Good Cytotoxic Activity Research Articles

Synthesis and anticancer activity of novel quinazolinone and benzamide derivatives

In trying to develop new anticancer agents, a series of quinazolinone and benzamide derivatives were synthesized via reaction of 6-iodo-2-phenyl-4H-benzoxazin-4-one with nitrogen nucleophiles, namely, formamide, ammonium acetate, hydrazine hydrate, hydroxylamine hydrochloride, substituted aromatic amines, benzyl amine, and/or thiocarbonohydrazide. All compounds were fully characterized by means of IR, MS, and 1H-NMR spectra. Some of the synthesized compounds were evaluated in vitro for their anti-proliferative activity against HePG-2 and MCF-7 cell lines. 2-(Benzoylamino)-N-(4-hydroxyphenyl)-5-iodobenzamide and tetrazino[1,6-c]quinazoline-3(4H)-thione derivative were the most potent against the two cancer cells comparable to that of doxorubicin. Most of the synthesized compounds also exhibited good cytotoxic activity.

Lysosomes-targeting imaging and anticancer properties of novel bis-naphthalimide derivatives

A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1–NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1–NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2.73 and 1.60 μM, respectively, better than the control drug (Amonafide). However, compounds NI5–NI8 conjugated with pyrrole derivatives showed weak cytotoxic activities against the all tested cell lines. Furthermore, their DNA binding properties, fluorescence imaging and cell cycle were investigated. Interestingly, compounds NI1 and NI4 showed fluorescence enhancement because of the strong binding with Ct-DNA, and exhibited fluorescence imaging with Hela cells on the lysosomes.

Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors.

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.

Synthesis and Cytotoxic Activity of Novel Resveratrol-Chalcone Amide Derivatives

Resveratrol is a type of natural phenol with a broad range of good biological activities. Based on former work, in order to look for new anticancer agents, a series of novel amide compounds between resveratrol and chalcone possessing piperazine moiety have been synthesized by connecting principle of active biological groups. The structures of compounds were characterized by IR, 1 H NMR, 13 C NMR and HRMS, and in vitro cytotoxic activity was evaluated against a panel of human tumor cell lines (Hela, A549 and SGC7901) by the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2 H -tetrazolium bromide (MTT) assay. The results demonstrated that amide compounds contributed good cytotoxic activity. Especially, ( E )-3-(2, 4-dimethoxy-6-(( E )-4-methoxystyryl)phenyl)-1-(4-( N -acryloyl)piperazin-1-yl)phenylprop-2-en-1-one ( 9 ) showed the best cytotoxic activity against A549 and Hela (IC 50 =0.26 and 7.35 μmol·L -1 , respectively), and fluorescence-activated cell sorter (FACs) analysis showed that compound 9 significantly induced apoptosis in A549 cell.

Molecular design and synthesis of new dithiocarbazate complexes; crystal structure, bioactivities and nano studies.

The syntheses of a new set of metal complexes MoO2L′(CH3OH), VOL′(CH3O)(CH3OH), , , SnL′Cl2 and SnL′I2 with a new ligand (L = (2,2′(disulfanediylbis((ethylthio)methylene)bis(hydrazin-2-yl-1-ylidene)bis(methanylylidene)) diphenol; L′ = S-ethyl-3-(2-hydroxyphenyl)methylenedithiocarbazate are described along with characterization by elemental analysis, mass spectrometry, spectroscopic (IR, 1H- and 13C-NMR) and TGA techniques. The crystal structures of compounds were determined by single crystal X-ray diffraction analysis and compared to powder X-ray diffraction (PXRD) patterns of the nano complexes obtained using ultrasonic methods. The PXRD results indicate that the compounds synthesized by ultrasonic methods have high crystallinity. The compounds were evaluated in an in vitro cytotoxicity study with two human cancer cell lines. The results of this study revealed that all complexes exhibit good cytotoxic activity when compared to the clinical drug, cisplatin. Interaction of the samples with human serum albumin (HSA) was investigated using fluorescence spectrophotometric methods and the Stern–Volmer quenching constant (KSV) and free energy changes (ΔG) were calculated at 298 K. The fluorescence quenching method is used to determine the number of binding sites (n) and association constants (Ka) at the same temperatures.

Synthesis and cytotoxic evaluation of some novel quinoxalinedione diarylamide sorafenib analogues.

A series of novel sorafenib analogues containing a quinoxalinedione ring and amide linker were synthesized. A total of 9 novel compounds in 6 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected which then followed by O-arylation with 5-chloro-2-nitroaniline to provide compound d. Reduction of the nitro group of compound d and cyclization of the diamine group of compound e with oxalic acid afforded compound f which on deacetylation yeilded compound g. Then compound g was reacted with different acyl halides to afford the target compounds 1h-1p. Chemical structures of synthesized compounds were confirmed by 1H NMR and FT-IR analysis. All compounds were evaluated at 1, 10, 50 and 100 μM concentrations for their cytotoxicity against HeLa and MCF-7 cancer cell lines. Some of the compounds showed good cytotoxic activity, especially compounds 1i and 1k-1n with the IC50 values of 19, 16, 22, 18, and 16 μM against MCF-7 cell line and 20, 18, 25, 20, and 18 μM against HeLa cell line, respectively.

Synthesis and Biological Evaluation of Novel Substituted Chalcone-piperazine Derivatives

A series of novel substituted chalcone-piperazine derivatives have been synthesized, and screened in vitro anti-inflammatory in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and cytotoxic activity against 3 strains human tumor cell lines. The results demonstrated that the substituents of the core ring and the NH group of piperazine ring had obvious influences on biological activities. Especially, 3, 4, 5-trimethoxy-4'-[ N -(2-oxopropyl)-1-piperazinyl]chalcone ( 11 ) showed better inhibitory effect on the generation of NO (IC 50 =3.81 μmol/L), and 4-bromo-4'-[ N -(4'-methyl-2-oxophenylethyl)-1-piperazinyl]chalcone ( 25 ) displayed good cytotoxic activity against A549, Hela and sk-ov-3 (IC 50 =0.54, 0.05 and 9.12 μmol/L, respectively).

Organotin(IV) 4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbodithioates: Synthesis, characterization and biological activities

A series of organotin(IV) derivatives R3SnL (1–3), R2SnLCl (4–6) and R2SnL2 (7–9) (where R = Me, Bu, Ph and L = 4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbodithioate) were prepared from the reaction of 4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbodithioate (L-salt) with the corresponding triorganotin(IV) chlorides and diorganotin(IV) dichlorides. All compounds were characterized by FT-IR, 1H, 13C and 119Sn NMR spectroscopy. Dimethylstannyl bis(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbodithioate) (7) was also characterized in the solid state by single crystal x-ray diffraction, showing a distorted octahedral geometry. The diorganotin(IV) derivatives have shown significant antibacterial and antifungal activity and good cytotoxic activity against ovarian cancer cells with IC50 values greater or comparable to that of cisplatin.

DNA intercalators based on (1,10-phenanthrolin-2-yl)isoxazolidin-5-yl core with better growth inhibition and selectivity than cisplatin upon head and neck squamous cells carcinoma

((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3–72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 104 M−1. Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT)2 and poly-d(GC)2, preferring an entrance by the minor groove of the poly-d(AT)2.

Marcanine G, a new cytotoxic 1-azaanthraquinone from the stem bark of Goniothalamus marcanii Craib

The ethanolic extract from the stem bark of Goniothalamus marcanii Craib was shown in preliminary brine shrimp lethality data having good cytotoxic activity. Further bioassay guided isolation was done by means of solvent partition, chromatography and precipitation to provide four isolated compounds: a novel compound 1 with the core structure of 1-azaanthraquinone moiety referred as marcanine G; as well as compounds 2–4 with known aristolactam structures namely, piperolactam C, cepharanone B and taliscanine. These compounds were characterised by spectroscopic techniques. The assessment of cytotoxicity was established on an SRB assay using doxorubicin as a positive control. Marcanine G (1) was considered the most active compound indicating the IC50 values of 14.87 and 15.18 μM against human lung cancer cells (A549) and human breast cancer cells (MCF7), respectively. However, 2 showed mild activity with the IC50 values of 83.72 and 82.32 μM against A549 and MCF7 cells, respectively.

A facile one pot C[sbnd]C and C[sbnd]N bond formation for the synthesis of spiro-benzodiazepines and their cytotoxicity

An efficient, multicomponent and environmentally benign protocol has been developed for the synthesis of spiro-benzodiazepines through CC and CN bond formations in a single step. This one-pot protocol proceeds via three component reaction of o-phenylenediamines, tetronic acid and isatins by using mild and inexpensive catalyst like sulphamic acid in water. A variety of spiro-benzodiazepine derivatives has been synthesized in excellent yields by using this protocol in a shorter reaction time. All the synthesized compounds were evaluated for their cytotoxic potential on different human cancer cell lines and most of the compounds exhibited moderate to good cytotoxic activity, while some of them like 4f, 4h, 4i, 4j and 4q showed promising cytotoxicity with IC50 values ranging between 1.14 and 1.69 μM.

Synthesis, spectroscopic characterization and in vitro cytotoxicities of new organometallic palladium complexes with biologically active β-diketones; Biological evaluation probing of the interaction mechanism with DNA/Protein and molecular docking

[Pd{(C,N)C6H4CH (CH3)NH}(CUR)] (3) and [Pd2{(C,N)C6H4CH(CH3)NH2}2(μ-N3CS2)] (4) [cur = 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dion] novel organometallic complexes with biologically active ligands have been prepared and characterized via elemental analysis, multinuclear spectroscopic techniques (1H, and 13C NMR and IR) and their biological activities, including antitumoral activity and DNA-protein interactions have been investigated. Fluorescence spectroscopy used to study the interaction of the complexes with BSA have shown the affinity of the complexes for these proteins with relatively high binding constant values and the changed secondary structure of BSA in the presence of the complexes. In the meantime, spectroscopy and competitive titration have been applied to investigate the interaction of complexes with Warfarin and Ibuprofen site markers for sites I and II, respectively, with BSA. The results have suggested that the locations of complexes 3 and 4 are sites II and I, respectively. UV–Vis spectroscopy, emission titration and helix melting methods have been used to study the interaction of these complexes with CT-DNA, indicating that complexes are bound to CT-DNA by intercalation binding mode. In addition, good cytotoxic activity against MCF-7 (human breast cancer) and JURKAT (human leukemia) cell line has been shown by both complexes whereas low cytotoxicity was exerted on normal peripheral blood mononuclear cells.

Design, Synthesis, Antitumor activity, cell cycle analysis and ELISA assay for Cyclin Dependant Kinase-2 of a new (4-aryl-6-flouro-4H-benzo[4, 5] thieno[3, 2-b] pyran) derivatives.

A series of benzo[b]thiophene and their benzo[4,5]thieno[3,2-b]pyran derivatives (3a-f), (4a-f), (5a-f) and 6 were synthesized and characterized by spectroscopic and elemental analysis. All compounds were subjected to one dose anticancer screening in NCI- America, but only the compounds gave high percent growth inhibition were further subjected to five dose screening. A good result of compound 4f with GI50 = 0.15 µmol, TGI= 1.14 µmol and 4c with GI50 = 1.09 µmol, TGI = 10.19 µmol, LC50 = 100 µmol on HT-29 cell line. To explore mechanism of cytotoxicity, compound 4f and 4c were allowed to affect cell cycle progression using HT-29 cell line (human colon cancer) in two-time interval (24 and 48 hr). The cytotoxicity of 4f and 4c was correlated with induction of apoptosis causing pre-G1apoptosis and cell growth arrest at G2/M in a time dependant manner through inhibition of CDK-2. For exploring the SAR for all synthesized compounds, IC50 of 5d was determined which was equal to 0.32 ±0.05 µmol, IC50 of 6 was equal to be 0.15 ±0.01 µmol while IC50 of erlotinib reference was equal to 0.3±0.02 µmol. Finally we were able to synthesize a series of benzo[b] thiophene, benzo[4,5]thieno[3,2-b]pyran having a good cytotoxic activity suggesting promising anticancer derivatives.

Cytotoxic Cardiac Glycoside from the Parasitic Plant Cuscuta reflexa

Bioassay guided fractionation of the cytotoxic extract of the plant Cuscuta reflexa, employing cytotoxic assay against a panel of 60 cell lines, led to the isolation of 13 compounds identified as odoroside H (1), 21-hydroxyodoroside H (2), neritaloside (3), strospeside (4), 16-β-hydroxydigitoxin (5), N-trans and cis feruloyl tyramines (6 and 7), ethyl caffeate (8), coumarins (9 and 10), ursolic acid (11), β-sitosterol glucoside (12), and 4-O-p-coumaroyl-β-D-glucoside (13). Compound 2 was found to be a new natural product while 1, 3, 4, 5, 6, 7, 10, and 11 are known compounds isolated from this source for the first time. Compounds 1, 3, and 4 possessed very good cytotoxic activity against renal and prostate cancer cell lines. Of these compounds, 1 showed a positive hollow fiber test and was selected for in vivo xenograft testing. The structures of compounds 1–5 have been established through chemical and spectral studies including UV, IR, mass, NMR (1H and 13C), and 2D NMR (COSY-45°, NOESY, HMQC, HMBC, and J-resolved) experiments.

Porcine skin gelatin-silver nanocomposites: synthesis, characterisation, cell cytotoxicity, and antibacterial properties.

Silver nanoparticles (AgNPs) were synthesised with hydrothermal autoclaving technique by using AgNO3 salt (silver precursor) at different concentrations (0.01, 0.1, 0.55, 1.1, 5.5, and 11 mM) and porcine skin (1% (w/v) ) gelatin polymeric matrix (reducing and stabiliser agent). The reaction was performed in an autoclave at 103 kPa and 121°C and the hydrothermal autoclaving exposure time and AgNO3 molar concentration were varied at a constant porcine skin gelatin concentration. The as-prepared AgNPs were characterised by UV-visible spectroscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. The antibacterial properties of AgNPs were tested against gram-positive and gram-negative bacteria. Furthermore, 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide and 2,2-diphenyl-1-picrylhydrazyl assays were used to test whether the synthesised AgNPs can be potentially applied in cancer therapy or used as an antioxidant. This approach is a promising simple route for synthesising AgNPs with a smaller average particle 10 nm diameter. Furthermore, AgNPs exhibited a good cytotoxicity activity, reducing the viability of the liver cancer cell line HepG2 with a moderate IC50; they also showed a low-to-fair antioxidant activity. In addition, AgNPs had a remarkable preferential antibacterial activity against gram-positive bacteria than gram-negative bacteria. Therefore, these fabricated AgNPs can be used as an antibacterial agent in curative and preventive health care.

Synthesis of chalcone-imide derivatives and investigation of their anticancer and antimicrobial activities, carbonic anhydrase and acetylcholinesterase enzymes inhibition profiles

The new 1-(4-(3-(aryl)acryloyl)phenyl)-1H-pyrrole-2,5-diones (5a–g) were prepared from 4′-aminchalcones (3a–g) and screened for biological activities. All compounds (3a–g and 5a–g), except 3d and 3e displayed good cytotoxic activities with IC50 values in the range of 7.06–67.46 μM. IC50 value of 5-fluorouracil (5-FU) was 90.36 μM. Moreover, most of compounds 5a–g showed high antibacterial activity with 8–20 mm of inhibition zone (19–25 mm of Sulbactam-Cefoperazone (SCF)). In addition, they showed good inhibitory action against acetylcholinesterase (AChE), and human carbonic anhydrase I, and II (hCA I and hCA II) isoforms. Also, these compounds demonstrated effective inhibition profiles with Ki values of 426.47–699.58 nM against hCA I, 214.92–532.21 nM against hCA II, and 70.470–229.42 nM against AChE. On the other hand, acetazolamide, clinically used drug, showed a Ki value of 977.77 ± 227.4 nM against CA I, and 904.47 ± 106.3 nM against CA II, respectively. Also, tacrine inhibited AChE showed a Ki value of 446.56 ± 58.33 nM.

Qualitative HPLC-DAD/ESI-TOF-MS Analysis, Cytotoxic, and Apoptotic Effects of Croatian Endemic Centaurea ragusina L. Aqueous Extracts.

Centaurea ragusina L., an endemic Croatian plant species, revealed a good cytotoxic activity of aqueous extracts (AE) on human bladder (T24) and human glioblastoma (A1235) cancer cell lines. The chemical constituents were tentatively identified using high performance liquid chromatography HPLC-DAD/ESI-TOF-MS in negative ionization mode. The main compounds of herba extract were sesquiterpene lactones: solstitialin A 3,13-diacetate and epoxyrepdiolide; organic acid: quinic acid. The main compounds of flower extract were organic acids: quinic acid, citric acid, and malic acid; sesquiterpene lactone: cynaropicrin; phenolic compounds: chlorogenic acid and phenylpropanoid: syringin. The AE of C.ragusina were investigated for correlation of their effects on human bladder (T24) and human glioblastoma (A1235) cancer cell lines using the MTT assay. Although both extracts showed significant dose- and time-dependent cytotoxic activity against both cancer cell lines, the flower extract exhibited slightly higher activity. In order to determine type of cell death induced by treatment, cell lines were exposed subsequently to a treatment with both flower and herba AE. The majority of the cells died by induced apoptosis treatment. Flower AE (26.25%), compared to a leaf AE (22.15%) showed slightly higher percentage of an apoptosis in T24 cells, when compared to a non-treated cells (0.04%).

Ring A-modified Derivatives from the Natural Triterpene 3-O-acetyl-11-keto-β-Boswellic Acid and their Cytotoxic Activity.

Natural triterpene boswellic acids (BAs) have attracted much interest due to their anticancer activity, but more chemical modification is necessary to explore their pharmacological value. In addition to subtle functionalization, transformations that alter the triterpene skeleton are viewed as an alternative approach. In this study, transformations altering ring A of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) were performed to obtain A-lactone, A-lactam, A-seco and A-contracted derivatives. Thirty-two new derivatives were synthesized, and their structures were confirmed by NMR and MS. Their anticancer activity against human cancer cell lines K562, PC3, A549 and HL60 was screened. Biological evaluation indicated that the ring A cleavage or contraction transformations themselves did not significantly enhance the cytotoxic activity, but most of the derivatives based on these ring A-modified skeletons exhibited good cytotoxic activity. Significantly improved cytotoxicity was discovered for the esterified analogues of the A-lactone and A-lactam series and the amidated analogues of the A-seco and ring A contracted series, especially those bearing two nitrogen-containing substituents. Among them, compounds 6a, 11b, 12k and 18e showed strong cytotoxic activity, with IC50 values of 5.0~3.5 μM against K562 cells, almost ninefold stronger than that of AKBA. Further study proposed that the antiproliferative activities of 6a, 11b, 12k and 18e may be due to apoptosis induction. The transformations of the ring A skeleton of AKBA provide new platforms to discover anticancer candidates.

Bioassay guided fractionation and cytotoxic activity of Daucus carota var. boissieri

The hexane extract and the hydro-distilled essential oil from red carrot fruits (Daucus carota var. boissieri) were evaluated for their cytotoxic activity against human tumor breast cell lines (MCF-7). Cell viability was evaluated by MTT assay. The extract exhibited good cytotoxic activity shown through its low IC50 (9.12 ± 0.58 μg/ml) against the standard 5-Flououracil (8.46 ± 0.63 μg/ml). Phytochemical investigation of the hexane extract using column chromatography yielded three compounds; 8-methoxypsoralen (1), α-asarone (2) and 3,4,5-trimethoxy-benzaldehyde (3), a compound isolated for the first time from D. carota and from family Apiaceae. Structure elucidation of the isolated compounds was carried out on the basis of their spectral data analysis (IR, MS, 1H NMR an 13C NMR) The three isolated compounds were evaluated for their cytotoxic activity using the same conditions. Only compound (1) exhibited good cytotoxic activity (IC50; 9.38 ± 0.78 μg/ml), compound (2) had moderate activity (46.12 ± 1.31 μg/ml), while compound (3) had no cytotoxic activity (100.6 ± 3.11 μg/ml). These compounds need to be more investigated against other cell lines; also they are considered as a good substrate for future SAR study and modifications to produce more potent cytotoxic derivatives.

Triterpenoid saponins and other glycosides from the stems and bark of Jaffrea xerocarpa and their biological activity

Six previously undescribed triterpenoid saponins and two previously undescribed norlupane triterpenes were isolated with five known saponins, three known lupane derivatives, 17,20-didehydro-20-deoxyjujubogenin, rutin, (±) 3α-O-β-d-glucopyranosyl-lyoniresinol, (±) 4-O-β-d-glucopyranosyl-maesopsin, three phenol glycosides, and uridine from the stems and bark of Jaffrea xerocarpa (Baill.) H. C. Hopkins & Pillon (= Basionym Alphitonia xerocarpus Baill.) (Rhamnaceae), an endemic tree of New Caledonia. The chemical structures of the purified compounds were identified by nuclear magnetic resonance and mass spectrometry. The isolated compounds were tested for their antioxidant, antityrosinase, antibacterial and cytotoxic activities. The aqueous methanol extract showed antioxidant activity (DPPH assay) due to the presence of rutin and other phenolic compounds. Three lupane triterpenes showed good cytotoxic activities against KB cells line (IC50 from 7.7 to 8.5 μM). The previously undescribed 2α-formyl-A(1)norlup-20(29)-en-28-oic acid showed antibacterial activity against Staphylococcus aureus and Enterococcus faecalis with both MIC values of 4 μg/mL.