New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies

Synthesis of a new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold is described. Their in vitro antiproliferative activities against 9 human melanoma cell lines were tested. Compounds 12, 13, 15, and 21–23 showed the highest potency against A375P melanoma cell line. In addition, compounds 10–15 and 19–24 showed high potency over the NCI 8 tested melanoma cell-lines panel. The IC₅₀ values for compound 23 were 0.36 μM and 0.84 μM over LOX IMVI and M14 cell lines, respectively. Compounds 21 and 23 showed high, dose-dependent inhibition of ERK kinase. Virtual screening was carried out through docking of compound 21 into the domain of V600E-B-RAF and the binding mode was studied.     

Solvent-free, microwave assisted Knoevenagel condensation of novel 2,5-disubstituted indole analogues and their biological evaluation

A rapid, efficient and environmental benign methodology for the preparation of 2,5-disubstituted indole analogues is developed. 2,5-Disubstituted indole-3-carboxaldehydes (1a–c) undergo Knoevenagel condensation with barbiturates (2 & 4), thiazolidine-2,4-dione (6) and 3-methyl-1H-pyrazol-5(4H)-one (8) in solvent-free, NH₄OAc catalyzed, microwave assisted reaction. Structures of the products thus obtained were confirmed by their m.p, Elemental analysis, IR, ¹H NMR, ¹³C NMR and Mass spectral data. The in vitro antioxidant and cytotoxic activities against three tumor cell lines were evaluated and discussed in terms of their structural differences. Among the screened compounds 9b, 9c, 7b and 5b exhibited excellent antioxidant activity. Compounds 9b, 9c and 7b have shown strong cytotoxicity among the compounds tested.     

5th International Potsdam Symposium on Tick-borne Diseases: Tick-borne Encephalitis and Lyme-Borreliosis Berlin, den 26.–27. Februar 1999 Berlin, den 26.–27. Februar 1999

B. b. sensu lato , FSMEV, Rickettsia conorii ) sowie Biologie und ?kologie der Taubenzecke ( Argus reflexus ) und ihrer humanmedizinischen Bedeutung.     

Design, synthesis and docking studies of new quinoline-3-carbohydrazide derivatives as antitubercular agents

Three new series of 4-hydroxy-8-trifluoromethyl-quinoline derivatives were synthesized through multi step reactions. All the newly synthesized compounds were characterized by spectral and elemental analyses. The structure of 5j was evidenced by X-ray crystallographic study. The newly synthesized title compounds were evaluated for their antimicrobial activities including antimycobacterial activity. Amongst the tested compounds, 5b, 5e, 5h, 5j, 6c and 7c displayed promising antimicrobial activity. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands, 5b, 5e, 5h, 5j and 6c.     

Lycium Barbarum Inhibits Growth of Estrogen Receptor Positive Human Breast Cancer Cells by Favorably Altering Estradiol Metabolism

Selective estrogen receptor modulators represent accepted therapy for estrogen receptor positive (ER ⁺ ) breast cancer, exhibit adverse side effects, and reduce patient compliance. The use of phytoestrogen containing herbal medicines is limited because of efficacy and safety concerns. The ER ⁺ MCF-7 model examined growth inhibitory effects of the medicinal herb Lycium barbarum (LB) and identified mechanistic leads for its efficacy. The MCF-7 cells maintained in 0.7% serum (17β-estradiol, E ₂ < 1 nM) exhibited 11%–87% increased growth after treatment with 1nM to 20 nM E ₂ . Growth promotion with 20 nM E ₂ exhibited 5.2-fold increased estrone (E ₁ ), 35.7% increased 2-hydroxyestrone (2-OHE ₁ ), 15.4% increased 16α -hydroxyestrone (16α -OHE ₁ ), and eightfold increased estriol (E ₃ ) formation. Treatment of E ₂ stimulated cells with LB exhibited a dose-dependent growth inhibition of 9.5%–42.8% at Day 3 and 33.9%–83.9% at Day 7. The 3-day inhibitory response to 1% LB (maximum cytostatic concentration) exhibited 84.8% increased E ₁ , 3.6-fold increased 2-OHE ₁ , 33.3% decreased 16α -OHE ₁ , and 9.2-fold increased E ₃ formation. Thus, MCF-7 cells retain their mitogenic and metabolic response to E ₂ and LB downregulates E ₂ -stimulated growth via the formation of antiproliferative 2-OHE ₁ and accelerated conversion of mitogenic 16α -OHE ₁ to antimitogenic E ₃ .     

Do Flavonoid Intakes of Postmenopausal Women With Breast Cancer Vary on Very Low Fat Diets?

In the Women's Intervention Nutrition Study (WINS), a very low-fat eating pattern decreased breast cancer recurrence. We assessed whether the women's flavonoid intakes varied on the very low fat diet. A total of 550 randomly selected WINS participants who had been treated with conventional therapy (surgery, chemotherapy, and/or radiation) for primary breast cancer were randomized to either a very low fat diet (15% of calories from fat, N = 218) or their usual diets (30% calories from fat, N = 332). We compared their intakes of total flavonoids and 6 flavonoid classes (isoflavones, flavones, flavanones, flavonols, flavan-3-ols, and anthocyanins) for these 2 groups using the U.S. Department of Agriculture food flavonoid database and a flavonoid dietary supplement database on three 24-h dietary recalls at baseline and 12 mo after randomization. At baseline, neither mean fat intakes (31.7% ± 6.8 SD of calories, n = 332 in the usual diet group and 31.6% ± 6.8 SD of calories, n = 218 in the very low fat diet group; P = NS) nor flavonoid intakes (218 ± 283 SD mg/day, n = 332 in the usual diet group and 236 ± 393 SD mg/day, n = 218 in the very low fat diet group; P = NS) differed. Over half of the women's flavonoid intakes were from the flavan-3-ols. After 12 months of intervention, with 39 participants lost to follow-up, dietary fat intakes were 30.7 ± 8.4 SD calories (n = 316) among those on their usual diets but were significantly lower among those on the very low fat diet intervention: 21.4 ± 8.3 SD calories (n = 195), P = < 0.05. However, flavonoid intakes remained similar in both groups (201 ± 252 SD mg/day, n = 316 in the usual diet group vs. 235 ± 425 SD mg/day, n = 195 in the very low fat group; P = NS). In this random sample of WINS participants, neither total flavonoid intakes nor intakes of subclasses of flavonoids differed between those who had dramatically decreased their fat intakes and those who had not. Flavonoid intakes are therefore unlikely to account for WINS results on differences between the groups in cancer recurrence.     

Pancreatic lipase inhibitory stilbenoids from the roots of Vitis vinifera

Bioassay-guided isolation of an aqueous methanolic extract of Vitis vinifera using pancreatic lipase inhibitory activity led to isolation of seven stilbenoids, wilsonol C (1), heyneanol A (2), ampelopsin A (3), pallidol A (4), cis-piceid (5), trans-piceid (6) and trans-resveratrol (7). The structures were established on the basis of NMR and MS spectroscopic data interpretation. All isolates were evaluated for their inhibitory effects on pancreatic lipase, and stilbenoid 1 exhibited potent inhibitory effect on pancreatic lipase with IC₅₀ values of 6.7?±?0.7?µM.     

Hantzsch reaction: synthesis and characterization of some new 1,4-dihydropyridine derivatives as potent antimicrobial and antioxidant agents

In the present study two new series of Hantzsch 1,4-dihydropyridine derivatives (1,4-DHPs) containing substituted pyrazole moiety (4a–f and 5a–f) were synthesized by the reaction of 3-aryl-1H-pyrazole-4-carbaldehydes with 1,3-dicarbonylcompounds (ethylacetoacetate and methylacetoacetate) and ammonium acetate. The newly synthesized compounds were characterized by IR, NMR, mass spectral study and also by C, H, N analyses. New compounds were screened for their antimicrobial activity by well plate method (zone of inhibition). Antioxidant studies of the synthesized compounds were also performed by measuring the DPPH radical scavenging assay. Compounds 4c, 4e and 4f were found to be potent antibacterial and antioxidant agents. The acute oral toxicity study for the compounds 4c, 4e and 4f were carried out and the experimental studies revealed that compounds 4c and 4e is safe up to 3000 mg/kg and no death of animals were recorded. However in compound 4f, we found mortality above 2000 mg and also significant behavioral changes in experimental animals.     

New imidazo[2,1-b]thiazole derivatives: synthesis, in vitro anticancer evaluation, and in silico studies

A series of 18 new imidazo[2,1-b]thiazole derivatives was synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 15, 16, 18, 22, 26–28, and 31 showed superior potency against A375P to sorafenib. In addition, compounds 26 and 27 showed selectivity toward melanoma cell lines than for other cancer types. Both compounds exerted sub-micromolar IC₅₀ values over 7 (including A375P) and 6 melanoma cell lines, respectively. In silico studies are also reported. ADME profiling, in silico toxicity, drug-likeness, and drug-score data of compounds 26 and 27 are promising.     

Suppression of Tumor Growth by Palm Tocotrienols Via the Attenuation of Angiogenesis

Previous studies have revealed that tocotrienol-rich fractions (TRF) from palm oil inhibit the proliferation and the growth of solid tumors. The anticancer activity of TRF is said to be caused by several mechanisms, one of which is antiangiogenesis. In this study, we looked at the antiangiogenic effects of TRF. In vitro investigations of the antiangiogenic activities of TRF, δ -tocotrienol ( δ T₃), and α -tocopherol ( α Toc) were carried out in human umbilical vein endothelial cells (HUVEC). TRF and δ T3 significantly inhibited cell proliferation from 4 μ g/ml onward ( P < 0.05). Cell migration was inhibited the most by δ T ₃ at 12 μ g/ml. Anti-angiogenic properties of TRF were carried out further in vivo using the chick embryo chorioallantoic membrane (CAM) assay and BALB/c mice model. TRF at 200 μ g/ml reduced the vascular network on CAM. TRF treatment of 1 mg/mouse significantly reduced 4T1 tumor volume in BALB/c mice. TRF significantly reduced serum vascular endothelial growth factor (VEGF) level in BALB/c mice. In conclusion, this study showed that palm tocotrienols exhibit anti-angiogenic properties that may assist in tumor regression.     

Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9–12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19–21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA_A receptor agonists, with ED₅₀ values of 252, 380, 251 mg/kg; TD₅₀ values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD₅₀ values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.     

Diastereoselective synthesis and bioactivity of long-chain anti-2-amino-3-alkanols

An improved four-step approach for the stereoselective synthesis of long-chain anti-2-amino-3-alkanols is described. Using this method, the syntheses of antiproliferative (antitumoral) compounds, spisulosine (ES-285, 2), clavaminols A and B (3 and 4), the deacetylated products of clavaminols H and N (7 and 8), as well as (2S,3R)-2-aminododecan-3-ol (9) and xestoaminol C (10), have been achieved in excellent diastereoselectivities. In vitro study showed that these compounds induced cell death and dose-dependently inhibited cell proliferation in human glioblastoma cell line SHG-44, indicating the anti-tumor property of this series of compounds.     

Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues

The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1–11 and 12–16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1–11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC₅₀ (eqBuChE) = 2.9 ± 0.4 μM; IC₅₀ (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC₅₀ (EeAChE) = 0.61 ± 0.04 μM; IC₅₀ (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer’s disease.     

Book reviews

ASSERTIVE CHILDBIRTH: THE FUTURE PARENTS’ GUIDE TO A POSITIVE PREGNANCY by Susan McKay Englewood Cliffs, NJ: Prentice‐Hall, 1983

SPORTS, SEX RITES AND SEX IDENTITY by Ann M. Hall Ottawa, Ontario: Canadian Research Institute for the Advancement of Women, 1981     

New spirocyclic Δ²-isoxazoline derivatives related to selective agonists of α7 neuronal nicotinic acetylcholine receptors

A set of structural analogues of spirocyclic quinuclidinyl-Δ²-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a–3c, 4a–4c, 5a–5c, 6a–6c, and 7a–7c), synthesized via the 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles, showed an overall reduced affinity at the α7 subtype when compared with their model compounds. Solely Δ²-isoxazolines 3a, 3b, and 6c maintained a binding affinity in the nanomolar range at the α7 nAChRs (K_i = 230, 420 and 700 nM, respectively). The quaternary ammonium salt 6c retained also a noteworthy α7 vs. α4β2 subtype selectivity, whereas 3a and 3b showed a sharp reduction in selectivity compared with 1a and 1b, their quinuclidinyl higher homologues.     

Rosuvastatin and the JUPITER trial: critical appraisal of a lifeless planet in the galaxy of primary prevention

Abstract

In November 2008, the JUPITER trial was published in the New England Journal of Medicine. JUPITER is an acronym for Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. It was an AstraZeneca sponsored randomized double-blind trial comparing rosuvastatin 20 mg with placebo in 17,802 apparently healthy men and women with LDL cholesterol <3·4 mmol/L and elevated C-reactive protein (CRP). The results of the JUPITER trial have been widely publicized, and based on the trial, the main regulatory agencies have approved rosuvastatin for the indication of primary prevention of vascular events. However, the interpretation and clinical implications of the JUPITER trial have been questioned and remain controversial. The objective of this commentary is to evaluate the relevance, design, results, and conclusions of the JUPITER study.     

Molecular modeling study and synthesis of novel dicationic flexible triaryl guanidines and imidamides as antiprotozoal agents

A new series of fourteen dicationic flexible triaryl bis-guanidines 3a,b, bis-N-substituted guanidines 7a,b and 8a,b as well as bis-imidamides 9–12a,b having a 1,3- or 1,4-diphenoxybenzene scaffold backbone were synthesized. The in vitro activity of the novel dications as antiprotozoal agents against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.) was assessed. Interestingly, six of the newly synthesized dications viz3a,b, 7a,b and 8a,b were more active against P.f. than the reference drug pentamidine. Also, some of the dications showed moderate antitrypanosomal activity. Thermal melting analysis of the novel dications was performed to determine their ligand-DNA relative binding affinities. Finally, docking of the dications with an AT rich DNA oligonucleotide was executed to understand their binding mode with the minor groove.     

Cooking Matters for Kids Improves Attitudes and Self-Efficacy Related to Healthy Eating and Cooking

ObjectiveTo assess changes in self-efficacy and attitudes related to healthy eating and cooking in Cooking Matters for Kids participants.DesignPrepost study design.SettingCooking Matters for Kids programs offered by 35 organizations.ParticipantsPredominantly third- to fifth-grade children participating in Cooking Matters for Kids lessons during fiscal years 2012–17 with matched presurvey and postsurveys (n = 18,113).Intervention(s)Cooking Matters for Kids consists of six 2-hour experiential nutrition and cooking education lessons.Main Outcome Measure(s)Self-efficacy related to healthy eating and cooking and attitudes toward healthy foods assessed through the Cooking Matters for Kids Participant Survey.AnalysisChanges from the presurvey to postsurvey were assessed using mixed models and repeated measures ordered logistic regression accounting for clustering by course. Effect sizes were calculated using Cohen d for repeated measures. A Bonferroni adjustment was used to correct for multiple comparisons (α = 0.025).ResultsBoth overall and individual self-efficacy and attitude scores improved from presurvey to postsurvey (P < 0.0001). The effect sizes were 0.35 for overall self-efficacy score and 0.17 for overall attitude score.Conclusions and ImplicationsParticipation in Cooking Matters for Kids was associated with improvements in self-efficacy and attitudes related to healthy eating and cooking.     

Design, synthesis and antiepileptic properties of novel 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl)urea derivatives

Twenty new 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) urea derivatives were designed and synthesized. Antiepileptic screening was performed using MES and scPTZ seizures tests. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 5c, 5g, 5j and 5n were found active in MES model, while 5o showed significant antiepileptic activity in scPTZ model. Further all these five compounds were administered orally to rats, 5c, 5g and 5n showed better activity than Phenytoin in oral route. Among these compounds 5c revealed protection in MES at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration respectively. This molecule provided also protection in the scPTZ at a dose of 300 mg/kg in both time intervals.