Total Growth Inhibition Values Research Articles

Antiproliferative and antimicrobial studies of novel organic-inorganic nanohybrids of ethyl 2-((5-methoxy-1H-benzo[d]imidazol-2-yl)thio)acetate (EMBIA) with TiO2 and ZnO

Ethyl-2-((5-methoxy-1H-benzo[d]imidazol-2-yl)thio)acetate (EMBIA) was synthesized by the reaction of ethylchloroacetate and 5-methoxy-2-mercaptobenzamidazole in the presence of potassium hydroxide. EMBIA was used to produce novel organic: inorganic nanohybrids with newly synthesized ZnO and TiO2 nanostructures and fully characterized using FTIR, SEM, EDX, XRD and TEM. Furthermore, the synthesized nanohybrids were used to check their antibacterial and antifungal activities against some normal and antibiotic resistance bacteria (E. faecalis VRE, E. faecalis, S. aureus, S. aureus MSSA, S. aureus MRSA, E. coli, E. coli ESBL, P. aeruginosa AGME, S. mutans, S. gordonii, A. actinomycetemcomitans) and fungi (C. albicans). Furthermore, these nanohybrids were used to check their anticancer activity against brain cancer cell lines, gynaecological cancer cell lines, colon cancer cell lines, in addition to lung, retinal, and skin normal cells were used to check the toxicity. The value of total growth inhibition (TGI) was 43.27 and 79.01 µg/ml for EMBIA and EMBIA-TiO2, while it was 4.29 µg/ml for the EMBIA-ZnO against normal cell lines. The TGI values against cancer cell lines of EMBIA and EMBIA-TiO2 were better than those reported for the reference compound 5-fluorouracil (5FU).

Coordination of the natural ligand lapachol to iron(II): synthesis, theoretical study and antiproliferative activity

Lapachol is a natural naphthoquinone known for having a variety of biological properties, and in recent years, it has been used in the synthesis of metal complexes with biological applications. This work reports on the synthesis, properties and antiproliferative activity of one new metal complex obtained by the reaction of the natural naphthoquinone lapachol with Fe(II). Characterizations by CHN elemental analysis, electrochemical and spectroscopic techniques (infrared, UV–Vis and luminescence) allowed to infer the coordination of two lapachol molecules to the metallic Fe(II) ion through the phenolic and carbonyl oxygens, as well as the presence of two water molecules completing the complex coordination sphere. Molecular modeling was in good agreement with the [Fe(Lap)2(H2O)2] $$\cdot$$ 2H2O complex structure proposed from the experimental data. Antiproliferative activity assay revealed the efficiency of the [Fe(Lap)2(H2O)2] $$\cdot$$ 2H2O complex against some human tumor cell lines, with lowest TGI (Total growth inhibition) value and higher selectivity index for the glioma tumor cell line (U251).

Synthesis and biological evaluation of novel pyrimidine-5-carbonitriles featuring morpholine moiety as antitumor agents.

Aim: Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. Materials & methods: New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19derivatives (3b, 4a, 5-6, 9-12, 13a-e, 14a-c and 15-17) were evaluated for their invitro antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound 13e was evaluated against PI3K (α, β and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Results: Compound 13e possessed remarkable broad spectrum antitumor activity with GI50 (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66μM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC - positive apoptotic cells, also increased the level of active caspase-3. Moreover, 13e revealed good safety profile against transformed human liver epithelial-2 (THLE2).

Synthesis, characterization, crystal structure and in vitro antiproliferative assays of the 2-thiouracilato(triphenylphosphine)gold(I) complex

A gold(I) complex with triphenylphosphine and 2-thiouracil, named 2-thiouracilato(triphenylphosphine)gold(I) (Ph3P-Au-tuH), was synthesized and characterized by a set of chemical and spectroscopic techniques. By elemental and mass spectrometric (ESI-QTOF-MS) analyses, the molecular formula AuC22H18N2OSP was proposed, corresponding to a 1:1 metal/ligand composition. Spectroscopic studies based on the infrared (IR) and nuclear magnetic resonance (NMR) of 1H, 13C and 31P evidenced the conversion of the chlorido(triphenylphosphine)gold(I) into the 2-thiouracilato(triphenylphosphine)gold(I), with substitution of Cl− by thiouracil. The crystal structure of the Ph3P-Au-tuH complex was determined by single crystal X-ray diffraction and shows the coordination of 2-thiouracil to gold(I) by the thiol group. Further, the in vitro antiproliferative assays of the 2-thiouracilato(triphenylphosphine)gold(I) complex showed its high activity when compared to the chlorido(triphenylphosphine)gold(I) one against lung (NCI-H460) and colon (HT29) tumor cell lines, with total growth inhibition (TGI) values of 26.7 and 28.5 μg mL−1, respectively, and also high selectivity towards tumor cells when compared to the normal cell line (HaCat). In addition, the Ph3P-Au-tuH complex showed a TGI value lower than 0.25 μg mL−1 for the leukemia cell line (K-562) with a selectivity index (SI) of 24.4, exhibiting a better in vitro cytotoxicity and selectivity than doxorubicin against this specific cell.

Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives

This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines. Compounds 1e and 1g were the most promising analogues. Both compounds showed strong potency and broad-spectrum antiproliferative activity against the different tested cancer types. Their IC50 and TGI values were less than those of the reference drug, sorafenib, against most of the tested cell lines of the nine different cancer types. Furthermore, the most potent compounds 1d-g were tested against C-RAF kinase as a potential molecular target of this series of compounds. All of them showed high potency, and the most potent derivative was compound 1e (IC50 = 0.10 μM). It was further tested against a panel of another twelve kinases, and it showed selectivity against C-RAF kinase. This could be, at least in part, the possible mechanism of antiproliferative action of this series of compounds at molecular level. The binding modes of compounds 1e and 1g were studied by docking studies, which highlighted the importance of the urea linker compared with the amide linker.

Antiproliferative effect of synthetic cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against human cancer cell lines.

This work describes the antiproliferative potential of 14 cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against several human cancer cell lines. The antiproliferative effect was evaluated using the sulforhodamine B assay. Although some compounds from methylphtalimide and carboxylic acid phtalimide classes exhibited a selective antiproliferative activity, the itaconimides (11-14) exhibited the best results, especially compound 14, which presented a TGI (concentration that produces total growth inhibition) value of 0.0043 μM against glioma (U251), being inactive against the non-tumor cell line (HaCat). Absorption, distribution, metabolism and excretion in silico evaluations suggest that these compounds are promising candidates.

Mercuric chloride catalyzed synthesis of some anticancer 2-aryl-2,3-dihydroquinizolin-4(1H)-ones

A series of ten 2,3-dihydroquinizolin-4(1H)-one derivatives were synthesized by ethanol-mediated condensation of anthranilamide with various aryl aldehydes in presence of catalytic amount of mercuric chloride (HgCl2). The temperature of the reactions was maintained at 60 °C for good yield of the products. The highlights of the method include use of lab grade of chemicals as reagents and ease of work up in obtaining the product with high purity. Out of ten derivatives synthesized, three compounds 3f, 3i, and 3j are new and all the compounds were evaluated for their cytotoxic activity against six cancer cell lines. The compounds 3b (IC50: 26.1 µg mL−1), 3c (42.7 µg mL−1) ,and 3e (31.1 µg mL−1) have shown activity against the cell line MDA-MB-231. Compounds 3b, 3c, 3d, 3e, and 3g showed significant total growth inhibition (TGI) values against the cell line MDA-MB-231 and compound 3j showed good TGI value against the cell line PANC 1. Compounds were also screened for their antibacterial activity and antioxidant activity by DPPH method.

Antiproliferative activity, antioxidant capacity and chemical composition of extracts from the leaves and stem of Chresta sphaerocephala

In this study, antiproliferative and antioxidant activities of crude extracts (hexane, ethyl acetate and methanol) from leaves and stem of Chresta sphaerocephala DC., Asteraceae, were investigated. Antiproliferative activity was tested in vitro against ten human cancer cells and against VERO (no cancer cell). Antioxidant activities were determined using DPPH and ORAC-FL assays and the total phenolic content was estimated by Folin–Ciocalteu method. Hexane and ethyl acetate extracts (leaves and stem) exhibited antiproliferative activity against cancer cell lines with total growth inhibition (TGI) between 50.40 and 250μg/ml. For VERO cell, TGI values were >250μg/ml for all extracts, except to hexane extract of the stem (TGI 80.92μg/ml). In an initial evaluation, ethyl acetate and methanol extracts (leaves and stem) have shown levels of phenolic compounds between 6.94 and 30.96mg GAE/kg in Folin–Ciocalteu assay, DPPH free-radical scavenging activity with SC50 in the range of 75.22 and 400μg/ml and antioxidant capacity between 290.08 and 1088μmol TE/g of extract in ORAC-FL assay. HPLC-DAD and ESI-MS analysis allowed the identification of flavonoids in the methanol extract from the leaves of C. sphaerocephala. Three steroids and nine triterpenoids were identified in the bioactive hexane extracts using HRGC.

Abstract A129: Novel histone deacetylase inhibitors ITF-A and ITF-B exhibit efficacy in preclinical models of mature B-cell lymphomas.

Abstract Lymphomas are among the most common cancers. Despite significant progress made in their treatment, many patients still succumb to disease progression or relapse, or are refractory to current treatment regimens. Recently, the important role of epigenetic pathways in the pathogenesis of lymphomas has been highlighted, with several genes encoding epigenetic modifiers being shown to be selectively and prominently targeted by mutations and genomic aberrations. Histone deacetylase inhibitors (HDACi) are a class of molecules that have shown clinical efficacy in hematological malignancies, including T-cell lymphomas. Here, we have assessed the activity of two novel, class I, IIb, and IV HDACi, ITF-A and ITF-B, from Italfarmaco, in a panel of 29 non-Hodgkin lymphoma cell lines, comprising 21 diffuse large B-cell lymphoma (DLBCL) cell lines, 5 mantle cell lymphoma (MCL) cell lines, and 3 splenic marginal zone lymphoma (SMZL) cell lines. Cells were exposed to increasing concentrations of each HDACi and the MTT assay was performed after 72 hours to determine their cytotoxic and cytostatic effects estimating the IC50 (50%-inhibitory concentration), GI50 (50%-growth inhibition), LC50 (50%-lethal concentration), and TGI (total growth inhibition) values. Both ITF-A and ITF-B showed potent activities in most of the cell lines tested, irrespective of histological type, with the majority of IC50 values being below 100 nM. The median IC50 values were 13 nM (2-103 nM) and 33 nM (5-305 nM), for ITF-B and ITF-A, respectively. Median GI50 was 10 nM (1-63) for ITF-B, and 28 nM (2-217 nM) for ITF-A. The median LC50 values were 117 nM (10-2057 nM) and 42 nM (3-2388 nM) for ITF-A and ITF-B, respectively. The range of TGI values was 5-649 nM with a median of 59 nM for ITF-A, and 2-388 nM, with a median of 20n M for ITF-B. Both ITF-A and ITF-B induced apoptosis in the DLBCL and MCL tested as assessed by Annexin-V/7-AAD staining. Two DLBCL cell lines showing sensitivity to both HDACi, were chosen for further functional studies: DOHH2, a GCB-DLBCL cell line, and TMD8, a non-GCB DLBCL cell line. ITF-A and ITF-B presented both nuclear and cytoplasmic activity, as demonstrated by Western blotting analysis showing increased levels of both acetylated histone H3 and acetyl-α-tubulin following treatment with the two HDACi. Quantitative real-time PCR following 24 hours treatment of both cell lines with the two HDACi showed changes in the expression levels of STAT3, CDKN1A (p21) and MYC, suggesting roles for these genes in mediating the anti-proliferative effects of the two molecules. In conclusion, ITF-A and ITF-B showed promising activity in preclinical models of mature lymphomas and represent two new HDACi worthy of further pre-clinical evaluation as single agents and in combination with other agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A129. Citation Format: Afua A. Mensah, Eugenio Gaudio, Ivo Kwee, Andrea Rinaldi, Gianluca Fossati, Anastasios Stathis, Emanuele Zucca, Gianluca Caprini, Francesco Bertoni. Novel histone deacetylase inhibitors ITF-A and ITF-B exhibit efficacy in preclinical models of mature B-cell lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A129.

Biological activities of the essential oil from the leaves of Xylopia laevigata (Annonaceae)

The essential oil from the leaves of Xylopia laevigata was obtained by hydrodistillation and analyzed by gas chromatography/mass spectrometry (GC/MS) and GC/flame ionization detector (GC/FID). Thirty-six compounds representing 97.48% of the crude essential oil were identified. The major compounds identified were -muurolene (17.99%), -cadinene (13.45%), germacrene D (9.09%), bicyclogermacrene (7.00%), -copaene (5.98%), and (E)-caryophyllene (5.43%). The biological activities of the essential oil against Trypanosoma cruzi epimastigote forms, yeast, bacteria, Aedes aegypti larvae, antioxidant properties and antiproliferative activity against tumor cell lines were investigated. The essential oil showed trypanocidal activity with IC50 value of 93.9±2.6 μg/mL. For antibacterial and antifungal activities, the best results were observed against Staphylococcus aureus (ATCC14458), Staphylococcus epidermidis (ATCC1228) and Candida tropicalis (ATCC 157), all with a minimal inhibitory concentration value of 100 μg/mL. The essential oil showed antioxidant capacity of 1468.96 μmol of TE/g in the oxygen radical absorbance capacity (ORACFL) assay. The oil showed moderate larvicidal activity with LC50 value of 632.36 μg/mL. The essential oil exhibited potent antiproliferative activity against all cell lines evaluated with total growth inhibition (TGI) value <40 μg/mL, exception for K562 cell line (TGI>250 μg/mL). The highest activity was observed against cell lines of UACC-62, NCI-ADR/RES and NCI-H460, with TGI values of 4.03, 4.26 and 8.37 μg/mL, respectively. For the VERO cell (non-cancer cell line), the TGI value was of 15.94 μg/mL.

Synthesis, Antitumor and Antitubercular Evaluation of Certain New Xanthenone and Acridinone Analogs

6-Chloro-4-substituted methyl-4-xanthenones and 2,4-dichloro-1-substituted amino-9-(10 H)-acridinones were synthesized as tricyclic planar analogs and tested for their in vitro antitumor and antitubercular activity. The obtained derivatives were also evaluated for two biochemical, mechanism-based screens to explore their ability to inhibit the cell cycle control proteins cdc2 kinase and cdc25 phosphatase as molecular targets which may account for their antitumor activity. 4-(N1-Amidino)-sulphanilamidomethyl-6-chloro-9-xanthenone (10) proved to be the most active member of these derivatives exhibiting a broad spectrum antitumor potency against a wide range of human tumor cell lines with full panel median growth inhibition (GI50), total growth inhibition (TGI) and median lethal concentration (LC50) mean graph midpoint (MG-MID) values of 3.2, 12.7 and 21.8 mumol l-1, respectively. Meanwhile, compound 4-(N1-Acetyl)sulphanilamidomethyl-6-chloro-9-xanthenone (9) showed GI50, and TGI (MG-MID) values of 25.6 and 87.6 mumol l-1, respectively with a moderate selectivity for leukemia cell lines at the GI50 level. Compound 9 exhibited a weak in vivo growth inhibitory effect against many human tumor cells cultivated in hollow fibers and implanted into the intraperitoneal or subcutaneous physiologic compartments in mice. In addition, compounds 15, 20, 23-25 showed potential activity against mycobacterium strain H37Rv at 12.5 micrograms ml-1 concentration. The detailed synthess, spectroscopic and biological data are reported.

In vitro cytotoxicity of crude alkaloidal extracts of South African Menispermaceae against three cancer cell lines

The cytotoxicity of crude alkaloid extracts obtained from the leaves and rhizomes of all the South African members of the family Menispermaceae (seven genera and 13 species) was tested against MCF7 (breast), UACC62 (melanoma) and TK10 (renal) cancer cell lines. Extracts of ten of the thirteen species showed positive activity against all three cancer cell lines with significant inhibition of cellular growth at TGI (total growth inhibition) values lower than 6.25
g/ml for Albertisia delagoensis and Antizoma angustifolia leaves.

Furanoditerpenes from Pterodon pubescens benth with selective in vitro anticancer activity for prostate cell line

Activity guided fractionation of Pterodon pubescens Benth. methylene chloride-soluble fraction afforded novel 6α-acetoxi 7β-hydroxy-vouacapan 1 and four known diterpene furans 2, 3, 4, 5. The compounds were evaluated for in vitro cytotoxic activities against human normal cells and tumour cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-H460 (lung, non-small cells), OVCAR-03 (ovarian), PC-3 (prostate), HT-29 (colon), 786-0 (renal), K562 (leukemia) and NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance). Results were expressed by three concentration dependent parameters GI50 (concentration that produces 50% growth inhibition), TGI (concentration that produces total growth inhibition or cytostatic effect) and LC50 (concentration that produces -50% growth, a cytotoxicity parameter). Also, in vitro cytotoxicity was evaluated against 3T3 cell line (mouse embryonic fibroblasts). Antiproliferative properties of compounds 1, 4 and 5 are herein reported for the first time. These compounds showed selectivity in a concentration-dependent way against human PC-3. Compound 1 demonstrated selectivity 26 fold more potent than the positive control, doxorubicin, for PC-3 (prostrate) cell line based on GI50 values, causing cytostatic effect (TGI value) at a concentration fifteen times less than positive control. Moreover comparison of 50% lethal concentration (LC50 value) with positive control (doxorubicin) suggested that compound 1 was less toxic.

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER)+/p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER+/p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide.

Synergistic effect of ibandronate (Ib) and zoledronic acid (Zol) in different drug regimens in breast tumor growth inhibition (BTGI) in ATP-cell viability assay (ATP-CVA

791 Background: Breast cancer has a significant capacity to metastisizemetastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs like paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Methods: Potential antitumour effects in vitro of two bisphosphonates: Ib and Zol (each at 30 μM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/ docetaxel (EDoc) have been investigated using ATP-CVA. 20 cases of female primary, invasive breast cancers have been assessed. Percentages of total growth inhibition (TGI) were calculated according to the formula: 1-(TDC-MI)/(MO-MI) x 100 = %TGI. AUC values were calculated using the trapezoidal rule. Chemosensitivity was defined as AUC of more than 18000. Statistical significance was assumed if p was < 0.05 Results: Ib and Zol alone have shown inhibitory effect on breast cancer tumour cells in vitro. BTGI effect for those two drugs amounted to 22 and 25%, respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. In all cases, the differences between measured TGI values for drugs' combinations alone in comparison to drugs with IB or Zol were statistically significant. Addition of Zol to CMF or ET revealed higher median of TGI than EC or ET plus Ib. In the lowest dose of anticancer drug concentration (6.25%), enhancing effects of Zol and Ib on TGI were clearly visible in all combinations. Addition of Zol enhanced the chemotoxic action of CMF and ET better then Ib (p= 0.03) Conclusions: Combinations of anticancer drugs with Zol seem to be more effective in respect to tumour growth inhibition than combinations with Ib, at least in case of CMF or ET in the lowest dose concentrations of those antitumour drugs. No significant financial relationships to disclose.