Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety.

BACKGROUND: Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity. OBJECTIVE: In this study, we designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2- yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines. We further studied the selectivity of the compounds against the NIH/3T3 mouse embryonic fibroblast cell line. Cholinesterase inhibition effects of these compounds were also investigated to measure the relationship between anticancer activity and cholinesterases. METHODS: The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used to measure the proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used to measure apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages. RESULTS: Compounds 2e, 2f, and 2k were shown to be the most active antitumor agents with selective cytotoxicities (the results for A549 were 76.58±6.43, 55.13±5.75, and 32.94±3.02 µM, respectively; and for C6 they were 86.48±3.60, 97.12±30.21, and 59.29±3.95 µM, respectively), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines. CONCLUSION: The results showed that compounds 2e, 2f, and 2k have potential anticancer activity against A549 and C6 cell lines.

Bacterial Biotransformation and Anticancer Activities of Betulin against A549, HepG2 and 5RP7 Cancer Cell Lines.

BACKGROUND: A pentacyclic lupenane-type natural triterpenoid, betulin, has attracted attention in the field of medicinal chemistry since it exhibited a variety of biological activities, including anticancer activity. OBJECTIVE: The aim of this present work was to obtain derivatives of betulin through bacterial biotransformation and investigate its anticancer activity against A549, HepG2 and 5RP7 cancer cell lines. METHODS: Bacterial biotransformation studies were continued in an MBH broth medium for 7 days at 35oC. Anticancer activities of betulin against A549, HepG2 and 5RP7 cell lines were carried out using XTT assay, and their selectivity was determined using a healthy cell line of NIH/3T3. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measuring proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used for measuring apoptotic cell percentages, caspase 3 activation and mitochondrial membrane potential. RESULTS: Bacterial biotransformation studies with 7 bacteria of Staphylococcus aureus ATCC 6538, Proteus vulgaris NRRL B-123, Bacillus subtilis NRRL B-4378, Streptomyces griseolus NRRL B-1062, Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 43300 and Bacillus velezensis NRRL B-14580 produced no metabolite. In in vitro anticancer activity studies, betulin was found to exert anticancer activity against A549, HepG2 and 5RP7 cell lines with IC50 values of 207.7, 125.0 and 28.3 µg/mL, whereas SI values were found to be 30, 50 and 223, respectively. Early and late apoptotic percentages of betulin were found as 9.6, 12.1 and 85.4% on A549, HepG2 and 5RP7, respectively, while caspase 3 positive cell percentages were 2.3, 28.7 and 13.3% for IC50 concentrations. In addition, betulin caused G1 cell cycle arrest (49.5%) on 5RP7 cell line. CONCLUSION: The results have been shown that betulin activities against A549 and HepG2 cell lines were nonselective and limited its cytotoxic activity against healthy cells, but it is possible to say that it exerted selective activity against 5RP7 cell (28.33±1.53 µg/mL). Betulin effects on apoptosis were found to be dosedependent, while its effect on caspase 3 activation, mitochondrial membrane potential, and cell cycle arrest on G0/G1 phase was not dependent on doses. Therefore, betulin could be a good candidate for the treatment of H-ras active cancer types.

Congenital segmental emphysema in an adult patient.

Congenital segmental emphysema (CSE) is a disease characterized by severe hyperinflation of a specific segment of the lung without any intrinsic or extrinsic compression. It is most commonly observed in neonates and young children with acute respiratory distress. It is usually unilateral, and the left upper lobe of the lung is most often affected. Rarely, patients may remain asymptomatic until they are older and, therefore, may be diagnosed later. Cases unexplained until adulthood are sometimes detected incidentally as single-sided hyperinflation on a chest X-ray image. We have presented an extremely rare case where the patient remained asymptomatic until adulthood and did not exhibit any clinical findings.

Lipid transfer protein sensitization in an apple-allergic patient: a case report from northern Europe.

Summary: We describe a case of a woman who developed three separate episodes of urticaria and ana-phylaxis during exercise after consuming an apple, with immunological evidence that nonspecific lipid transfer proteins (LTP) may have been responsible for these reactions. LTP sensitivity can cause life-threatening allergies and anaphylaxis. Although LTP sensitization is common in Mediterranean countries, the frequency of knowledge and diagnoses is increasing in Europe. Despite the geographic differences, LTP allergy should be kept on sight when facing severe anaphylaxis after consuming LTP-included food.

New Quinoline Based Sulfonamide Derivatives: Cytotoxic and Apoptotic Activity Evaluation Against Pancreatic Cancer Cells.

BACKGROUND: Quinoline is a privileged scaffold especially known with antimalarial and antibacterial drugs before, presently followed anticancer efficiency with a new group of protein kinase inhibitors. OBJECTIVE: In this work, combining quinoline ring, hydrazone and sulphonamide groups, we have synthesized N'-arylidene-2-[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]acetohydrazide derivatives (3a-o) and evaluated their in vitro anticancer activity against cancerous cell lines PANC-1, CAPAN-1, and healthy cell line hTERT-HPNE. METHOD: Fifteen compounds were synthesized a simple, well-known three-step synthetic procedure starting from 8-quinolinesulfonylchloride. Cytotoxicity studies were performed according to the conventional MTT method. As a second stage, flow cytometric analysis was done to the nine most cytotoxic compounds for determining the mechanism of action which could be apoptosis and/or necrosis. RESULTS/CONCLUSION: According to anticancer activity evaluation, compound 3b bearing 4-methyl phenyl moiety exhibited significant cytotoxicity which has an IC50 value nearly four-fold lower than cisplatin displayed, whereas compound 3f bearing 4-trifluoromethyl phenyl moiety showed two-fold potency of the standard drug against PANC-1 cell line. Compounds 3h, 3k and 3n against CAPAN-1 also showed significant cytotoxicity, selectively. The most active compounds 3b, 3c, 3d, 3f, 3g, 3h, 3k and 3n against PANC-1 and compounds 3f, 3g, 3h, 3k and 3n against CAPAN-1 were selected to be studied in flow cytometry. Compound 3b induced apoptosis of PANC-1 cells with a percentage of 16.0%, whereas compound 3h induced apoptosis of CAPAN-1 cells with a value of 20.6%.

Some Thiazole Derivatives Combined with Different Heterocycles: Cytotoxicity Evaluation and Apoptosis Inducing Studies.

BACKGROUND: Thiazole ring is an outstanding structure found in many biologically active compounds and clinically available drugs. Because of synthesis simplicity of its derivatives and having a wide range of biological aspects along with high effectiveness, new thiazole derivatives have been studied by medicinal chemists since many years. OBJECTIVE: Some thiazole compounds combined with different heterocyclic rings were acquired in this study. Novel 5-(4-substituted benzylidene)-2-[(4,5-dimethylthiazol-2-yl)amino]thiazol-4(5H)-one derivatives (4a-g) and 2-(heteroaryl-2/3/5-yl)thio-N-(4,5-dimethylthiazol-2-yl)acetamide (4h-p) derivatives were synthesized starting from 2-amino-4,5-dimethylthiazole. The obtained compounds were evaluated to determine their antiproliferative activity. METHOD: Final compounds (4a-g) were obtained with a ring closure reaction; other final compounds (4h-p) were acquired via the reaction of mercapto heterocycles with Hantzsch thiazole synthesis intermediate. To evaluate antiproliferative activity of them, the compounds were tested on A549 adenocarcinomic human alveolar basal epithelial cells line, C6 rat glioma cell line and NIH/3T3 mouse embryo fibroblast cell line according to the conventional MTT method. Besides, the selected compounds were studied to find out which pathway cell deaths caused via Annexin V/PI staining. RESULTS: Compounds 4f, 4j and 4p exhibited the highest cytotoxicity on A549 with a non-toxic profile. Also, 4f, 4h, 4j and 4p were determined as the most antiproliferative compounds on C6 cell line. Furthermore, compound 4p induced apoptosis of A549 cell with a level of 23.5% and compound 4h induced C6 cell with a level of 37.5%. CONCLUSION: Considering the structure of the compounds, although thiazolidine containing compounds 4a-g exhibited higher activity in general, compounds 4p containing 5-chlorobenzothiazole moiety showed the highest cytotoxicity. It could be expressed with the conspicuous antitumor efficiency of benzothiazole ring.

Synthesis and Biological Evaluation of New 1,3,4-Oxadiazoles as Potential Anticancer Agents and Enzyme Inhibitors.

BACKGROUND: 1,3,4-Oxadiazoles have been known with a wide variety of pharmacological activities including anticancer activity. OBJECTIVE: In this study, novel 2,5-disubstituted 1,3,4-oxadiazole derivatives were synthesized and evaluated for determining their anticancer, anticholinesterase and lipoxygenase (LOX) inhibitory activity. METHODS: All compounds were tested against C6 rat glioma, A549 human lung carcinoma and NIH/3T3 mouse embryo fibroblast cell lines to define cytotoxic concentrations and apoptosis induction levels which they cause. RESULTS: Many of the compounds exhibited remarkable potency that compounds 2a, 2b, 2e, 2h and 2j against C6 cells and compounds 2a, 2b, 2d, 2g, 2i, 2j against A549 cells were found more active than cisplatin. Compound 2d namely, 2-[(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-chlorophenyl)ethan-1-one induced apoptosis of A549 cells with 74.9% whereas cisplatin caused 70.9% percentage. CONCLUSION: Among them, compounds 2d and 2j against A549 cell line, compounds 2b and 2e against both tumor cell lines showed selective cytotoxicity evaluating the inhibition concentration against NIH/3T3 cell line. None of the compounds showed significant acetylcholinesterase (AChE) and lipoxygenase inhibitory activities.

Synthesis and Evaluation of a New Series of Arylidene Indanones as Potential Anticancer Agents.

BACKGROUND: Arylidene indanones have attracted a great deal of interest due to their outstanding therapeutic applications. In particular, considerable research has pointed out the importance of arylidene indanones in the field of cancer research. OBJECTIVE: The aim of the current work was to design and synthesize arylidene indanone-based anticancer agents. METHOD: New arylidene indanones were obtained via the Claisen-Schmidt condensation of 5-chloro-6-methoxy- 2,3-dihydro-1H-inden-1-one with p-substituted benzaldehyde derivatives. MTT assay was performed to evaluate their cytotoxic effects on MCF-7 human breast adenocarcinoma, HeLa human cervix carcinoma and NIH/3T3 mouse embryonic fibroblast cell lines. The most effective derivatives were evaluated for their DNA synthesis inhibitory and apoptotic effects. The most apoptotic compounds were also investigated for their effects on caspase-3 activation in HeLa cells. The binding interactions of the most effective caspase-3 activator at the active site of caspase-3 were confirmed through molecular docking studies using Schrodinger's Maestro molecular modeling package. RESULTS AND CONCLUSION: Compounds 2, 3, 4, 5, 6 and 7 exhibited selective anticancer activity against HeLa cells, whilst compounds 7 and 10 showed selective anticancer activity against MCF-7 cells. Compound 10 caused significant DNA synthesis inhibition on MCF-7 cells, whereas compound 3 caused significant DNA synthesis inhibition on HeLa cells. Compounds 2 and 3 were determined as the most apoptotic agents against HeLa cells, whereas compounds 7 and 10 showed apoptotic activity against MCF-7 cells. Besides, compound 2 was identified as the most effective compound on caspase-3 activation in HeLa cells. Docking studies showed that compound 2 interacted with the residues His121 and Tyr204 forming π-π stacking interactions.

Cytotoxic, Antiproliferative and Apoptotic Effects of Perillyl Alcohol and Its Biotransformation Metabolite on A549 and HepG2 Cancer Cell Lines.

BACKGROUND: A monoterpene, perillyl alcohol, has attracted attention in medicinal chemistry since it exhibited chemo-preventive and therapeutic properties against a variety of cancers. OBJECTIVE: In the present work, it was aimed to obtain derivatives of perillyl alcohol through microbial biotransformation and investigate their anticancer activities against A549 and HepG2 cancer cell lines. METHOD: Biotransformation studies were carried out in a α-medium for 7 days at 25oC. XTT assay was performed to investigate the anticancer activities of perillyl alcohol and its biotransformation metabolite, dehydroperillic acid, against A549 and HepG2 cell lines and their selectivity using healthy cell line, NIH/3T3. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measurement of proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analyses were also carried out for measuring apoptotic cell percentages, caspase 3 activation and mitochondrial membrane potential. RESULTS: Biotransformation of perillyl alcohol with Fusarium culmorum yielded dehydroperillic acid in a yield of 20.4 %. In in vitro anticancer studies, perillyl alcohol was found to exert cytotoxicity against HepG2 cell line with an IC50 value of 409.2 µg/mL. However, this effect was not found to be selective because of its higher IC50 (250 µg/mL) value against NIH/3T3 cell line. On the other hand, dehydroperillic acid was found to be effective and also selective against A549 cell line with an IC50 value of 125 µg/mL and a selectivity index (SI) value of 400. Apoptosis inducing effects of dehydroperillic acid was better in A549 cell line. CONCLUSION: Dehydroperillic acid may be a good candidate for therapy of lung adenocarcinoma and may show this anticancer activity by inducing apoptosis.

Novel MASP1 mutations are associated with an expanded phenotype in 3MC1 syndrome.

BACKGROUND: 3MC1 syndrome is a rare autosomal recessive disorder characterized by intellectual disability, short stature and distinct craniofacial, umbilical, and sacral anomalies. Five mutations in MASP1, encoding lectin complement pathway enzymes MASP-1 and MASP-3, have thus far been reported to cause 3MC1 syndrome. Only one previously reported mutation affects both MASP-1 and MASP-3, while the other mutations affect only MASP-3. METHODS: We evaluated six unrelated individuals with 3MC1 syndrome and performed Sanger sequencing for all coding exons of MASP1. We also measured complement lectin and alternative pathway activities in an affected individual's serum. RESULTS: We found two novel splice site mutations, c.1012-2A > G in one and c.891 + 1G > T in two probands, and three novel missense mutations, c.1451G > A (p.G484E), c.1657G > A (p.D553N), and c.1987G > T (p.D663Y). Missense mutations affect only MASP-3, while splice site mutations affect both MASP-1 and MASP-3. In a proband who is homozygous for c.891 + 1G > T, we detected a total lack of lectin complement pathway activity and a 2.5-fold lower alternative pathway activity. The phenotype observed in patients whose both MASP-1 and MASP-3 are affected and in those whose only MASP-3 is affected does not appear to be different. We observed structural brain abnormalities, neonatal tooth, a vascular anomaly and a solid lesion in liver as novel phenotypic features of 3MC1 syndrome. CONCLUSION: Novel mutations and additional phenotypic features expand the genotypic and phenotypic spectrum of 3MC1 syndrome. Although patients with MASP-1 dysfunction in addition to disrupted MASP-3 have an altered complement system, their disease phenotype is not different from those having only MASP-3 dysfunction.

Synthesis and biological evaluation of some 1,2-disubstituted benzimidazole derivatives as new potential anticancer agents.

The synthesis of some new 1-(2-aryl-2-oxoethyl)-2-[(morpholine-4-yl)thioxomethyl]benzimidazole derivatives and investigation of their anticancer activities were the aims of this work. 2-(Chloromethyl)benzimidazole compound was reacted with sulfur and morpholine via Willgerodt-Kindler reaction to give 2-[(morpholine-4-yl)thioxomethyl]benzimidazole. Then, the obtained compound was reacted with appropriate α-bromoacetophenone derivatives in the presence of potassium carbonate to give the final products. Structure elucidation of the final compounds was achieved by FT-IR, (1)H NMR spectroscopy and MS spectrometry. The anticancer activities of the final compounds were evaluated by MTT assay, BrdU method, and flow cytometric analysis on C6, MCF-7, and A549 tumor cells. Most of the synthesized compounds exhibited considerable selectivity against the MCF-7 and C6 cell lines.

Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate moiety as new cholinesterase inhibitors.

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2-furyl)-5-aryl-2-pyrazolines with sodium salts of N,N-disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17, when compared with eserine. Compounds effective on AChE carry the 2-dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2-dimethylaminoethyl and 3,4-methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.

Drying of polyacrylamide composite gels formed with various kappa- carrageenan content.

Drying of polyacrylamide (PAAm)-κ-carrageenan (κC) composite gels were monitored by using steady-state fluorescence technique. Disc shaped gels were formed from acrylamide (AAm) and N, N'- methylenebisacrylamide(Bis) with various κ- carrageenan (κC) contents by free radical crosslinking copolymerization in water. Pyranine (P) was doped as a fluorescence probe, and scattered light, I (sc), and fluorescence intensities, I, were monitored during drying of these gels. It is observed that fluorescence intensity of pyranine increased as drying time is increased for all samples. The increase in I was modeled using Stern- Volmer equation and diffusion with moving boundary. It is found that desorption coefficient, D decreased as κC contents were increased. Supporting gravimetrical and volumetric experiments were also carried out during drying of PAAm- κC composite gels.

Arteriovenous malformations of the lung: diagnosis by thin-section HRCT and Cine-MRI.

We report a case in which a solitary large and multiple group of small pulmonary arteriovenous malformations were demonstrated by computed tomography and magnetic resonance images that could aid diagnosis and therapeutic planning without the need for catheter angiography.

Effects of a three-dimensional bimetric maxillary distalizing arch.

This study aimed to investigate the dental effects of a three-dimensional (3D) bimetric maxillary distalizing arch. The Wilson rapid molar distalization appliance for Class II molar correction was used in 14 patients (10 girls and four boys with a mean age of 12.18 years). The open coil springs were activated with bent Omega stops and Class II intermaxillary elastics. The mandibular anchorage was gained by a 0.016 x 0.016 utility arch with a 3D lingual arch or a lip bumper with a standard lingual arch. The lateral cephalograms taken before and after treatment formed the material of the research. A Wilcoxon test was used to statistically evaluate the treatment effects. The results showed that the distal tipping of the maxillary first and second molars, and first and second premolars and canines were statistically significant. Significant distal movement occurred in all posterior and canine teeth. The maxillary first molar distalization was found to be 3.5 mm. The maxillary incisor showed significant proclination and protrusion. The decrease in overbite was found to be statistically significant. The mandibular plane angle significantly increased by a mean of 0.5 mm. In addition, significant soft tissue changes were observed.

The retraction of upper incisors with the PG retraction system.

The aim of this study was to evaluate the effect on the dentoalveolar structures of the application of PG springs for retraction of upper incisors and to compare the outcome with the effect of a closed coil spring retraction system. Thirty-six subjects with Angle Class I or Class II malocclusions were selected for the study. Each subject had the two upper first premolars extracted and presented a symmetrical extraction space of at least 3 mm distal to the lateral incisors after canine retraction. The subjects were divided into two groups, the PG group with 17 subjects and the coil group with 19 patients. One group had the incisors retracted by PG universal retraction springs, whereas in the other a closed coil spring system was used. The average chronological ages were 18 years 4 months for the PG group, and 18 years 7 months for the coil group. In both groups the springs were activated to produce an initial force of 150 g per side. To examine the type of movement of the anterior and posterior teeth, and the time and rate of space closure, 20 parameters were measured and evaluated statistically with Wilcoxon and Mann-Whitney U-tests. In both groups the incisor retraction was accompanied by mesial movement of the buccal segments. Distal movement of the root apex of the incisors was observed in both groups, although more pronounced in the PG group (P < 0.01). A significant incisor intrusion resulting in a decrease in overbite was found in the PG group, whereas the deep bite increased significantly in the coil spring group. The PG spring produced a three-dimensional control in the movement of the upper incisors, so that application of additional intrusive mechanics after completion of the incisor retraction became unnecessary.