Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells

1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.     

禾叶山麦冬中一个新的C27甾体苷硫酸酯类化合物

为了对禾叶山麦冬(Liriope graminifolia(Linn.)Baker)进行植物化学和药理活性的研究,应用现代色谱技术对禾叶山麦冬植物的化学成分进行了提取分离,应用HR-MS、1H NMR、13C NMR、1H-1H COSY、HSQC、HMBC和NOESY技术对分离得到的4个化合物进行了结构确证。4个化合物分别鉴定为:(25S)-ruscogenin 1-sulfate-3-O-α-L-rhamnopyranoside(1)、(25S)-ruscogenin 1-O-β-D-xylopyranosyl-3-O-α-L-rhamnopyranoside(2)、橙皮苷(hesperidin,3)和4’,7-二羟基-5-甲氧基二氢黄酮(4)。其中化合物1为一个罕见的具有27个碳原子骨架结构的新的甾体苷硫酸酯类化合物,并对K562细胞及HL60细胞具有显著抑制作用。     

Cytotoxic evaluation of alkaloids and isoflavonoids from the Australian tree Erythrina vespertilio

A new glucoalkaloid, vespertilioside, together with three known alkaloids, including 11- β-methoxyglucoerysovine, erysotrine, and hypaphorine, were isolated from the fruits of E. vespertilio Benth. In addition, three known isoflavonoids, including phaseollin, alpiniumisoflavone, and phaseollidin, were identified from the plant stems. The structures of compounds were determined by 1D/2D NMR and mass experiments. The cytotoxic activity of all compounds was evaluated against a metastatic prostate cancer cell line (PC3) and neonatal foreskin fibroblast (NFF) using a real-time label-free cell analyser. Among the tested compounds, phaseollidin showed cytotoxic activities against PC3 (IC (50) = 8.83 ± 1.87 μM) and NFF (0.64 ± 0.37 μM) cell lines.     

Prenylterphenyllin and its dehydroxyl analogs, new cytotoxic substances from a marine-derived Fungus Aspergillus candidus IF10

Three novel cytotoxic substances named prenylterphenyllin (1), 4'-deoxyprenylterphenyllin (2), and 4'-deoxyisoterprenin (3) were isolated from a cultured marine-derived fungus of Aspergillus candidus IF10 together with 4'-deoxyterprenin (4). Their chemical structures were elucidated on the basis of 2D NMR analysis. These compounds 1 approximately 4 showed cytotoxic activity against human epidermoid carcinoma KB cells (KB3-1) with IC(50) of 8.5, 3.0, 2.5, and 4.5 microg/ml, respectively.     

Adlumiceine methyl ester,a new alkaloid from Fumaria vaillantii

A new alkaloid, adlumiceine methyl ester (1), together with two known alkaloids, parfumine (2) and N-methylhydrastine methyl ester (3), was isolated from aerial parts of Fumaria vaillantii. The structures of compounds were determined by 1D/2D NMR and MS data. All three compounds were tested for cytotoxic activity against PC3 and MCF7 cell lines using Alamar blue assay. The tested compounds showed no significant cytotoxic activity (IC₅₀>50 μM) against PC3 and MCF7 cell lines.     

Three new polymeric isopropenyl benzofurans from Ligularia stenocephala

Three new polymeric isopropenyl benzofurans, 4-methyl-2,4-bis(5,6-dimethoxy-2-benzofuranyl)-1-pentene, stenocephalin A (1), 4,6-dimethyl-2,4,6-tri(5,6-dimethoxy-2-benzofuranyl)-1-heptene, stenocephalin B (2) and 4,6,8-trimethyl-2,4,6,8-tetra(5,6-dimethoxy-2-benzofuranyl)-1-nonene, stenocephalin C (3), together with seven known compounds (4-10) were isolated from the roots of Ligularia stenocephala. The structures of the new compounds were elucidated on the basis of spectral evidence, especially on 2D NMR. In addition, the cytotoxic activity and the anti-bacterial activity of compounds 2, 3, 5 and 6 were tested.     

Bioactive coumarin derivatives from the fern Cyclosorus interruptus

Three new coumarin derivatives, compounds 1-3, three new furanocoumarins, compounds 4-6, and a novel dioxocane derivative, compound 7, were isolated from the fern Cyclosorus interruptus (Willd.) H. It?. Based on spectrometric and spectroscopic analysis (FAB or El mass spectrometry as well as 1D and 2D NMR experiments) their structures were characterised as 5,7-dihydroxy-6-methyl-4-phenyl-8-(3-phenylpropionyl)-1-benzopyran-2-one (1), 5,7-dihydroxy-6-methyl-4-phenyl-8-(3-phenyl-trans-acryloyl)-1- benzopyran-2-one (2), 5,7-dihydroxy-8-(2-hydroxy-3-phenylpropionyl)-6-methyl-4-phenyl-1- benzopyran-2-one (3), 8-benzyl-5,8-dihydroxy-6-methyl-4-phenylfuro[2,3-h]-1-benzopyran-2,9- dione (4), 8-benzyl-5,8 beta,9 beta-trihydroxy-6-methyl-4-phenyl-8,9-dihydro- furo[2,3-h]-1-benzopyran-2-one (5), 8-benzyl-5,8 beta,9 alpha-trihydroxy-6-methyl-4-phenyl-8,9-dihydro- furo[2,3-h]-1-benzopyran-2-one (6) and 5,11-dihydroxy-6-methyl-4-phenyl-11-(1-phenylmethyl)-7,10-dioxocane [5,6-h]-1-benzopyran-2,12-dione (7). For these compounds we propose the trivial names interruptins A-F. Compounds 1, 5/6 and 7 showed antibacterial activity while compounds 1 and 2 were cytotoxic to a KB cell line.     

Three new pimaren diterpenoids from marine mangrove plant, Bruguiera gymnorrhiza

Three new pimaren diterpenoids, ent-8(14)-pimarene-15R, 16-diol (1), ent-8(14)-pimarene-1alpha,15R,16-triol (2), and (5R, 9S, 10R, 13S, 15S)-ent-8(14)-pimarene-1-oxo-15R,16-diol (3), along with three known diterpenoids (4-6) have been isolated from the stem of mangrove plant Bruguiera gymnorrhiza. The structures of compounds 1-3 were determined by extensive spectroscopic (2D NMR, MS, IR, and CD) analysis, and 3 and 5 showed moderate cytotoxic activities against L-929 and K562, respectively.     

A novel degraded sesquiterpene from the fresh stem of Aquilaria sinensis

A novel degraded sesquiterpene, named aquilarin B (1), together with two known compounds (2 and 3), was isolated from the EtOH extract of the fresh stem of Aquilaria sinensis (Lour.) Gilg. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR (HMQC, ¹H–¹H COSY, HMBC, and ROESY). The cytotoxic activities of the three compounds against three human tumor cell lines K562, SMMC-7721, and SGC-7901 were evaluated, and compound 3 exhibited obvious cytotoxic activity.     

海洋真菌Aspergillus sp.HH-3中1个新的抗肿瘤硫代二酮哌嗪类化合物

目的 研究海泥真菌Aspergillus sp.HH-3的次级代谢产物及其抗肿瘤活性。方法 使用硅胶色谱柱、LH-20凝胶色谱等对代谢粗提物进行分离纯化;运用核磁共振、质谱等方法并结合文献报道数据确定化合物的结构;采用CCK-8法评价化合物对三种肿瘤细胞(A549、HepG2、Hela)的抑制活性。结果 从Aspergillus sp.HH-3中分离获得六个化合物,包括一个新的硫代二酮哌嗪类化合物aspersin(1)与五个已知化合物dehydroxymethylbis(dethio)bis(methylthio)gliotoxin(2)、trypacidin(3)、monomethylsubchrin(4)、verruculogen(5)及chaetominine(6)。化合物1、2和6显示有一定的肿瘤细胞抑制活性。结论 化合物1为新的硫代二酮哌嗪类化合物;化合物1、2和4具有肿瘤细胞毒活性。     

Two new sesquiterpenes from the fruits of Fissistigma villosissimum

Two new sesquiterpenes, namely fissistinone (1) and fissistinol (2), along with ten known compounds (3–12), were isolated from the fruits of Fissistigma villosissimum. Their structures were elucidated on the basis of spectral data analysis, including one-dimensional (1D), two-dimensional (2D)-nuclear magnetic resonance (NMR), and high-resolution–electrospray ionization–mass spectrometry (HR–ESI–MS). Compounds 1–8 were evaluated for their cytotoxic activities against KB cell line; however, all these compounds did not show cytotoxic activity.     

New cytotoxic diarylheptanoids from the rhizomes of Alpinia officinarum

Bioassay-guided fractionation of the cytotoxic MeOH extract from the rhizomes of Alpinia officinarum Hance led to the isolation of two new diarylheptanoids named alpinoid D (1) and E (2), together with fifteen known diarylheptanoids (3 - 17). The structures of compounds 1 and 2 were elucidated on the basis of spectroscopic data and chemical evidence. The cytotoxic activity of the isolated diarylheptanoids was evaluated against the IMR-32 human neuroblastoma cell line. Among the tested compounds, 11, 12 and 14 exhibited the most potent activities with IC (50) values of 0.83, 0.23 and 0.11 microM, respectively.     

一种新强心苷类化合物的结构鉴定及其活性研究

目的 从弯蕊开口箭（Tupistra wattii Hook.f.）中寻找抗癌活性先导化合物。方法 使用稻瘟霉活性筛选体系进行活性追踪分离，并通过波谱分析，特别是二维核磁手段结合化学方法对分离得到的化合物进行结构鉴定。结果 从弯蕊开口箭中分离得到3个具有很强细胞毒活性的强心苷，其中化合物2wattosideF是一个新化合物，并且它的细胞毒活性在3个强心苷中最强，其IC50值为0.011μmol/L。结论 wattoside F是一个具有很强细胞毒活性的新的强心苷类化合物。     

Neobulgarones A approximately F from cultures of Neobulgaria pura, new inhibitors of appressorium formation of Magnaporthe grisea

Six new dimeric anthraquinone derivatives, neobulgarones A (3a), B (3b), C (4a), D (4b), E (5a) and F (5b), were isolated from the mycelia of the ascomycete Neobulgaria pura together with the monomeric carviolin (1) and 1-O-methylemodin (2). All new compounds inhibited the formation of appressoria in germinating conidia of Magnaporthe grisea on inductive (hydrophobic) surface. The compounds exhibited moderate cytotoxic, but no antifungal, antibacterial, or phytotoxic activities.     

Chemical constituents from the roots of Lindera aggregata and their biological activities

Three new benzylisoquinoline alkaloids, (1′S)-12′-hydroxyl-linderegatine (1), (1S)-5′-O-p-hydroxybenzoyl norreticuline (2), (1R, 1′R)-11,11′-biscoclaurine (3), along with 18 known compounds were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures were determined on the basis of extensive spectroscopic analysis (IR, UV, HR-ESI–MS, 1D and 2D NMR). The absolute configurations of three new compounds were determined by comparing their experimental and calculated ECD for the first time. Compounds (4) and (9) showed cytotoxic activities against human colon carcinoma cell line (HCT-116), with IC50 values of 51.4 and 27.1 μM, respectively. Furthermore, compounds (10) and (11) showed inhibitory activities on nitric oxide production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells, with IC50 values of 37.8 and 38.7 μM, respectively.     

Phenolic compounds from Nicotiana tabacum and their biological activities

Three new phenolic compounds, nicotphenols A-C (1-3), together with 14 known phenols (4-17), were isolated from the leaves of Nicotiana tabacum. Their structures were established by means of spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were tested for their anti-HIV-1 activities and cytotoxicities. They all showed significant cytotoxic abilities and modest anti-HIV-1 activities, respectively.     

Cytotoxicity of some azines of acetophenone derived mono-Mannich bases against Jurkat cells

Acetophenone derived mono-Mannich bases (Ig1-Ig4), 1-aryl-3-amino-1-propanone hydrochlorides, which are known to have cytotoxicity in Jurkat cells, were synthesized. Then, they were converted to corresponding azine derivatives (D1-D4), N, N'-bis(3-amino-1-aryl-propylidene)hydrazine dihydrochlorides, which are bifunctional agents. The aryl part was replaced by phenyl in Ig1, Ig2, Ig3, D1, D2, and D3, and by p-hydroxyphenyl in Ig4 and D4. The amine part was replaced by dimethylamine in Ig1, D1, Ig4 and D4, by piperidine in Ig2 and D2, and by morpholine in Ig3 and D3. The aim of this study was to investigate whether the modification in chemical structure, converting the mono-Mannich base to a corresponding azine derivative, improves the cytotoxicity. In addition, the effect of the representative compound, D3, N, N'-bis(3-morpholine-4-yl-1-phenylpropylidene)hydrazine dihydrochloride, on cellular glutathione level after 1 h exposure in phosphate buffer at 37 degrees C was also determined to provide information on a possible mechanism of cytotoxic action. Compounds D2-D4 are reported for the first time in this study. Except for Ig2 and D2, the cytotoxicity of mono-Mannich bases, Ig1, Ig3 and Ig4 and corresponding azine derivatives, D1, D3 and D4 were higher than the reference compound 5-FU. Azine derivatives D1 and D4 had almost equal cytotoxic potency with corresponding mono-Mannich bases Ig1 and Ig4, respectively. On the other hand, azine derivatives D2 and D3, had 1.28 and 1.90-times less cytotoxicity in Jurkat cells compared with the mono-Mannich bases, Ig2 and Ig3, respectively, from which they are derived. Azine derivative D3 dose-dependently decreased the total cellular glutathione level, suggesting that azine derivatives may exert cytotoxicity by thiol alkylation. Azine derivatives with equal or less cytotoxic potency compared to the mono-Mannich bases they are derived from seemed to be less suitable derivatives for the development of new cytotoxic compounds.     

Cytotoxic biotransformed products from triptonide by Aspergillus niger

The diterpenoid triepoxides are the major active constituents of Tripterygium wilfordii with potent antitumor and immune activities. But the strong toxicity of these compounds has restricted their application to a great extent. In order to find more effective compounds with less toxicity, structural modifications of triptonide (1) by Aspergillus niger (AS 3.739) were investigated and four biotransformed products were obtained. Based on their chemical and spectral data, their structures were elucidated as 5alpha-hydroxytriptonide (2), triptolide (3), 17-hydroxytriptonide (4), and 16-hydroxytriptonide (5), among which 2, 4 and 5 are new compounds. All the three new transformed products showed cytotoxic activities against the majority of the human tumor cell lines tested, however, they are found to possess less cytotoxic activity when compared with 1. Both compounds 4 and 5 showed similar cytotoxic activity and their IC (50) values were 5-15 fold less than 1, while 2 is about 100 times less active than 1.     

Antiplatelet effect and selective binding to cyclooxygenase by molecular docking analysis of 3-alkylaminopropoxy-9,10-anthraquinone derivatives

In an effort to develop potent cytotoxic inhibitors of cyclooxygenase (COX), a series of cytotoxic 3-alkylaminopropoxy-9,10-anthraquinone derivatives was screened to evaluate their antiplatelet effect on washed rabbit platelets and human platelet-rich plasma (PRP). Thrombin, arachidonic acid (AA), collagen, and platelet-activating factor (PAF) induced platelet aggregations were potently inhibited by compounds 1, 2, and 3 (each at 300 microM). Of the compounds tested in human PRP, compounds 1, 8, and 10 showed significant inhibition of primary and secondary aggregation induced by epinephrine and had a weak inhibitory effect on cyclooxygenase-1 (COX-1). Molecular docking studies revealed that compounds, 1, 8, and 10 were bound in the active sites of COX-1. This indicated that the antiplatelet effect of these three compounds was partially mediated through the suppression of COX-1 activity and reduced thromboxane formation. It is concluded that the cytotoxic compounds 1, 8, and 10 may interfere the conversion of arachidonic acid to prostaglandin (PG)H(2) in the active site of COX-1.     

New cassaine diterpenoid amides with cytotoxic activities from the bark of Erythrophleum fordii

A phytochemical investigation of the bark of Erythrophleum fordii led to six new cassaine diterpenoid amides (2, 4-8), together with two known compounds of the same skeleton, nor-cassamide ( 1) and nor-erythrosuamide (3). The structures were mainly established on the basis of 1D, 2D NMR and HR-MS analysis. The compounds 1, 2, 4, 6-8 exhibited selective cytotoxic activities (IC50 values < 10 microM) against A2780, KB, Bel-7402, BGC-823, MCF-7, HCT-8, Hela, PC-3M, A549 and Ketr3 human cancer cell lines in the MTT test.