Antiproliferative Activity Of Compounds Research Articles

Antiproliferative Dimeric Aporphinoid Alkaloids from the Roots of Thalictrum cultratum.

Inspired by the intriguing structures and bioactivities of dimeric alkaloids, 11 new thalifaberine-type aporphine-benzylisoquinoline alkaloids, thalicultratines A-K, a tetrahydroprotoberberine-aporphine alkaloid, thalicultratine L, and five known ones were isolated from the roots of Thalictrum cultratum. Their structures were defined on the basis of NMR and HRESIMS data. The antiproliferative activities of compounds 1-17 were evaluated against human leukemia HL-60 and prostate cancer PC-3 cells. Most alkaloids showed potent cytotoxicity against selected cancer cells. Preliminary SARs are discussed. The most active new compound (3), with an IC50 value of 1.06 μM against HL-60 cells, was selected for mechanism of action studies. The results revealed that compound 3 induced apoptosis and arrested the HL-60 cell cycle at the S phase with the loss of mitochondria membrane potential. The nuclear morphological Hoechst 33258 staining assay was also carried out, and the results confirmed apoptosis.

Quassinoids from the Root of Eurycoma longifolia and Their Antiproliferative Activity on Human Cancer Cell Lines.

Background:The roots of Eurycoma longifolia Jack have traditionally been used as an aphrodisiac tonic besides the other remedies for boils, fever, bleeding gums, and wound ulcer. Recently, the antiproliferative activity of E. longifolia has been reported and remained attractive to natural chemists.Objective:The objective of this study was to study on antiproliferative compounds from the root of E. longifolia.Materials and Methods:Column chromatography was used to separate individual compounds, spectroscopic data including nuclear magnetic resonances and mass spectrometry were analyzed to determine the chemical structure of the isolates and for biological testing, antiproliferative activity of compounds was tested on seven human cancer cell lines (KATO III, HCT-15, Colo205, HepG2, PC-3, Jurkat, HL-60) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method.Results:Nine quassinoids including a new C19 longilactone-type quassinoid glycoside were characterized from the roots of the title plant. Among them, the major quassinoid eurycomanone exhibited selectively potential antiproliferative activities on the leukemia cell lines (HL-60 and Jurkat) and had very low toxic effects on normal skin fibroblast cell line (NB1RGB).Conclusion:The current study reveals one new quassinoid glycoside and the potential active component (eurycomanone) from E. longifolia for the leukemia treatment.SUMMARY Nine quassinoids (1-9) including one new quassinoid glycoside (9) and eight known ones were isolated from the roots of Eurycoma longifoliaThe structure of the new quassinoid 9 was determined by extensive chemical and spectroscopic analysesThe major quassinoid, eurycomanone (3), exhibited selectively potential antiproliferative activities on both Jurkat and HL-60 leukemia cells and had very low toxic effects on normal skin fibroblast cell line (NB1RGB). Abbreviations used: COSY: Correlation spectroscopy; HMBC: Heteronuclear multiple-bond correlation; HMQC: Heteronuclear multiple quantum correlation; NMR: Nuclear magnetic resonance; NOESY: Nuclear Overhauser enhancement spectroscopy; TLC: Thin layer chromatography.

Bioactivity-guided isolation of anti-proliferative compounds from endemic Centaurea kilaea

Context: The genus Centaurea L. (Asteraceae) is one of the largest genera in Turkey. Compounds and extracts obtained from different Centaurea species have significant anti-cancer activity against various cancer cell lines.Objective: To determine the anti-proliferative activity of isolates from the chloroform extract of C. kilaea Boiss.Materials and methods: Eleven compounds were isolated using column chromatography and preparative TLC from the chloroform extract of aerial parts of endemic C. kilaea. The structures of the isolated compounds were elucidated by various spectroscopic methods, including UV, lH-NMR and 13C-NMR. Anti-proliferative activity of compounds (0.5–50 μg/mL) were measured against one normal cell line (L-929, mouse fibroblast) and three human cancer cell lines (Hela, cervix carcinoma; MCF-7, breast carcinoma; PC-3, prostate carcinoma) using MTT assay. Results were expressed as IC50 values.Results: None of the 11 compounds displayed activity against L-929 and HeLa. Two of these compounds, cnicin and cirsimaritin, showed fairly strong activity against MCF-7 and PC-3 with IC50 values of 3.25 and 4.3 μg/mL, respectively.Discussion and conclusion: This is the first report on cirsimaritin. Cirsimaritin and cnicin could serve as potential anti-cancer drug candidates against breast and prostate cancer, respectively.

Synthesis of monomeric and dimeric steroids containing [1,2,4]triazolo[1,5-a]pyrimidines

The synthesis of several monomeric and dimeric steroidal [1,2,4]triazolo[1,5-a]pyrimidines (TPs) derived from steroids are described. These derivatives were prepared from α,β-unsaturated carbonyl compounds through a Claisen Schmidt condensation and rearrangement of the spiro moiety followed by a cycloaddition with 3-amino-1,2,4-triazole. The antiproliferative activity of compounds 7, 13–15 was tested against human cancer cells; several IG50 values were below 10μM.

Synthesis and antiproliferative activity of some N′-substituted 2,4-dihydroxybenzothiohydrazides

The paper shows that new N'-substituted 2,4-dihydroxybenzocarbothiohydrazides are able to inhibit the in vitro proliferation of human tumor cell lines. The compounds were prepared by the reaction of sulfinylbis[(2,4-dihydroxyphenyl)methanethione] (STB) or its analogs with the hydrazines. The panel of N'-substitution included aryl, pyridinyl and pyrimidinyl rings. The highest antiproliferative activity for N'-(4-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)-5-ethyl-2,4-dihydroxybenzothiohydrazide (5b) was found. The antiproliferative potency of some compounds was similar to that of cisplatin. Analogs with the Et substituent on benzenediol moiety displayed higher potency than with the unsubstituted one. The influence of N'-substitution on antiproliferative activity of compounds was discussed.

Two new sesquiterpenoid glycosides from the leaves of Lycium barbarum

Two new sesquiterpenoid glycosides, lyciumionosides A–B (1–2), together with four known compounds (3–6), were isolated from the leaves of Lycium barbarum. Their structures were mainly established on the basis of MS, 1D and 2D NMR spectroscopic techniques. The antiproliferative activities of compounds 1–5 were evaluated. Compound 1 showed highest inhibitory activity against A549 cells with IC50 value of 32.6 ± 2.6 μM, compound 3 showed highest inhibitory activity against PC-3 cells with IC50 value of 36.0 ± 2.9 μM, and compound 5 exhibited highest inhibitory activity against HeLa cells with IC50 value of 32.3 ± 4.2 μM.

Antiproliferative activity of some tautomeric hydrazones derived from chalcones

A new series of hydrazones synthesized from chalcones. Synthesized compounds have been characterized by IR, 1 H-NMR and elemental analysis. Antiproliferative activity of compounds was investigated on Hela, A549, MCF7, HCC1937, MRC5 cells. All compounds exhibited cytotoxicity. Especially compounds 1b , 1c , 1f and 1i having 4-metylsulfonyl phenyl showed higher cytotoxicity against all of the cell lines compared to reference drug doxorubicin with low value of IC 50 =5,56-21,93 µM. The most active compounds 1b , 1c , 1f and 1i were analyzed for their effect on autophagic processes. HCC1937 cells were treated with these compounds at IC 50 concentration for 24 hours. An immunoblotting assay was performed to analysis autophagy markers and total polyubiquitinated protein levels. Compounds 1b , 1c , 1f and 1i significantly increased the conversion of LC3-I to LC3-II at IC 50 concentration. None of the tested compounds changed the level of total polyubiquitinated proteins. Keywords: chalcones, hydrazones, antiproliferative activity

Quali-quantitative determination of triterpenic acids of Ziziphus jujuba fruits and evaluation of their capability to interfere in macrophages activation inhibiting NO release and iNOS expression

Ziziphus jujuba Mill fruits are recognized as an outstanding source of biologically active compounds including triterpenic acids. In order to evaluate the triterpenic profile of these edible and little commercial fruits and to contribute to the improvement of their potential value as food, a quali-quantitative study along with biological assays were carried out.The phytochemical investigation of the triterpenic fraction yielded nine triterpenic acids, ceanothic acid (1), alphitolic acid (2), maslinic acid (3), 3-O-cis-coumaroyl alphitolic acid (4), 3-O-trans-coumaroyl alphitolic acid (5), 3-O-trans-coumaroyl maslinic acid (6), 3-O-cis-coumaroyl maslinic acid (7), betulinic acid (8), and oleanolic acid (9). In order to perform the quantitative determination of compounds 1–9 in Z. jujuba fruits, an analytical method based on liquid chromatography coupled to mass spectrometry with ESI source and triple quadrupole analyzer (LC-ESI(QqQ)MS), using the very sensitive and selective mass tandem experiment called Multiple Reaction Monitoring (MRM), was developed and validated.Furthermore, the antiproliferative activity of compounds 1–9 was determined on three different cultured cell lines, namely J774A.1, MCF7 and A459 cells. For compounds 1, 2, 5 and 9, exhibiting no significant antiproliferative activity, the effects on nitrite production by LPS-stimulated J774.A1 cultured macrophages were evaluated (10–100μM), showing the ability of alphitolic acid (2), and 3-O-trans-coumaroyl alphitolic acid (5) to reduce significantly (P<0.001) and in a concentration related manner NO production. The capability of compounds 2 and 5 to influence the expression of the inducible nitric oxide synthase (iNOS) was also investigated, showing that both compounds reduced iNOS expression in a concentration related manner.

A novel nucleoside from the edible mushroom, Tricholoma japonicum.

A novel nucleoside, 9-β-D-ribopyranosylpurine (2), along with three known nucleosides, adenosine (1), uridine (3) and nebularine (4), were isolated from the edible mushroom, Tricholoma japonicum. The structure of 2 was determined as 9-β-D-ribopyranosylpurine by comparing the reported spectral data of 2 with that of a synthetic compound. Isolation of the glycoside, which contains the sugar ribopyranose, from natural resources is very unusual. There are reports on the synthesis of 9-β-D-ribopyranosylpurine (2), but this is the first report on the isolation from natural resources. The antiproliferative activity of compounds 1-4 was evaluated using human umbilical vein endothelial cells. Compound 4 showed the highest inhibitory activity.

Synthesis and antiproliferative evaluation of some novel B-nor-D-homosteroids

Using 3β-hydroxy-5-androsten-17-one as a starting material, a series of novel nitrogen-containing B-nor-D-homosteroids were designed and synthesized by the oximation, Beckman rearrangement, ozonation, cyclization and condensation reaction. The structures of all new compounds were determined by analysis of their NMR, MS and IR spectra. The antiproliferative activity of compounds was evaluated against HT-29 (colonic carcinoma), HeLa (human cervical carcinoma) and Bel 7404 (human liver carcinoma) cells.

A new pregnane glycoside from Rubus phoenicolasius and its antiproliferative activity

Chemical investigations of the whole plant ethanol extract of Rubus phoenicolasius led to the isolation and identification of a new pregnane glycoside, 3-O-β-glucopyranosyl-3β,15β-dihydroxypregn-5-en-20-one (1), along with other nine known compounds (2–10). All the isolates were reported from this plant for the first time. The structure of compound 1 was determined by detailed analysis of its spectral data including 1D and 2D NMR. In vitro anti-proliferative activities of compounds 1–3 on MCF-7 and NCI-H460 tumour cell lines were evaluated, and compound 1 was active against the two cell lines with IC50 values of 15.6 and 13.5 μM, respectively.

Bioactivity-guided Isolation of Antiproliferative Compounds from the Roots of Onopordum acanthium

Onopordum acanthium has been considered in traditional medicine to be effective against different cancers. The chloroform extracts of the root, which displayed antiproliferative effect against human tumor cell lines, was subjected to bioactivity-guided multistep chromatographic separation. This experiment resulted in the isolation of the sesquiterpene lactones 4beta,14-dihydro-3-dehydrozaluzanin C (1), zaluzanin C (2) and 4beta,15,11beta,13-tetrahydrozaluzanin C (3), the neolignan nitidanin-diisovalerianate (4), besides 13-oxo-9Z,11 E-octadecadienoic acid (5), 24-methylenecholesterol (6), alpha-linolenic acid, linoleic acid, stigmasterol and beta-sitosterol. The structures of the isolated compounds were established through analytical data (NMR, MS), and by comparison of these with those reported in the literature. All the aforementioned compounds were detected for the first time from this plant. The antiproliferative activities of compounds 1-6 were assessed on cervix adenocarcinoma HeLa, breast adenocarcinoma MCF7 and skin epidermoid carcinoma A431 cells by using the MTT assay. It was found that, 4beta,14-dihydro-3-dehydrozaluzanin C (1), the most active antiproliferative compound of the extract, exerted remarkable tumor cell growth inhibitory activity (IC50 2.7-15.1 microM).

Abstract 2257: Thailanstatins: New pre-mRNA splicing inhibitors and potent antiproliferative agents discovered from Burkholderia Thailandensis MSMB43.

Abstract Natural products have been traditionally sought from actinomycetes, filamentous fungi and medicinal plants. Gram-negative bacterial species, such as Burkholderia, Chromobacterium, Lysobacter, Pseudomonas and Xenorhabdus, however, have recently captured attention as new sources of diverse bioactive natural products. Mining the genome sequence of B. thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster highly resembling that of FR901,464, a prototype pre-mRNA splicing inhibitor produced by Pseudomonas sp. No. 2663. Transcriptioal analysis identified a cultivation condition in which a representive gene of the cryptic gene cluster is adequately expressed. Consequently, three new compounds, thailanstatins A, B and C, were isolated from the fermentation broth of B. thailandensis MSMB43 through natural product chemistry. Thailanstatins belong to the FR901,464-family of microbial products biosynthesized by a hybrid polyketide synthease-nonribosomal peptide synthetase pathway. They have an oveall structural similarity with FR901,464, but feature an extra acetic acid unit which endows the compouds with a significantly higher stability than FR901,464 under physiologically relevant conditions. In vitro assays showed that thailanstatins inhibit pre-mRNA splicing as potently as FR901,464, with half-maximal inhibitory concentrations in the single to sub μM range, causing pre-mRNA to accumulate and preventing the production of mRNA and splicing intermediates. In vitro cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range (Table 1). This work provides new chemical entities for research and development, and validates the Burkholderia species as an exciting new source of bioactive natural products. Table 1.Antiproliferative activities of compounds in human cancer cell lines (GI50 in nM).CompoundDU-145 (prostate cancer)H232A (non-small cell lung cancer)MDA-MB235 (triple-negative breast cancer)SKOV-3 (ovarian cancer)Thailanstatin A1.11±0.022.26±0.172.58±0.112.69±0.37Thailanstatin B3.00±0.922.50±0.066.22±1.674.94±1.76Thailanstatin C2.98±0.903.67±0.538.82±2.205.57±2.01FR901,4641.05±0.021.94±0.242.10±0.191.06±0.01 Citation Format: Xiangyang Liu, Sreya Biswas, Michael G. Berg, Christopher M. Antapli, Feng Xie, Qi Wang, Man-Cheng Tang, Gong-Li Tang, Lixin Zhang, Gideon Dreyfuss, Yi-Qiang Cheng. Thailanstatins: New pre-mRNA splicing inhibitors and potent antiproliferative agents discovered from Burkholderia Thailandensis MSMB43. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2257. doi:10.1158/1538-7445.AM2013-2257

Abstract 5365: Molecular and pharmacological (EGFRi, MEKi) characterisation of a colorectal cancer (CRC) cell line panel to evaluate cellular phenotype and efficacy of targeted therapies in CRC

Abstract A broad range of targeted agents are in early development for treatment of solid tumours. It is important that patients receive treatments which are tailored to work optimally based on their individual tumour biology. Retrospective analysis of clinical data for the EGFR tyrosine kinase inhibitor, Iressa, in lung cancer demonstrated cell line panels can provide a platform to direct targeted therapies towards specific patient subpopulations. In order to evaluate targeted agents in colorectal cancer we have characterized a panel of 49 colorectal tumour cell lines derived from Dukes stage A-D of CRC for commonly occurring mutations (KRas, BRAF, PI3Ka, PTEN), microsatellite instability, gene copy number alterations (Agilent 244K ArrayCGH), mRNA expression (Affymetrics HG_U133_plus_2) and miRNA expression (TLDA – 177 miRNAs). These data have been used to characterize the differentiation status of the cell lines and to link to compound activity. We have probed the anti-proliferative activity of compounds from several growth factor pathways, EGFR, RAS/MEK and PI3K to evaluate pathway dependence and linkage to molecular data. The greatest activity of the EGFR TKI inhibitor was in Ras, Raf, PTEN, PI3K wild type (quadruple negative (QN)) CRC lines, in agreement with clinical data for EGFR antibodies. However, of the 9 QN lines profiled, only 4 were hypersensitive (GI50 &amp;lt;0.5uM), the hypersensitive lines had an epithelial phenotype (E-cadherin mRNA, miR200c &amp; B-Cat protein positive; vimentin mRNA negative). In contrast the QN lines that did not respond to EGFR inhibition had either a mesenchymal (E-cadherin mRNA, miR200c, B-Catenin protein negative, vimentin positive) or an intermediate phenotype (E-cadherin mRNA, miR200c &amp; B-Cat protein low; vimentin negative). KRAS and BRAF mutant cell lines were relatively resistant to EGFRi compared to QN cell lines (p = 0.009 and 0.06 respectively), with the exception of two lines with G13D KRAS mutations which had GI50s of 0.3 and 1.8uM. Interestingly, the epithelial QN lines were co-sensitive to EGFR, MEK and PI3K inhibitors. In contrast the mesenchymal QN lines were relatively insensitive to the kinase inhibitors used. The QN lines with an intermediate phenotype did not respond to EGFR or MEKi but did respond to PI3K inhibition. In conclusion, the data suggests that both mutation status and cellular differentiation status contribute to the response to targeted agents. Through profiling the anti-proliferative activity of inhibitors from across a range of pathways co-dependencies of kinase targets were revealed as well as anti-correlations which indicate potential combination strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5365. doi:10.1158/1538-7445.AM2011-5365

EFFECT OF ORGANIC MODIFIER ON THE LIPOPHILICITY OF ANTIPROLIFERATIVE ACTIVE 4-(5-AMINO-1,3,4-THIADIAZOL-2-YL)BENZENE-1,3-DIOLS BY REVERSED-PHASE OVERPRESSURED LAYER CHROMATOGRAPHY

The retention behavior of compounds of antiproliferative activity from the 4-(5-amino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols group by OPLC was investigated. RP-18 stationary phase and five different organic modifiers were used. In the case of ethanol as an organic solvent the highest concentration of water in the eluent can be applied. On the base of the linear relationship between the retention and the concentration of organic solvent, various lipophilicity descriptors were determined. Moderate correlations between the chromatographic parameters and the calculated log P values according to the Villar approach were found. The RMw parameters were compared with the antiproliferative activity of compounds against human cancer cell T47D (breast cancer) to find QSAR equations. The best results for ethanol as the organic solvent were found.

The metabolites of mangrove endophytic fungus Zh6-B1 from the South China Sea

Two new metabolites, 3R,5R-Sonnerlactone (1) and 3R,5S-Sonnerlactone (2), were isolated from the mangrove endophytic fungus Zh6-B1 obtained from the South China Sea. Their structures were elucidated by MS and NMR. The absolute configuration of compound 1 was determined by single-crystal X-ray analysis using Cu Kα radiation. The absolute configuration of compound 2 was determined by NOESY analysis and comparing circular dichroism spectroscopy with compound 1. The antiproliferative activity of compound 1 and 2 against the multi-drug resistant human oral floor carcinoma cells (KV) was evaluated.

Identification and Antiproliferative Activity Evaluation of a Series of Triterpenoids Isolated from Flueggea virosa (Roxb. ex Willd.)

Problem statement: Medicinal plants derived anticancer were now being subjects of many research groups especially, the secondary metabolite triterpenoids trees which had enormous potential to inspire and influence modern antiproliferative research. The study aimed to investigate the chemical constitution and their potential use as antiproliferative activity of purified compounds derived from F. virosa. Approach: The F. virosa was selected and percolated with hexane, ethyl acetate, acetone and methanol. The extracts were purified and elucidated chemical structures. Furthermore, the isolated compounds were tested for biological activity. The bioassays were performed on two cancer cell lines, adriamycin-sensitive erythroleukemia cells (K562) and adriamycin-resistant erythroleukemia cells (K562/Adr) which overexpressed P-glycoprotein (MDR1/ABCB1). Results: Friedelin (1), epifriedelanol (3), stigmasterol (4) and betulinic acid (5) were isolated from the leaves and twigs of F. virosa. The molecular structures of these compounds were determined using several spectroscopic methods. The compounds i.e., 1, a chemically modified compound 1 heptanolide (2), 3 and 4 showed a limited cytotoxic activity towards human cancer cell lines mainly due to a low aqueous solubility which prevented their use in cell viability assays. Interestingly, compound 5 exhibited a high cytotoxicity characterized by an effective concentration value (IC50) equal to 9.7±2.1 µg.mL-1 (21.2±4.6 µM) and 7.1±0.7 µg.mL-1 (15.5±1.5 µM) for K562 and K562/Adr, respectively. Moreover, the antiproliferative activity of compound 5 was independent of the multidrug resistance phenotype exhibited by the K562/Adr cell line suggesting that compound 5 was not the effluxes out of the K562/Adr cells by MDR1 (ABCB1). Conclusion: The results clearly showed that the betulinic acid of the four isolated compounds from F. virosa could be considered as high potential source of cytotoxic activity.

Bicyclononane Aldehydes and Antiproliferative Constituents fromAmomum tsao-ko

A racemic mixture of a new bicyclononane aldehyde, (1 RS,5 SR,6 RS)-5-hydroxybicyclo[4.3.0]non-2-ene-2-carbaldehyde (1) was isolated from the fruits of Amomum tsao-ko, together with 12 known compounds (2-13). The structure of 1 was determined on the basis of extensive spectroscopic analysis, including 1D and 2D NMR data. The antiproliferative activity of compounds 1-13 was assessed in the murine neuroblastoma cell line N2a.

Synthesis and biological evaluation of 3,5-diaminoindazoles as cyclin-dependent kinase inhibitors

A novel series of 3,5-diaminoindazoles were prepared and found to be CDK inhibitors. Potent inhibitors against CDK1 and CDK2 were obtained by introduction of 1lambda(6)-isothiazolidine-1,1-dioxide at 5-position of indazole. Anti-proliferative activities of compounds were evaluated using EJ, HCT116, SW620, and A549 cancer cell lines.

Antiproliferative Hopane and Oleanane Glycosides from the Roots ofGlinus lotoides

Three new hopane saponins, lotoidosides A - C (1 - 3), and four new oleanane saponins, lotoidosides D - G (4 - 7), were isolated from the roots of Glinus lotoides L. (Molluginaceae). Their structures were determined by extensive 1D- and 2D-NMR spectroscopy and ESI-MS analysis. The antiproliferative activity of compounds 1 - 7 was evaluated using three continuous murine and human culture cell lines J774.A1, HEK-293, WEHI-164. Compounds 1 and 3 - 7 showed significant cytotoxicity against the three cancer cell lines with IC50 values ranging from 0.018 to 0.62 microM, while compound 2 exerted a weak activity only against the cell line HEK-293.