Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)₃(dmphen)(ptolICN)]⁺, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.     

Some divalent metal(II) complexes of salicylaldehyde‐derived Schiff bases: Synthesis,spectroscopic characterization,antimicrobial and in vitro anticancer studies

Mononuclear transition metal(II) complexes of the type M(L)₂?2H₂O (where M = Co, Ni, Cu, Zn) have been synthesized from uninegative Schiff base ligands (HL₁–HL₄) designed by condensation of 4‐fluorobenzylamine with 2‐hydroxy‐1‐naphthaldehyde/3,5‐dichlorosalicylaldehyde/3,5‐dibromosalicylaldehyde/3‐bromo‐5‐chlorosalicylaldehyde. The compounds were successfully characterized using spectroscopic and physiochemical methods together with elemental analysis. Spectroscopic elucidation indicates a monobasic bidentate nature of ligands coordinated via deprotonated phenolic oxygen and azomethine nitrogen atom which suggests an octahedral geometry around the central metal ions. The complexes and ligands were screened for their in vitro antimicrobial activity against bacterial and fungal strains, the zinc(II) complexes being more active against the tested microbial strains. Further, the metal complexes were found to be more active than the uncomplexed ligands due to chelation process and, moreover, the complexes were more active against fungal strains than bacterial strains. Cytotoxic activities of all compounds were evaluated towards human alveolar adenocarcinoma epithelial cell line (A549), human breast adenocarcinoma cell line (MCF7), human prostate cancer cell line (DU145) and one normal human lung cell line (MRC‐5) using MTT colorimetric assay with doxorubicin as a standard. The zinc complexes were most active against the cancer cell lines and also found to be less toxic against MRC‐5 normal cell line than standard doxorubicin.     

Synthesis and Structure–Activity Relationship Study of Novel Pyrazolylthiazoles as Potential Anti‐Breast Cancer Agents

A novel series of pyrazolylthiazole has been synthesized from the reaction of 5‐(4‐fluorophenyl)‐3‐aryl‐4,5‐dihydropyrazole‐1‐carbothioic acid amide derivatives with different reagents. The mechanism and structures of all the novel products were assured on the foundation of spectral information and elemental analyses. The antitumor activity of all the synthesized compounds was estimated versus MCF‐7 cell line. The outcomes showed that some of the tested samples revealed powerful activity against human breast cancer cell line. In addition, the relation between the structure and the activity has been discussed.     

The human mast cell line‐1 cell membrane chromatography coupled with HPLC‐ESI‐MS/MS method for screening potentical anaphylactic components from chuanxinlian injection

Chuanxinlian injection is a traditional Chinese medicine injection widely used in China to treat sore throat, cough and dysentery, although a high occurrence of severe adverse reactions has been reported in clinical practice in recent years. In the present study, a human mast cell line‐1 cell membrane chromatography coupled with HPLC‐ESI‐MS/MS method was established to screen and identify potentical anaphylactic components in chuanxinlian injection, and the dehydroandrographolide was identified as a potential anaphylactic component. In vitro anaphylactic assay showed that intracellular Ca²⁺ concentration clearly increased under dehydroandrographolide (100 μm ) treatment. β ‐Hexosaminidase and histamine release in human mast cell line‐1 cells were both markedly enhanced with increased concentrations of dehydroandrographolide, confirming the anaphylactic activity of dehydroandrographolide. The application for chuanxinlian injection in this study suggested that the developed human mast cell line‐1 cell membrane chromatography coupled with HPLC‐ESI‐MS/MS system may be effective and rapid for screening the potentical anaphylactic components from complex samples.     

Synthesis,characterization and cytotoxicity of Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4’‐substituted terpyridine

Eight novel Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4’‐substituted terpyridine were synthesized and characterized by elemental analysis, UV, IR, NMR, electron paramagnetic resonance, high‐resolution mass spectrometry and molar conductivity measurements. The cytotoxicity of these complexes against HL‐60, BGC‐823, KB and Bel‐7402 cell lines was evaluated by MTT assay. All the complexes displayed cytotoxicity with low IC₅₀ values (<20 μm ) and showed selectivity. Complexes 3 , 5 , 7 and 8 exerted 9‐, 5‐, 12‐ and 7‐fold higher cytotoxicity than cisplatin against Bel‐7402 cell line. The cytotoxicity of complexes 3 , 5 , 6 , 7 and 8 was higher than that of cisplatin against BGC‐823 cell line. Complexes 3 , 7 and 8 showed similar cytotoxicity to cisplatin against KB cell line. Complex 7 exhibited higher cytotoxicity than cisplatin against HL‐60 cell line. Among these complexes, complex 7 demonstrated the highest in vitro cytotoxicity, with IC₅₀ values of 1.62, 3.59, 2.28 and 0.63 μm against HL‐60, BGC‐823, Bel‐7402 and KB cells lines, respectively. The results suggest that the cytotoxicity of these complexes is related to the nature of the terminal group of the ligand, the metal center and the leaving groups. Copyright © 2013 John Wiley & Sons, Ltd.     

4‐Chlorothiazole‐5‐carbaldehydes as Potent Precursors for Synthesis of Some New Pendant N‐heterocyces Endowed with Anti‐Tumor Activity

In our approach to synthesize bioactive molecules, a series of novel N‐heterocycles were synthesized and evaluated for their in vitro antitumor activity against a panel of three human cancer cell lines, namely, human breast cancer cell line (MCF‐7), human cervical cancer cell line (HeLa), and human prostate cancer PC‐3. The majority of the tested compounds exhibited significant cytotoxic activity toward the tested tumor cell lines. Analogues 33 , 34 , 31 , 38 , 21 , 23 , 22 , and 20 exhibited considerable cytotoxic activities comparable with standard drug 5‐fuorouracil. Compound 33 displayed superior cytotoxicity with IC₅₀ value of 4.12 ± 1.21 μg/mL against HeLa tumor cell line.     

Electrochemical Initiated C‐N Coupling of 3‐Methylcatechol and n‐Hexylamine in a Flow Cell Monitored with ESI‐MS

The electrochemical initiated heterocoupling of 3‐methylcatechol and n‐hexylamine was investigated. The oxidation of 3‐methylcatechol was performed in an electrochemical flow cell with glassy carbon as the working electrode. As a result, the two‐electron, two‐proton oxidised chinone intermediate undergoes a C‐N coupling reaction in the presence of an amine (Michael addition). This mono coupling product can undergo a second two‐electron, two‐proton oxidation depending on acidic or basic conditions and substrate ratios. This flow cell was coupled on‐line with electrospray ionisation mass spectrometry to identify the possible coupling products. Higher substrate concentrations were performed off‐line as first scale‐up experiments in a two‐step procedure.     

Exploring Orthogonal Hydrogen Bonding towards Designing Organic‐Salt‐Based Supramolecular Gelators: Synthesis,Structures, and Anticancer Properties

A series of primary ammonium monocarboxylate (PAM) salts derived from β‐alanine derivatives of pyrene and naphthalene acetic acid, along with the parent acids, were explored to probe the plausible role of orthogonal hydrogen bonding resulting from amide???amide and PAM synthons on gelation. Single‐crystal X‐ray diffraction (SXRD) studies were performed on two parent acids and five PAM salts in the series. The data revealed that orthogonal hydrogen bonding played an important role in gelation. Structure–property correlation based on SXRD and powder X‐ray diffraction data also supported the working hypothesis upon which these gelators were designed. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and cell migration assay on a highly aggressive human breast cancer cell line, MDA‐MB‐231, revealed that one of the PAM salts in the series, namely, PAA.B2 , displayed anticancer properties, and internalization of the gelator salt in the same cell line was confirmed by cell imaging.     

Synthesis and Cytotoxicity of Some Thieno[2,3‐d]pyrimidine Derivatives

A series of compounds 5‐amino‐2‐ethylmercapto‐4‐phenyl‐6‐subistitutedthieno[2,3‐d]pyrimidines ( 8a–d ), 4‐chloro‐7‐ethylmercapto‐9‐phenylpyrimido[5′,4′:4,5]thieno[3,2‐d]triazine ( 9 ), and 2‐ethylmercapto‐8‐oxo‐4‐phenyl‐7‐(4‐chlorophenyl)pyrimido [4′,5′:4,5]thieno[2,3‐d]pyrimidine ( 10 ) were synthesized and their structures were confirmed by ¹H NMR , ¹³C NMR, and MS . All compounds were evaluated for their IC₅₀ values against three cancer cell lines (MCF ‐7, HUH ‐7 and BHK ) and WISH cells. The IC₅₀ of compound ( 8d ) was calculated for each cell line. Interestingly, the IC₅₀ for the normal human amnion WISH cell line was much higher (723 µg/mL) than those found for the tumor cell lines BHK (17 µg/mL), HUH ‐7 (5.8 µg/mL), and MCF ‐7 (8.3 µg/mL). The proliferation inhibition of normal (WISH ) and tumor (BHK , HUH ‐7, and MCF ‐7) cells by compound ( 8d ) was investigated using MTT assay, and the IC₅₀ was calculated after 48 h of treatment for each cell line.     

New Sesquiterpene Formamides from the Marine Sponge Axinyssa sp.

Chemical investigation of an extract of the marine sponge Axinyssa sp., collected from the South China Sea, led to the isolation and identification of two new sesquiterpene formamides, (4R*,5R*,10R*)‐4‐formamidoeudesm‐7‐ene ( 1 ) and (4R*,5R*,7S*,10R*)‐4‐formamidoeudesman‐11‐ol ( 2 ), together with the known 4α‐formamidogorgon‐11‐ene ( 3 ). Their structures were elucidated by spectroscopic methods, including 1D‐ and 2D‐NMR spectroscopy, high‐resolution ESI‐TOF mass spectrometry, as well as X‐ray single‐crystal diffraction experiments. Possible biosynthetic pathways for 1 – 3 were also proposed. The human nasopharyngeal cancer cell line CNE‐2, human cervical cancer cell line HeLa, and human normal liver cell line L02 were used to examine the cytotoxic activities of 1 – 3 in vitro. As the results, 1 showed significant cytotoxic activity against CNE‐2, HeLa, and L02 cell lines with the IC₅₀ values of 13.8, 7.5, and 38.0 μg/ml, resp.     

Synthesis and Biological Activities of 1‐Azaaurone Derivatives

A series of 1‐azaaurone derivatives were designed and synthesized from 3,5‐dimethoxyaniline and 2‐chloroacetonitrile. Their structures were characterized by melting point, ¹H NMR, IR, and elemental analysis, as well as ¹³C NMR. The target compounds were evaluated for antitumor activities against human hepatocellular liver carcinoma cell line (HepG‐2) and human cervix carcinoma cell line (Hela) using methyl thiazolyl tetrazolium method. The results revealed that several 1‐azaaurones exhibited strong proliferation inhibition efficacy against HepG‐2 and Hela with an IC₅₀ range of 5.6–8.8 μg/mL without damaging normal cell.     

Synthesis of Novel Trifluoromethyl Group Containing Pyrido Furo/Thieno Pyrimidinone Derivatives and Their Anticancer Activity

A series of novel trifluoromethyl group containing pyridofuro/thieno pyrimidinone derivatives 5a–p were prepared starting from 2‐oxo/thioxo‐6‐phenyl/thien‐2‐yl‐4‐(trifluoromethyl)‐1,2‐dihydropyridine‐3‐carbonitrile 1 compound on reaction with bromoethylacetate and further different primary aliphatic amines, under their refluxing conditions to afford amide tagged furo/thieno pyridine derivatives 4 . Compound 4 on reaction with trifluoroacetic acid and obtained novel trifluoromethyl group containing pyridofuro/thieno pyrimidinone derivatives 5a–p . All the synthesized compounds 5a–p were tested for anticancer activity on four cancer cell lines such as HeLa cervical cancer (CCL‐2), COLO 205 colon cancer (CCL‐222), HepG2 liver cancer (HB‐8065), MCF7 breast cancer (HTB‐22), and one normal cell line (HEK 293); compounds 5m , 5n , and 5p are found to be more promising anticancer activity at micromolar concentration and found to be nontoxic on normal cell line.     

Synthesis,structural characterization and in vitro cytotoxicity of diorganotin complexes with Schiff base ligands derived from 3‐hydroxy‐2‐naphthoylhydrazide

A series of diorganotin complexes with Schiff base ligands, (E)‐N′‐(5‐bromo‐2‐hydroxybenzylidene)‐3‐hydroxy‐2‐naphthohydrazide, H₂L1, and (E)‐N′‐(5‐chloro‐2‐hydroxybenzylidene)‐3‐hydroxy‐2‐naphthohydrazide, H₂L2, were synthesized and characterized by elemental analysis, IR, ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy. The molecular structures of the complexes, [(5‐bromo‐2‐oxidobenzylidene)‐3‐hydroxy‐2‐naphthohydrazidato]di(o‐chlorobenzyl)tin(IV) 6 and [(5‐chloro‐2‐oxidobenzylidene)‐3‐hydroxy‐2‐naphthohydrazidato]dibutyltin(IV) 9, were determined through single‐crystal X‐ray diffraction and revealed a distorted trigonal‐bipyramidal configuration. The in vitro cytotoxic activity of the Schiff bases and their diorganotin complexes was also evaluated against several human carcinoma cell lines, namely HT29 (human colon carcinoma cell line), SKOV‐3 (human ovarian cancer cell line), MCF7 (hormone‐dependent breast carcinoma cell line) and MRC5 (non‐cancer human fibroblast cell line). [(5‐Bromo‐2‐oxidobenzylidene)‐3‐hydroxy‐2‐naphthohydrazidato]dibutyltin(IV) 2 and [(5‐bromo‐2‐oxidobenzylidene)‐3‐hydroxy‐2‐naphthohydrazidato]dibenzyltin(IV) 5 were the most active diorganotin complexes of H₂L1 ligand. Among the diorganotin complexes of H₂L2 ligand, [(5‐chloro‐2‐oxidobenzylidene)‐3‐hydroxy‐2‐naphthohydrazidato]dicyclohexyltin(IV) 11 showed good cytotoxic activity against all the tested cell lines. As such, the above compounds can be considered agents with potential anticancer activities, and can therefore be investigated further in in vitro or in vivo anticancer studies. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis,spectroscopic characterization,biological screening and in vitro cytotoxic studies of 4‐methyl‐3‐thiosemicarbazone derived Schiff bases and their Co (II), Ni (II), Cu (II) and Zn (II) complexes

A series of twenty compounds inclusive of bidentate Schiff bases derived from condensation of 4‐methyl‐3‐thiosemicarbazide with substituted derivatives of napthaldehyde/benzaldehyde/salicylaldehyde and their mononuclear Co (II), Ni (II), Cu (II) and Zn (II) complexes in molar ratio (1:1) were synthesized and characterized. The coordination behavior, modes of bonding and overall geometry of the compounds was known from the elemental analysis, spectral techniques (IR, UV–Vis, ¹H NMR, ¹³C NMR, ESR and ESI‐mass), magnetic moment measurements, molar conductance, thermal and powder XRD studies. The studies revealed octahedral geometry for all the complexes where ligands coordinated in a neutral bidentate manner (NS) via nitrogen atom of azomethine group and sulphur atom of thione group with the metal centre. In vitro biological effects of the compounds were tested against four bacterial species and two fungal strains. The results indicated that the metal complexes showed a marked enhancement in biocidal activity in comparable with the parent Schiff bases. In vitro anticancer activity against the malignant tumor cell lines; human alveolar adenocarcinoma epithelial cell line (A549), human breast adenocarcinoma cell line (MCF7), human prostate cancer cell line (DU145) and human normal lung cell line (MRC‐5) using MTT assay, exposed compound 16 as a leading member with lowest IC₅₀ value of 10.6 ± 0.14 μM against (A549) cell line.     

Electrochemical Detection of a Cancer Biomarker mir‐21 in Cell Lysates Using Graphene Modified Sensors

In the present study, the voltammetric and impidimetric detection of microRNA‐21, mir‐21 from cell lysates was investigated for the first time by using graphene modified disposable pencil graphite electrodes (GME). The surface characterization of GME was performed via electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). Upon passive adsorption of inosine substituted antimicroRNA‐21, antimir‐21 probe, InP, onto the surface of GME and then solid phase hybridization of InP with mir‐21, the target, the electrochemical detection was performed by using Differential Pulse Voltammetry (DPV) and EIS techniques. This developed biosensor, GME has presented a 2.77 times lower detection limit of 2.09 µg/mL (3.12 pmol) with respect to unmodified pencil graphite electrode (GE). Moreover it is capable of analyzing mir‐21 in the cell lysates of mir‐21 positive breast cancer cell line (MCF‐7) contrast to mir‐21 negative hepatoma cell line (HUH‐7). The proposed electrochemical yes‐no system does not require any purification and/or amplification step prior to fast detection of mir‐21 from real samples.     

Synthesis and QSAR Study of Some Novel Heterocyclic Derivatives as In Vitro Cytotoxic Agents

2,3‐Diaryloxirane‐2,3‐dicarbonitriles have employed in heterocyclic synthesis in many organic reactions. Authors highlight its use as intermediate in the synthesis of various organic compounds through the reaction with different nitrogen nucleophiles as methyl hydrazine, thiourea, thiosemicarbazide, methylglycinate, and others to furnish new heterocyclic derivatives. They are also used as key starting materials to construct some important heterocycles. Structures of all newly synthesized products are substantiated by studying their micro analytical and spectral data. Some of newly synthesized compounds were evaluated for their in vitro cytotoxic effects against a panel of three human tumor cell lines, namely, Hep‐G2, Hela, and MCF‐7. Most of the newly synthesized compounds ( 1a , 2a , 2d , 3 , 4 , 5 , 6a , 6c , 6d , 7a , and 7b ) inhibited cell proliferation with IC₅₀ values in range of 0.52–5.21 μΜ. For activity against HepG2 cell line, compounds 5 , 6a , 6d , and 7b emerged as the most active members. The Hela cell line showed highest sensitivity toward compounds 2a , 2d , and 6c whereas compounds 2d and 6c showed the highest inhibitory activity against MCF‐7 cell line.     

One‐pot synthesis of benzimidazole‐pyrazines and their anticancer activities

The skeleton of fused benzimidazole‐pyrazine was constructed via an Ugi/deprotection/cyclization (UDC) and hydroamination cascade reaction. This four‐step reaction was carried out in a one‐pot procedure with only one‐time column chromatography purification. The representative compound 7b exhibited 67% cell growth inhibitory activity against human breast cancer cell line MDA‐MB‐453 at the concentration of 10μM.     

Novel Synthetic Route to α‐Aminophosphonates Containing Benzothiazole Moiety

A novel and ef?cient synthetic route to α‐aminophosphonates containing benzothiazole moiety via a cascade three‐component reaction from conveniently available starting materials has been developed. The target compounds 3a – 3g , 7 and 8a , 8b were evaluated for their anticancer activities against the cancer cell line HL‐60 in vitro by the MTT method. Compound 3g showed good cancer inhibitory activity against the tested cell line. Further study is necessary to find out the potential antitumor activities.     

Synthesis of (±)‐Spongiolactone Enabling Discovery of a More Potent Derivative

An eleven‐step synthesis of (±)‐spongiolactone from 1,3‐cyclohexanedione is reported that relies on a diastereoselective, nucleophile‐catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β‐lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure–activity studies that revealed a regio‐ and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.     

Aurovertin‐Type Polyketides from Calcarisporium arbuscula with Potent Cytotoxic Activities against Triple‐Negative Breast Cancer

Two new polyene polyketides, namely aurovertins T and U ( 1 and 2 ), were isolated from Calcarisporium arbuscula, together with aurovertins B ( 3 ), D and E ( 4 and 5 ), and M ( 6 ). The structures were elucidated by extensive spectroscopic methods (especially 2D‐NMR techniques). The cytotoxic activities of all isolates against human triple‐negative breast cancer cell line (MDA‐MB‐231) were evaluated. As a result, compounds 3 , 4 , and 6 exhibited more potent cytotoxic activities against MDA‐MB‐231 cell line than the positive control taxol. Also, discussion about the relationships between structure and activity of these aurovertins was presented.