Synthesis of Murrayaquinone-A Derivatives and Investigation of Potential Anticancer Properties.

A series of novel murrayaquinone a derivatives were synthesized and their anti-cancer activity were evaluated on healthy colon cell lines (CCD-18Co), primary (Caco-2) and metastatic (DLD-1) colon cancer cell lines. The results showed that the cytotoxicity of murrayaquinone molecules is significantly high even in micromolar levels. The DNA binding, cell cycle arrest and metabolic activity studies of these molecules were also carried out and the results showed that these molecules induce apoptosis. In conclusion, the data support further studies on murrayaquinone derivatives toward selection of a candidate for cancer treatment.

Inhibition of human DNA topoisomerase IIα by two novel ellipticine derivatives.

Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an antineoplastic agent that intercalates into DNA and alters topoisomerase II activity. Unfortunately, this compound displays a number of adverse properties. Therefore, to investigate new ellipticine-based compounds for their potential as topoisomerase II-targeted drugs, we synthesized two novel derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2). As determined by DNA decatenation and cleavage assays, ET-1 and ET-2 act as catalytic inhibitors of human topoisomerase IIα and are both more potent than the parent compound. Neither compound impairs the ability of the type II enzyme to bind its DNA substrate. Finally, the potency of ET-1 and ET-2 as catalytic inhibitors of topoisomerase IIα appears to be related to their ability to intercalate into the double helix.

Synthesis of new ibuprofen derivatives with their in silico and in vitro cyclooxygenase-2 inhibitions.

Cyclooxygenase-2 (COX-2) is one of the important targets for treatment of inflammation related diseases. In the literature, most of drug candidates are first synthesized and then their COX-2 inhibitory activities are tested by in vitro and in vivo experiments. However, synthesis of dozens of drug analogues without any interpretations on their inhibitory activity can result in loss of time and chemicals. Therefore, synthetic drug designs with molecular modeling are of importance to synthesize selective drug candidates against inflammatory diseases. The synthesis of the novel ibuprofen derivatives through their in silico and in vitro COX-2 inhibitory activities were investigated in the present study. Starting from ibuprofen, ibuprofen amide and ibuprofen acyl hydrazone derivatives were synthesized. According to the results of the in silico molecular docking and in vitro enzyme inhibition studies, the synthesized novel ibuprofen derivatives have selective COX-2 inhibition, and molecule 3a and 3c were showed higher inhibition compared to ibuprofen. In conclusion, the newly synthesized ibuprofen derivatives can be used in model in vivo studies.

(4,9-Dimethyl-9H-carbazol-3-yl)meth-anol.

In the title compound, C15H15NO, the carbazole skeleton includes a methanol group at the 3-position. The indole ring system is almost planar [maximum deviation = 0.045 (2) Å]. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into zigzag chains along the b-axis direction. There are weak C-H⋯π inter-actions within the chains and linking neighbouring chains forming sheets lying parallel to (001).

2-{N-[(2,3,4,9-Tetra-hydro-1H-carbazol-3-yl)meth-yl]methyl-sulfonamido}-ethyl methane-sulfonate.

In the title compound, C17H24N2O5S2, the indole ring system is nearly planar [maximum deviation = 0.032 (1) Å] and the cyclo-hexene ring has a half-chair conformation. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into a chain running along the b-axis direction. Weak C-H⋯O hydrogen bonds and weak C-H⋯π inter-actions are observed between the chains.

Ethyl 4,9-dimethyl-9H-carbazole-3-carboxyl-ate.

In the title compound, C17H17NO2, the carbazole skeleton includes an eth-oxy-carbonyl group at the 3-position. The indole three-ring system is almost planar [maximum deviation = 0.065 (2) Å], and the ethyl ester group is inclined to its mean plane by 15.48 (2)°. In the crystal, there are π-π stacking inter-actions between parallel benzene rings and between parallel benzene and pyrrole rings of adjacent mol-ecules [centroid-centroid distances = 3.9473 (8) and 3.7758 (8) Å, respectively]. Weak C-H⋯π inter-actions are also present.

3,9-Dimethyl-2,3-dihydro-spiro-[carb-az-ole-1,2'-[1,3]dithio-lan]-4(9H)-one.

The title compound, C16H17NOS2, consists of a carbazole skeleton with methyl and dithiol-ane groups as substituents. In the indole ring system, the benzene and pyrrole rings are nearly coplanar, forming a dihedral angle of 1.02 (11)°. The cyclo-hexenone ring has a twisted conformation, while the dithiol-ane ring adopts an envelope conformation with one of the CH2 C atoms at the flap. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into supra-molecular chains nearly parallel to the c axis. These hydrogen bonds together with weak C-H⋯π inter-actions link the molecules into a three-dimensional supramolecular network.

2-{4-Methyl-N-[(2,3,4,9-tetra-hydro-1H-carbazol-3-yl)meth-yl]benzene-sulfon-amido}-ethyl 4-methyl-benzene-sulfonate.

In the title compound, C29H32N2O5S2, the indole ring system is nearly planar, with a maximum deviation of 0.013 (2) Å, and the cyclo-hexenone ring has an envelope conformation with the methine C atom as the flap. The two methyl-benzene rings are approximately perpendicular to each other, making a dihedral angle of 89.09 (8)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into a chain running along the a-axis direction, and weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions are observed between the chains.

Development of fluorescent array based on sol-gel/chitosan encapsulated acetylcholinesterase and pH sensitive oxazol-5-one derivative.

A highly sensitive fluorescent enzyme array for quantitative acetylcholine detection is developed. The enzyme array has been constructed by spotting of pH sensitive fluorophore 2-phenyl-4-[4-(1,4,7,10-tetraoxa-13-azacycloopentadecyl)benzylidene]oxazol-5-one and acetylcholinesterase doped in tetraethoxysilane/chitosan matrix via a microarrayer. The constructed tetraethoxysilane/chitosan network provided a microenvironment in which the enzyme molecule was active biologically. The optimal operational conditions for the array developed were investigated. The response of the developed biosensor array to acetylcholine was highly reproducible (RSD = 3.27%, n = 6). A good linearity was observed for acetylcholine in the concentrations up to 1 × 10(-8) M, with a detection limit of 0.27 × 10(-8) M.

2-(Naphthalen-1-yl)-4-(naphthalen-1-yl-methyl-idene)-1,3-oxazol-5(4H)-one.

In the title compound, C(24)H(15)NO(2), the oxazole ring is oriented at dihedral angles of 10.09 (4) and 6.04 (4)° with respect to the mean planes of the naphthalene ring systems, while the two naphthalene ring systems make a dihedral angle of 4.32 (3)°. Intra-molecular C-H⋯N hydrogen bonds link the oxazole N atom to the naphthalene ring systems. In the crystal, inter-molecular weak C-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers. π-π contacts between the oxazole and naphthalene rings and between the naphthalene ring systems [centroid-centroid distances = 3.5947 (9) and 3.7981 (9) Å] may further stabilize the crystal structure. Three weak C-H⋯π inter-actions also occur.

2-(Naphthalen-1-yl)-4-(thio-phen-2-yl-methyl-idene)-1,3-oxazol-5(4H)-one.

The asymmetric unit of the title compound, C(18)H(11)NO(2)S, contains two crystallographically independent mol-ecules. In one mol-ecule, the oxazole and thio-phene rings are oriented at dihedral angles of 17.40 (9) and 18.18 (7)° with respect to the naphthalene ring system, while the oxazole and thio-phene rings are oriented to each other at a dihedral angle of 0.86 (9)°. In the other mol-ecule, the corresponding angles are 3.05 (8), 9.62 (6) and 7.02 (8)°, respectively. In each mol-ecule, a weak intra-molecular C-H⋯N hydrogen bond links the oxazole N atom to the naphthalene group. Weak inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure. π-π stacking between the oxazole and thio-phene rings, between the thio-phene and naphthalene rings, and between the oxaozole and naphthalene rings, [centroid-centroid distances = 3.811 (2), 3.889 (2), 3.697 (2) and 3.525 (2) Å] may further stabilize the crystal structure.

Ethyl 4-oxo-2,3,4,9-tetra-hydro-1H-carbazole-3-carboxyl-ate.

In the title compound, C(15)H(15)NO(3), the carbazole skeleton includes an eth-oxy-carbonyl group at the 3-position. In the indole ring system, the benzene and pyrrole rings are nearly coplanar, forming a dihedral angle of 0.89 (4)°. The cyclo-hexenone ring has an envelope conformation. In the crystal, inter-molecular N-H⋯O and C-H⋯O hydrogen bonds link the mol-ecules into a three dimensional network. A weak C-H⋯π inter-action is also observed.

11-Butyl-3-meth-oxy-11H-benzo[a]carbazole.

The title compound, C(21)H(21)NO, consists of a carbazole skeleton with a meth-oxy-benzene ring fused to the carbazole, and a butyl group attached to the carbazole N atom. The carbazole skeleton is nearly planar [maximum deviation = 0.078 (2) Å], and it is oriented at a dihedral angle of 4.22 (4)° with respect to the adjacent meth-oxy-benzene ring.

Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase-negative cells.

BACKGROUND: DNA topoisomerase and telomerase enzymes are popular targets of several anti-tumor drugs. Smooth proceeding of telomeric recombination requires Topoisomerase II (Top2), which is involved in telomere-telomere recombination through functioning in relaxation of positive supercoils among the cells adopting telomerase-independent Alternative lengthening of telomere (ALT) pathway. Most of the inhibitors reported so far have been designed to targetsolely telomerase-positive cells, which can potentially lead to therapeutic failure because tumor cells treated with telomerase inhibitors can activate the ALT pathway for telomere maintenance. Knowing that ALT cells are more sensitive against a Top2 inhibitor, ICRF-93 agent, compared to telomerase-positive cells, we analyzed two selected ellipticine derivatives that we recently reported as TopII-targeting compounds, to assess their effects on the formation of DNA breaks and suppression of ALT pathway. METHODS: Cell viability, Comet, C-Circle assays, dot blot, immunofluorescence staining, and telomere fluorescence in situ hybridization (FISH) staining were used for determining the effect of the compounds on ALT status of tumor cells. RESULTS AND CONCLUSIONS: Treatment of ALT cells with ellipticine derivatives resulted in the formation of DNA breaks and suppression of ALT-associated phenotypes in vitro. Our results will contribute to the development of therapeutic strategies combining telomerase and ALT pathway inhibitors.

Synthesis and spectroscopic studies of 3,6-diphenyl-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dion's N,N'-dialkyl derivatives.

3,6-diaryl-2,5-dihydro-1,4-diketopyrrolo[3,4-c]pyrrole-1,4-dione (DPPD) derivatives are used commercially as red pigments, because of their color strength, brightness, and very low solubility in most common solvents. These products, although highly colored, appear to be of limited value as dyes, since they show a tendency to form an aggregate when incorporated into a solvent. Monoalkyl and dialkyl derivatives of DPPD were synthesized and then characterized with IR, 1HNMR, UV-Vis absorption and emission spectroscopy. Molar absorption coefficient, singlet energy level and Stokes' shift values of DPPD derivatives were declared. Monoalkyl and dialkyl derivatives of DPPD's solubilities were measured from saturated solutions of dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (ACN) and toluene and they are compared with each other.

Ethyl 4-hydr-oxy-9-tosyl-9H-carbazole-3-carboxyl-ate.

In the title compound, C(22)H(19)NO(5)S, the carbazole skeleton is nearly planar [maximum deviation = 0.043 (1) Å] with the pyrrole ring oriented at dihedral angles of 2.32 (6) and 1.77 (6)° with respect to the adjacent benzene rings. The dihedral angle between the benzene ring of the tosyl group and the carbazole skeleton is 82.25 (5)°. Intra-molecular O-H⋯O hydrogen bonding results in the formation of a planar six-membered ring, which is oriented at a dihedral angle of 3.06 (4)° with respect to the adjacent carbazole skeleton. In the crystal structure, weak inter-molecular C-H⋯O inter-actions link the mol-ecules into infinite chains and π-π contacts between the benzene rings and between the pyrrole and benzene rings [centroid-centroid distances = 3.374 (1) and 3.730 (1) Å, respectively] may further stabilize the structure. A weak C-H⋯π inter-action is also present.

Ethyl 1-oxo-1,2,3,4-tetra-hydro-9H-carbazole-3-carboxyl-ate.

The title compound, C(15)H(15)NO(3), contains a carbazole skeleton with an ethoxy-carbonyl group at the 3 position. In the indole ring system, the benzene and pyrrole rings are nearly coplanar, forming a dihedral angle of 1.95 (8)°. The cyclo-hexenone ring has an envelope conformation. In the crystal structure, pairs of strong N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers with R(2) (2)(10) ring motifs. π-π contacts between parallel pyrrole rings [centroid-centroid distance = 3.776 (2) Å] may further stabilize the structure. A weak C-H⋯π inter-action is also observed.

Neural Network Modeling of AChE Inhibition by New Carbazole-Bearing Oxazolones.

Acetylcholine esterase (AChE) is one of the targeted enzymes in the therapy of important neurodegenerative diseases such as Alzheimer's disease. Many studies on carbazole- and oxazolone-based compounds have been conducted in the last decade due to the importance of these compounds. New carbazole-bearing oxazolones were synthesized from several carbazole aldehydes and p-nitrobenzoyl glycine as AChE inhibitors by the Erlenmeyer reaction in the present study. The inhibitory effects of three carbazole-bearing oxazolone derivatives on AChE were studied in vitro and the experimental results were modeled using artificial neural network (ANN). The developed ANN provided sufficient correlation between several dependent systems, including enzyme inhibition. The inhibition data for AChE were modeled by a two-layered ANN architecture. High correlation coefficients were observed between the experimental and predicted ANN results. Synthesized carbazole-bearing oxazolone derivatives inhibited AChE under in vitro conditions, and further research involving in vivo studies is recommended. An ANN may be a useful alternative modeling approach for enzyme inhibition.

Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation.

AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [125I-Sar1-Ile8] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest.

Copper ion sensing with fluorescent electrospun nanofibers.

In this work, the use of electrospun nanofibrous materials as highly responsive fluorescence quenching-based copper sensitive chemosensor is reported. Poly(methyl methacrylate) and ethyl cellulose were used as polymeric support materials. Sensing slides were fabricated by electrospinning technique. Copper sensors based on the change in the fluorescence signal intensity of fluoroionophore; N'-3-(4-(dimethylamino phenly)allylidene)isonicotinohydrazide. The sensor slides exhibited high sensitivities due to the high surface area of the nanofibrous membrane structures. The preliminary results of Stern-Volmer analysis show that the sensitivities of electrospun nanofibrous membranes to detect Cu(II) ions are 6-20-fold higher than those of the continuous thin films. By this way we obtained linear calibration plots for Cu(II) ions in the concentration range of 10(-12)-10(-5)M. The response times of the sensing slides were less than 1 min. Stability of the employed ionophore in the matrix materials was excellent and when stored in the ambient air of the laboratory there was no significant drift in signal intensity after 6 months. Our stability tests are still in progress.