Baker Jawabrah Al-Hourani

Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors

A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a-e showed IC(50) values ranging from 0.42 to 8.1 mM for COX-1 and 2.0 to 200 μM for COX-2. Most potent compound 3c (IC(50) (COX-2)=2.0 μM) was further used in molecular modeling docking studies.

Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors.

A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC(50) values of 6 and 7 μM for COX-2. All compounds showed IC(50) values greater 100 μM for COX-1 inhibition.

Cyclooxygenase-2 inhibitors: a literature and patent review (2009 – 2010)

Introduction: COXs catalyze the complex conversion of arachidonic acid to prostaglandins and thromboxanes, which trigger as autacoids with autocrine and paracrine biological effects many physiological and pathophysiological responses. The structural similarities of the COX-1 and -2 enzymes make the search for selective inhibitors for COX-2 versus -1 a formidable challenge. Areas covered: The present review provides a survey of the development of novel COX-2 inhibitors covering literature and patents between 2009 and 2010. The presence of a central, typically 1,2-diaryl substituted, heterocycle or carbocycle as a characteristic structural motif in many selective COX-2 inhibitors represents the basis of their classification in this review. The classification in this review includes COX-2 inhibitors based on five- and six-membered heterocycles, benzoheterocycles (e.g., benzopyrans, benzopyranones, indoles and quinolines), quinones, chalcones, natural products and miscellaneous. When available, COX-2 inhibitors are presented with their related COX-2 inhibitory potency and selectivity. Expert opinion: The availability of detailed information on the crystal structure of the COX-2 enzyme with various substrates, cofactors and inhibitors, and the recently reported increased risk of cardiovascular events associated with selective COX-2 inhibitors will further stimulate development of COX-2 inhibitors with favorable COX-2 inhibition profiles without adverse effects to the cardiovascular system.

The cycloaddition of cyclopropenes to enones

Abstract A number of 1- and 1,2-disubstituted cyclopropenes undergo [4+2]-cycloaddition to methyl vinyl ketone or acrolein at ambient temperature to produce 2-oxabicyclo[4.1.0]hept-3-enes. When 1-phenyl-2-trimethylsilyl-cyclopropene is treated with 0.4 mol. equiv. of m-chloroperbenzoic acid, the derived ring-opened enone undergoes [4+2]-cycloaddition to the remaining starting material at ambient temperature.

Synthesis and evaluation of fluorobenzoylated di- and tripeptides as inhibitors of cyclooxygenase-2 (COX-2).

A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.

Structure-activity relationship of novel series of 1,5-disubstituted tetrazoles as cyclooxygenase-2 inhibitors: Design, synthesis, bioassay screening and molecular docking studies.

A novel class of modified 1,5-disubstituted tetrazoles was designed and synthesized, their biological activity as cyclooxygenases inhibitors was screened, and their molecular docking studies were performed. The structural modifications of the first category included the 4-methylsulfonyl phenyl at C-1 of the central moiety and the linkers (-OH, -CH2OH, -CH2CH2OH) with different lengths at the para position of the N-1 phenyl group. For the second category, the 4-methylsulfonyl phenyl group at C-1 was replaced with 4-aminosulfonyl phenyl. While for the third category, a methylene unit was inserted between the C-1 of the tetrazole central ring and the 4-(methylsulfonyl)phenyl group, keeping the same linkers of various extensions at the para position of the N-1 phenyl group. Among the screened compounds, tetrazole 4i showed the best inhibition potency and selectivity values for both COX-2 enzyme (IC50=3μM, SI>67) and COX-1 isoenzyme (IC50>200μM). Compounds 4e, 4h, and 4i, which have the highest inhibition potency toward COX-2 were selected for the molecular docking studies to verify their inhibition and selectivity for COX-2 over COX-1 with their modified structure. The obtained theoretical studies are in agreement with the in vitro bioassay screening results, which supports the importance of the structural modifications for our studied compounds.

REGIO-AND STEREOSELECTIVE SYNTHESIS OF THIAZOLE-SUBSTITUTED HISTAMINE AND ADENINE DERIVATIVES BY NUCLEOPHILIC ATTACK AT ALLENYL ISOTHIOCYANATE

The ambident oligonucleophiles histamine and adenine were reacted with allenyl isothiocyanate to yield N-(5-methylthiazol-2-yl) substituted derivatives of the natural products. Whereas histamine led selectively in three clean steps or alternatively in a one-pot procedure to a final product bearing three thiazole units, adenine gave exclusively the mono derivative with a thiazolyl group at N-7. The regio- and stereochemistry of these transformations were proved by single-crystal X-ray analyses of the title compounds.

Molecular Docking Studies and X-ray Structure Determination of 1-{4-(Methylsulfonyl)phenyl}-5-phenyl-1H-tetrazole

The structure of 1-{4-(methylsulfonyl)phenyl}-5-phenyl-1H-tetrazole was determined by Xray crystallography. The latter crystallizes in the monoclinic space group Ia. The cell dimensions of the azole are a = 12.2393 (6) A, b = 12.4076 (6) A, c = 10.0409 (5) A,  = 112.5240 (5)°, V = 1408.50 (12) A 3 , and Z = 4, and its structure was refined to R1 = 0.0230, wR2 = 0.0614. The tetrazole ring is essentially planar, while the aryl rings at the 1- and 5-positions of this compound show consistent twist from the tetrazole plane, with tetrazole-aryl dihedral angles in the range of 38.63(4)° to 47.23(5)°. No strong intermolecular hydrogen bonds were observed. Docking study of the studied tetrazole with cyclooxygenase-2 enzyme was preformed. Amino acid residues in the binding site that interact with the molecule were identified and their interactions with the ligand were discussed.

In vitro anticancer, anti-inflammatory, and antioxidant potentials of Ephedra aphylla

Purpose: The goal of our study is to test whether a naturally occurring plant, Ephedra aphylla, will show antiproliferative ability against tested cell lines and to test its anti-inflammatory and antioxidative potentials. Materials and Methods: In our study, we used four solvents with different polarities – aqueous, chloroform, methanol, and n-hexane – to extract different compounds from the aerial parts of E. aphylla. Antioxidant activity of E. aphylla was determined by measuring nitric oxide (NO) and hydrogen peroxide (H2O2) scavenging activities. The anti-inflammatory activity was studied using the inhibition of albumin denaturation assay. Finally, the antiproliferative activity of breast cancer cell lines (T47D, MCF-7) and Vero cell line (African green monkey kidney) was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: Phytochemical screening for various extracts of E. aphylla showed the presence of medicinally important compounds including cardiac glycosides, alkaloids, triterpenes, tannins, and flavonoids. The scavenging activity for H2O2 of various solvent extracts was in the order of methanol > aqueous > chloroform > ethyl acetate > n-hexane. In addition, E. aphylla solvent extracts also exhibited a scavenging activity for NO in the order of methanol > ethyl acetate > aqueous > chloroform > n-hexane. All of the solvent extracts showed IC50 inhibition of albumin denaturation at a concentration between 209.5 ± 8.1 and 225 ± 11 μg/ml. Moreover, all extracts displayed strong antiproliferative potential against MFC7, T47D tested cell lines and very weak cytotoxic activity against Vero normal cell line. Conclusions: E. aphylla has a promising potential to be used as a drug source for breast cancer treatment based on its strong antiproliferative activity.

Synthesis and Characterization of Spectroscopically Encoded Nanocomposites

Three sulfur-containing styrene monomers with different leaving groups, 4-vinylphenyl ethanethioate, 1,2-bis(4-vinylphenyl)disulfane, and butyl(4-vinylphenyl)sulfane, were synthesized through nucleophilic substitution/addition reactions and purified through column chromatography. In aqueous solution, these monomers could bind to the surface of gold nanoparticles and form self-assembled monolayers (SAMs). SAMs were analyzed by Raman spectroscopy and showed SERS activity with enhancement factors of more than 10 5 . In addition, SAMs were also formed on the surface of gold/silver nano-island films. The bulk Raman and SERS spectra of monomers on different gold nanostructured materials were very similar. The enhancement factors and the formation of SAMs depended on monomer structure and fabrication method. Also depending on the deposition conditions, laser induced polymerization of the mercaptostyrene monomers SAMs was observed.