Design,Synthesis and Antitubulin Activity of Novel Podophyllotoxin Derivatives as Potent Anticancer Agent

Twenty novel podophyllotoxin derivatives(1―20) were designed and synthesized. The anti-proliferation activities of these compounds were evaluated against three human cancer cell lines(HepG2, Calu-1 and MCF-7) using podophyllotoxin and Combretastatin A4(CA-4) as positive controls. Among all the compounds, compound 2 displayed more significant anti-proliferation activities against MCF-7 and Calu-1 cell lines and showed lower toxicity towards non-cancer cells. Furthermore, the cell cycle and apoptosis analysis results revealed that compound 2 can cause cell arrest at G2/M phase, leading to cancer cell apoptosis. Meanwhile, it can also reduce the adhesive ability of Calu-1 cells to fibronectin and laminin. The docking simulation results demonstrated that compound 10 can nicely bind to the colchicine site of tubulin. The podophyllotoxin derivatives are worthy to be further investigated to obtain more potent anti-cancer drugs.     

Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII

Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) have been prepared and their structural information on these nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) using (1)HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide.     

Synthesis and antitumor activity of novel podophyllotoxin derivatives

In order to find compounds with superior bioactivity and overcoming multidrug resistance,a novel series of 4β-N-substituted podophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents.Seven novel podophyllotoxin derivatives were synthesized by linking-4β-amino-4-deoxypodophyllotoxin with alcohols through maleic acid and tested against K562 and K562/A02 using MTT assay in vitro.     

Synthesis and insecticidal activities of novel derivatives of podophyllotoxin

In order to find the biorational pesticides, eight novel 4beta-substituted phenoxyaniline derivatives of podophyllotoxin (4a-h) have been synthesized with significant stereoselectivity and improved yields by employing the BF(3).Et(2)O/NaI reagent system and evaluated for insecticidal activity against Pieris rapae as well as for their antifeedant effect against fifth instar larvae of P. rapae. The results showed that all these derivatives of PPT showed delayed insecticidal activity, which is different from the traditional neurotoxic insecticides. Among them, compounds possessing a 4beta-phenoxyaniline moiety substituted at para (CO(2)C(2)H(5), Cl, and OH) position exhibited greater insecticidal activity against P. rapae than podophyllotoxin. Also, the antifeedant activities showed that these compounds exhibited less potency than podophyllotoxin.     

Design and synthesis of novel cytotoxic podophyllotoxin derivatives

<正>In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives,novel 4-Nand 4-C-substituted 4'-O-demethylepipodophyllotoxin derivatives were designed and synthesized.All the compounds were tested against A549 and MCF-7 tumor cells in vitro,and six compounds showed significant cytotoxicity.The most active compound 9f was superior to GL-331,and exhibited potent cytotoxicity with IC_(50) value at 10~(-7) mol/L level.     

Synthesis and cytotoxicity of novel podophyllotoxin derivatives

In order to find novel synthetic antitumor agents with superior cytotoxicity and overcoming multidrug resistance,a novel series of 4β-N-substituted podophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents.Seven novel podophyllotoxin derivatives were synthesized by linking 4β-amino-4-deoxypodophyllotoxin with N-substituted 5-methylindol-3- yl-glyoxyl chlorides and tested against K562 and K562/A02 using SRB methods in vitro,KB and KBV using MTT methods in vitro.     

Two new podophyllotoxin glucosides from Sinopodophyllum emodi (Wall.) Ying.

Two new aryltetralin-type lignans, isopodophyllotoxin 7'-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside (1) and 4-demethyl-picropodophyllotoxin 7'-O-beta-D-glucopyranoside (2), along with eight known podophyllotoxin derivatives: 4-demethyl-podophyllotoxin 7'-O-beta-D-glucopyranoside (3), podophyllotoxin 7'-O-beta-D-glucopyranoside (4), deoxypodophyllotoxin (5), picropodophyllotoxin (6), podophyllotoxin (7), 4-demethyl-picropodophyllotoxin (8), 4-demethyl-podophyllotoxin (9), and 4-demethyl-deoxypodophyllotoxin (10), were isolated from the roots and rhizomes of Sinopodophyllum emodi (Wall.) Ying (Berberidaceae). Their structures were identified based on NMR spectral data and chemical evidence.     

新的4’-去甲表鬼臼衍生物的合成及其抗癌活性

根据鬼臼毒衍生物和5-氟尿嘧啶的抗癌机理和构效关系,合成了7个新的4β- 5-氟尿嘧啶取代-4’-去甲表鬼鬼臼毒衍生物。在抑制金属基质蛋白酶I和胶原酶I 活性测试中,化合物2.4和2.6的抑制活性比鬼臼乙叉甙（VP-16）和5-氟尿嘧啶（ 5-Fu）强的3倍和5倍,在治疗癌细胞转移方面值得进一步探讨。     

Synthesis of Novel Spin‐Labeled Derivatives of Podophyllotoxin as Potential Antineoplastic Agents

Five novel nitroxyl spin‐labeled ester derivatives of podophyllotoxin have been prepared by reacting the corresponding N‐(1‐oxyl‐2,2,6,6‐tetramethyl‐4‐piperidinyloxycarbonyl) amino acids with the hydroxy group of podophyllotoxin in the presence of dimethylaminopyridine and N,N‐dicyclohexylcarbodiimide and evaluated as potential antitumor agents. All of the target compounds showed more significant cytotoxicity against P‐388 murine leukemia and A‐549 human lung carcinoma in vitro than etoposide.     

Synthesis and anti-tumor activity evaluation of novel podophyllotoxin derivatives

In order to investigate the effects on the cytotoxicity of indole-3-oxalylamino podophyllotoxin analogs, seven novel podophyllotoxin derivatives were synthesized.The compounds were tested against Hela, K562 or K562/A02 cancer cells in vitro,four of which showed significant cytotoxicity.Among them 9a,9b and 9c were superior to the positive control VP-16.     

Anticancer Drugs ( Ⅳ )——New Derivatives of Podophyllotoxin

Four new derivatives of podophyllotoxin, N'-podophyllic acid-N-[3-(2, 2, 5, 5-te-tramethyl-pyrrolinenyloxy)] semicarbazide(GP-11, 6), podophyllic acid [3-(2,2,5,5-te-tramethyl-pyrrolinenyloxy)]hydrazone (GP-12, 7), podophyllic acid-[4-(2, 2, 6, 6-tetramethyl-1-hydroxy piperidine)]hydrazone(GP-1-OH, 8) and podophyllic acid[4-(2,2, 6, 6-tetramethyl piperidine)]hydrazone(GP-1-H, 9) were synthesized. The inhibition effect of the four new compounds on L-1210 cells were determined. The antitumor activity and toxicity of GP-1(2), GP-1-OH(8), GP-1-H(9) and VP-16-213(1) were discussed.     

自旋标记鬼桕类化合物圆二色谱的研究

给已知抗癌药物分子中引入稳定氮氧自由基,合成较母体药物高效低毒的抗癌药物已引起国内外学者的重视.我们在具有抗癌活性的鬼桕毒分子中引入稳定氮氧自由基,药理试验表明其活性保持或增加,而毒性却显著地降低.     

1,2,7,9-四取代去氢骆驼蓬碱衍生物的合成及体外抗肿瘤活性

为了寻找高效低毒的抗肿瘤候选化合物, 以去氢骆驼蓬碱为原料, 对β-咔啉环的2-,7-和9-位3个结构位点进行了结构改造, 合成了11个去氢骆驼蓬碱衍生物, 化合物的结构经核磁共振、 红外光谱、 质谱及元素分析确证. 采用四甲基偶氮唑盐(MTT)法初步测试了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7)活性, 结果表明化合物4a, 4b, 8a和8b具有显著的体外抗肿瘤活性.     

An Efficient One-pot Synthesis of Certain Stereoselective Spiro[pyrazole-4,5'-isoxazoline]-5-one Derivatives: In vitro Evaluation of Antitumor Activities,Molecular Docking and In silico ADME Predictions

A library of novel spiro[pyrazole-4,5'-isoxazoline]-5-one derivatives were designed and synthesized using a concise and efficient one-pot reaction protocol through 1,3-dipolar cycloaddition between 4-benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and chlorooximes. The synthesized derivatives were elucidated and characterized based on their spectroscopic data, including infrared spectrometry(IR), ¹H NMR, ¹³C NMR, and elemental and mass spectral analysis. The synthesized compounds were evaluated for their antitumor inhibition potency against four human cancer cell lines, including human prostatic adenocarcinoma (PC3), human colorectal carcinoma(HCT116), human liver hepatocellular carcinoma(HepG2) and breast adenocarcinoma (MCF7). The outcomes were compared with the standard reference drug Doxorubicin. Among the synthesized chlorooximes, compounds 6d and 6e were the most active compounds on all cell lines. The spiro[pyrazole-4,5'-isoxazoline]-5-one derivatives 7a and 7c were active on the HepG2 liver cancer cell line. In comparison, compounds 7f and 7g were moderately active on the MCF7 cell line. The structure-activity relationship was explored for the synthesized compounds. Besides, in silico analysis of physicochemical, adsorption, distribution, metabolism, excretion and toxicity(ADMET) properties were done to determine the potential capacity of drug candidates. Molecular docking study onto the epidermal growth factor(EGF) tyrosine kinase receptor(3POZ) was done for the most active compounds to validate the reliability of in vitro anticancer screenings.     

Synthesis and insecticidalactivity of novel dimers of celangulin-V and podophyllotoxin

Celangulin-V (1) and podophyllotoxin (2) are both natural compounds with significant insecticidal activity. The identical and nonidentical dimers of celangulin-V and podophyllotoxin (3, 4, 5) were synthesized using succinic acid as the linker, and their insecticidal activities against 3rd instar larvae of Mythimna separata were tested. Only the identical dimer of celangulin-V (3) show some insecticidal activity.     

Synthesis and antitumor activity of novel pyridino[2,3-d]pyrimidine urea derivatives

A series of novel N-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrrolidine-1-carboxamide and 1-(3-((6-bromopyrido[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3-propylurea derivatives were synthesized. Their antitumor activities against human breast carcinoma cells (MCF-7) and human colon cancer cells (HCT-116) in vitro were evaluated, using sorafenib as a positive control drug. Anticancer bioassays indicated that several compounds exhibited appreciable anticancer activity against MCF-7 and HCT-116 cells. Particularly, compounds 9g and 8b demonstrated the most significant inhibitory effect against HCT-116 and MCF-7 cells, with inhibition ratios of 25.56% and 26.46%, respectively. Additionally, the synthesized pyridine[2,3-d]pyrimidine derivatives containing a urea group moieties exhibited antitumor activities against MCF-7 and HCT-116 cells in vitro.     

Synthesis and insecticidal activity of novel 4beta-halogenated benzoylamino podophyllotoxins against Pieris rapae Linnaeus

Twelve new 4beta-halogenated benzoylamino compounds (7.1-7.12) of podophyllotoxin have been synthesized, and their structures were confirmed by IR, 1H-NMR, MS spectra as well as CHN elemental analysis. These compounds showed delayed insecticidal activity against 5th instar larvae of Pieris rapae Linnaeus in vivo, when tested by a leaf-dipping method at a concentration of 250ppm. By preliminary qualitative structure-activity relationship analysis, we found the following results: 1) Compounds 7.2, 7.5-7.9 were more potent than the nature parent product in the mortality after 15 d against P. rapae in vivo. Especially compounds 7.5 and 7.6 bearing meta- and para-chlorobenzene substituents respectively, were the most potent of these compounds; 2) Substitution on the benzene ring moiety of 4beta-benzoylamino podophyllotoxin (PPT) with Cl, Br, I at the para or at the meta position yielded compounds which were as potent or more potent than those containing the corresponding substituting group at the ortho position. 3) Substitution on the benzene ring moiety of 4beta-benzoylamino podophyllotoxin with I either at the ortho, meta or para position yielded less potent compounds (7.10-7.12) when compared with PPT.     

Oxyfunctionalization products of terpenoids with dimethyldioxirane and their biological activity

Oxyfunctionalization of the bioactive terpenoids, ursolic acid acetate (1), oleanolic acid acetate (5), lupeol acetate (12), and kaurenic acid (17), with dimethyldioxirane (DMDO) was investigated. Treatment of the terpenoids with DMDO under mild conditions afforded a variety of oxidation and oxydegradation products to yield naturally occurring and/or novel compounds in one step. After chromatographic separation, the structures of the individual isolated products were determined using spectroscopic methods including several homonuclear (1H-1H) and heteronuclear (1H-13C) shift-correlated 2D-NMR techniques. The inhibitory activity of the terpenoid derivatives against alpha-glucosidase was investigated and compounds 1, 3, 7, and 9 were found to exhibit potent activity.     

Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline

The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is also described.     

Novel rearrangements of sesquiterpenoid panasinsane derivatives under acidic conditions

The sesquiterpenoid panasinsane derivatives 11 and 14-16 have been prepared from caryophyllene oxide (7). The novel rearrangement reactions of compounds 11 and 14 under TCNE-catalyzed solvolysis conditions and the reactions of compounds 15 and 16 under superacid conditions (HSO3F/Et2O, -63 degrees C) have been investigated. The ginsenol derivative 17 is obtained from compounds 11 and 14 under TCNE-catalyzed conditions. The rearrangement of compounds 15 and 16 under superacid conditions leads to the novel sesquiterpene derivatives (1S,4S,7S,10S,11S)-3,3,10,11-tetramethyltricyclo[5.3.1.0(4,10)]undecan-1,11-yl sulfate (19) and (1S,4S,5S,8S)-2,2,4,8-tetramethyl tricyclo[3.3.2.1(4,8)]undecan-11-one (20). The influence of the secondary hydroxyl group at C-5 of the panasinsane derivatives on the course of these rearrangements is discussed.