymerization of methacryloyl-type monomers containing them with water-soluble vinyl monomers such as acrylic acid, methacrylic acid, vinylpyrroli-done, acrylamide, and 4(5)-vinylimidazole with AIBN as initiator. Complex formation between the copolymers and RNA and between the copolymers having complementary nucleic acid bases in aqueous solution and a DMSO-ethylene glycol was studied by means of UV spectroscopy. These copolymers were found to release the N-hydroxyethyl derivatives of 5-FU, thymine, or adenine by hydrolysis of the ester of the polymer side chain under mild conditions. The effects of the kind of water-soluble comonomer, temperature, pH, and the imidazole group as catalyst on the hydrolysis of the ester are discussed.     

Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives

A number of 2,3-diarylquinoline derivatives were synthesized and evaluated for antiproliferative activities against the growth of six cancer cell lines including human hepatocellular carcinoma (Hep G2 and Hep 3B), non-small cell lung cancer (A549 and H1299), and breast cancer (MCF-7 and MDA-MB-231) cell lines. The preliminary results indicated that 6-fluoro-2,3-bis{4-[2-(piperidin-1-yl)ethoxy]phenyl}quinoline (16b) was one of the most active compounds against the growth of Hep 3B, H1299, and MDA-MB-231 with a GI(50) value of 0.71, 1.46, and 0.72 μM respectively which was more active than tamoxifen. Further investigations have shown that 16b induced cell cycle arrest at G2/M phase followed by DNA fragmentation via an increase in the protein expression of Bad, Bax and decrease in Bcl-2, and PARP which consequently cause cell death.     

Synthesis and Biological Evaluation of Novel Uracil and 5-Fluorouracil-1-yl Acetic Acid-Colchicine Conjugate

A series of novel uracil and 5-fluorouracil-1-yl-acetic acid-colchicine derivatives(6a-6n) was synthesized via coupling uracil and 5-fluorouracil(5-FU) with C-10 analogues of colchicine. The antitumor activities of the target compounds against human hepatocellular carcinoma(BEL7402) cells, human ovary carcinoma(A2780) cells, human lung adenocarcinoma(A549) cells and human breast carcinoma(MCF7) cells were tested in vitro, and the structure-activity relationship(SAR) of the compounds was also studied. The bioassay results demonstrate that most of the tested compounds display significant activity and particularly, compounds 6a, 6e, 6h and 6l show more potent cytotoxic activities than 5-fluorouracil and colchicine. The results show that the new derivatives of colchicine are potential suppressors on human cancer.     

Synthesis and Cytotoxicity of 6‐Pyrrolidinyl‐2‐(2‐Substituted Phenyl)‐4‐Quinazolinones

In our continuing search for potential anticancer candidates, 2‐(3‐methoxyphenyl)‐6‐pyrrolidinyl‐4‐quinazolinone ( JJC‐1 ) was selected as the lead compound. Starting 5‐pyrrolidinyl‐2‐aminobenzamide was prepared using standard methodology from 5‐chloro‐2‐nitrobenzoic acid by reaction with SOCl₂, NH₃, pyrrolidine, and H₂. The starting benzamide then was reacted with 2‐substituted benzaldehyde or benzoyl chloride in N,N‐dimethylacetamide (DMAC) in the presence of NaHSO₃ at 150 °C. Thermal cyclodehydration/dehydrogenation gave the target 6‐pyrrolidinyl‐2‐(2‐substituted phenyl)‐4‐quinazolinones ( 15–22 ). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI‐3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI‐3 cells, with EC₅₀ values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.     

Cytotoxic cardenolide and sterols from Calotropis gigantea

The dichloromethane extract from the leaves of Calotropis gigantea Linn. was strongly cytotoxic against non-small cell lung carcinoma (A549), colon carcinoma (HCT 116) and hepatocellular carcinoma (Hep G2), and non toxic to Chinese hamster ovary (AA8). The extract afforded uscharin (1), 3,5,8-trihydroxy-24-methylcholest-6,22-diene (2), a mixture of (24R)-3beta-hydroxy-24-ethylcholest-5-en-7-one (3a) and 6beta-hydroxy-24-ethylcholest-4,22-dien-3-one (3b), and another mixture of (24R)-24-ethylcholest-4-en-3-one (4a) and (24S)-24-ethylcholest-4,22-dien-3-one (4b). Cardenolide 1 exhibited extreme toxicity to A549, HCT 116 and Hep G2 with IC50 values of 0.003 microg/mL, 0.013 microg/mL, and 0.018 microg/mL, respectively, while sample 3 exhibited an IC50 of 1.35 microg/mL, 4.46 microg/mL, and 3.83 microg/mL, respectively.     

N9位芳基取代嘌呤-8-酮类衍生物的合成及抗肿瘤活性

合成了一系列N9位芳基取代嘌呤-8-酮类衍生物, 利用核磁共振氢谱(¹H NMR)、 核磁共振碳谱(¹³C NMR)和高分辨质谱(HRMS)进行了结构确证. 采用四甲基偶氮唑盐(MTT)法测定了目标化合物的体外抗肿瘤细胞增殖活性. 结果表明, 嘌呤酮环的C2位及N9位的取代对活性有较大影响, C2位引入对位由含氮六元环取代的苯胺, N9位引入对三氟甲基苯均有利于提高抗肿瘤活性. 化合物12c对人白血病细胞(K562)、 人前列腺癌细胞(PC-3)、 人乳腺癌细胞(MDA-MB-231)及人结肠癌细胞(HCT116)的抑制效果明显优于阳性对照药R-Roscovitine.     

One-pot,four-component synthesis of benzylpyrazolyl naphthoquinone derivatives and molecular docking studies

A highly efficient, green, one-pot, four-component approach for the synthesis of benzylpyrazolyl naphthoquinone derivatives (5a–p) have been developed by the domino reaction of 2-hydroxy naphthoquinone, aromatic aldehyde, ethyl acetoacetate, and phenyl hydrazine derivatives in water and employed p-toluene sulfonic acid (p-TSA) as the right choice of catalyst at reflux. Docking simulation was performed to position compounds 5a, 5b, and 5g into the anaplastic lymphoma kinase (ALK) structure active site to determine the probable binding model.