SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors

Background: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and H) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and H by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K-i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K-i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors

Structure elucidation of organic compounds from natural sources using 1D and 2D NMR techniques

In our continuing studies on Lamiaceae family plants including Salvia, Teucrium, Ajuga, Sideritis, Nepeta and Lavandula growing in Anatolia, many terpenoids, consisting of over 50 distinct triterpenoids and steroids, and over 200 diterpenoids, several sesterterpenoids and sesquiterpenoids along with many flavonoids and other phenolic compounds have been isolated. For Salvia species abietanes, for Teucrium and Ajuga species neo-clerodanes for Sideritis species ent-kaurane diterpenes are characteristic while nepetalactones are specific for Nepeta species. In this review article, only some interesting and different type of skeleton having constituents, namely rearranged, nor-or rare diterpenes, isolated from these species will be presented. For structure elucidation of these natural diterpenoids intensive one- and two-dimensional NMR techniques (H-1, C-13 APT, DEPT, NOE/NOESY, H-1-H-1 COSY, HETCOR, COLOC, HMQC/HSQC, HMBC, SINEPT) were used besides mass and some other spectroscopic methods. (C) 2007 Published by Elsevier B.V

Constituents of Salvia microphylla

A new phenolic ester 2-(p-hydroxyphenyl) ethyl eicosaheptanoic acid ester ( 1) and a known one hexacosylferulate ( 2) were isolated from the acetone extract of Salvia microphylla. In addition, two sesquiterpenes beta-eudesmol ( 3) and 8 alpha-hydroxy-beta-eudesmol ( 4), a diterpene carnosic acid 12-methyl ether (12-methoxycarnosic acid) ( 5), three triterpenes erithrodiol 3-acetate, oleanolic acid, lupeol and beta-sitosterol were obtained as known compounds from this plant extract. The structures of the isolated compounds were elucidated by spectroscopic methods, including one- and two-dimensional H-1- and C-13-NMR and MS spectroscopies. The selected compounds were tested for antimicrobial activity against standard bacterial strains, and only carnosic acid 12-methyl ether showed antimicrobial activity against S. aureus at 78 mu g mL(-1)

Complete C-13 NMR assignments for ent-kaurane diterpenoids from Sideritis species

In this work, the detailed NMR studies and full C-13 NMR assignments for five diterpenoids isolated from Sideritis caesarea and Sideritis athoa are described. The assignments are based on a combination of 1D and 2D NMR techniques including H-1, C-13, H-1-H-1 COSY, gHSQC [(1)J(C,H)] and gHMBC delta(C) [(n)J(C,H) (n = 2 and 3)] and NOESY experiments. Copyright (C) 2011 John Wiley & Sons, Ltd

Cytotoxic, Apoptotic and Genotoxic Effects of Lipid-Based and Polymeric Nano Micelles, an In Vitro Evaluation

Self-assembly systems (SAS) mainly consist of micelles, and liposomes are the classes of Nano Drug Delivery Systems with superior properties compared to traditional therapeutics in targeting cancer tumors. All commercially available nano-formulations of chemotherapeutics currently consist of SAS. According to our knowledge, a specific toxicity comparison based on material differences has not yet been performed. The purpose of this study was to evaluate and compare the toxicity of two SAS consisting of Sterically Stabilized Micelles (SSM) made of a lipid-based amphiphilic distearoyl-sn-glycero-phosphatidylethanolamine-polyethylene glycol (PEG)-2000 and a polymeric micelle (PM) consisting of Y-shape amphiphilic block copolymer, synthesized using poly ε-caprolactone and PEG. The mechanism of cytotoxicity and genotoxicity of micelles on L-929 healthy mouse fibroblast cells was assessed using Sulforhodamine-B, WST-1, Acridine Orange/Ethidium Bromide and alkaline single-cell gel electrophoresis assays. Results showed that SSM in conc. of 40 mg/mL shows very low cytotoxicity at the end of 24, 48 and 72 h. The DNA damage caused by SSM was much lower than PM while the latter one showed significant toxicity by causing apoptosis with the ED50 value of 3 mg/mL. While the DNA damage caused by SSM was ignorable, some DNA chain breaks were detected on cells treated with PM

Chemical Composition of Natural Colophony from Pinus brutia and Comparison with Synthetic Colophony

The compositions of colophony resins obtained from Pinus brutia Ten trees by three different methods (acid paste, carved hole and scraping) from Ayvacik, Gokova and Kemalpasa in Turkey were analyzed by capillary GC-MS The main components were the monoterpenes alpha-pmene, beta-pinene, and Delta(3) carene, and the diterpenic resin acids palustric, abietic, kaur-9(11)-16-en-18-oic and neoabietic acid The synthetic colophony resins exhibited similar contents to those of the natural resins obtained from the Gokova and Kemalpasa regions of Turkey However, colophony resins from Ayvacik exhibited only half the diterpenic acid content as those of the Gokova and Kemalpasa resins Out of the three techniques, the carved hole method caused rather different percentages in the constituents of the essential oil