Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents

Abstract

New N-(5-methyl-4-phenylthiazol-2-yl)-2-(substituted thio)acetamides were synthesized and studied for their anticancer activity. The title compounds were procured by reacting 2-chloro-N-(5-methyl-4-phenylthiazol-2-yl)acetamide with some mercapto derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR and LC-MS/MS spectral data and elemental analyses. The synthesized compounds were investigated for their antitumor activities against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell line for determining their selective cytotoxicity. 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenylthiazol-2-yl)acetamide (4c) showed high selectivity, and whose IC₅₀ value was determined as 23.30?±?0.35?µM and >1000?µM against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell lines, respectively. 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4a) and 2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4c) exhibited the highest apoptosis percentage among those tested, but not as high as the standard, cisplatin.     

[Cu3(dppm)3(μ 3-I)2][(0.5TCNQ)], a radical salt derived from a donor with a copper(I) trimer

A radical salt 1, [Cu₃(dppm)₃(μ ₃-I)₂][(0.5TCNQ)], has been prepared by reaction of CuI, dppm (diphenylphosphinomethane) and TCNQ (7,7′,8,8′-tetracyanoquinodimethane) with a molar ratio of 1 : 1 : 0.5 and characterized by IR, UV–Vis and solid-emission spectroscopy. Its structure was determined by X-ray crystallography. 1 also has photoluminescence (λ _max = 653 nm) at room temperature. Magnetic properties indicate that TCNQ is in the reduced state (TCNQ^2?).     

Synthesis of poly[S-(2–9′-acridinylethyl)-L-cysteine] and its TCNQ salt

Poly[S-(2–9′-acridinylethyl)-L -cysteine] ( 5 ) was synthesized by the N-carboxy anhydride procedure. It was converted to the trifluoroacetic acid salt ( 6 ), which was treated with LiTCNQ in methanol to give the TCNQ anion radical salt ( 7 ). 7 showed electrical conductivity of 10^?8 S/cm at 295 K.     

Organic Diodes Based on Redox-Polymer Bilayer-Film-Modified Electrodes

The synthesis of four electropolymerizable 2,2′-bipyridinium salts with tuned reduction potential (E₁^°) is described (N,N′-ethylene-4-methyl-4′-vinyl-2,2′-bipyridinium dibromide ( 4 ; E₁^° ?–0.48 V), 4-methyl-N, N′-(trimethylene)-4′-vinyl-2,2′-bipyridinium dibromide ( 5 ; E₁^°? ?0.66 V), N,N′-ethylene-4-methyl-4′-[2-(1H-pyrrol-1-yl)ethyl]-2, 2′-bipyridinium bis(hexafluorophosphate) ( 6b ; E₁^°? ?0.46 V), and 4-methyl-4′-[2-(1H-pyrrol-1-yl)ethyl]-N, N′-(trimethylene)-2,2′-bipyridinium bis(hexafluorophosphate) ( 7b ; E₁^°? ?0.66 V)). E₁^°-Tuning is based on the torsional angle C(3)–C(2)–C(2′)–C(3′), imposed by the N,N′-ethylene and N,N′-(trimethylene) bridge. The vinylic compounds 4 and 5 undergo cathodic, the pyrrole derivatives 6b and 7b anodic electropolymerization on glassy carbon electrodes from MeCN solutions, yielding thin, surface-confined films with surface concentrations of redox-active material in the range 5 · 10^?9 < Γ < 2.10^?8 mol/cm², depending on experimental conditions. The modified electrodes exhibit reversible ‘diquat’ electrochemistry in pure solvent/electrolyte. Copolymerization of 6b or 7b with pyrrole yields most stable electrodes. Bi ayer-film-modified electrodes were prepared by sequential electropolymerization of the monomers. The assembly electrode/poly- 6b /poly- 7b behaves as a switch, it transforms – as a Schmitt trigger – an analog input signal (the electrode potential) into a digital output signal (redox state of the outer polymer film). Forward-(electrode/poly- 7b /poly- 6b ) and reverse-biased assemblies (electrode/poly- 6b /poly- 7b ) were coupled to the electrochemical reduction of redox-active solution species, e.g. N- (cyanomethyl)-N′-methyl-4,4′-bipyridinium bis(hexafluorophosphate) ( 8 ). Zener-diode-like behavior was observed. Aspects of redox-polymer multilayer-film assemblies, sandwiched between two electronic conductors, are discussed in terms of molecular electronic devices.     

Infrared and Raman spectroscopic evidence of ground state charge densities at TCNQ sites in crystalline Cs2 (TCNQ)3

The reported Raman spectrum of the Rb TCNQ salt allows, for the first time, examination of all the vibrational features of the TCNQ ^? radical anion. The knowledge of the TCNQ fundamental frequencies as well as of those for neutral TCNQ makes it possible to interpret the infrared and Raman spectra of Cs₂ (TCNQ)₃ and to conclude that in this salt both neutral and negatively charged TCNQ units are present in the crystal. The result is a first fruitful application of vibrational spectroscopy to the study of complex TCNQ salts, opening the way to an extensive investigation of TCNQ semiconducting salts.     

Ruthenium(II)-Phthalocyaninate(2–): Darstellung und Eigenschaften von Acido(carbonyl)phthalocyaninato(2–)ruthenat(II), [Ru(X)(CO)Pc2−]− (X = Cl,Br, I,NCO, NCS,N3)

Ruthenium(II) Phthalocyaninates(2–): Synthesis and Properties of (Acido)(carbonyl)phthalocyaninato(2–)ruthenate(II), [Ru(X)(CO)Pc^2?]^? (X = Cl, Br, I, NCO, NCS, N₃) (ⁿBu₄N)[Ru(OH)₂Pc^2?] is reduced in acetone with carbonmonoxid to blue-violet [Ru(H₂O)(CO)Pc^2?], which yields in tetrahydrofurane with excess (ⁿBu₄N)X acido(carbonyl)phthalocyaninato(2–)ruthenate(II), [Ru(X)(CO)Pc^2?]^? (X = Cl, Br, I, NCO, NCS, N₃) isolated as red-violet, diamagnetic (ⁿBu₄N) complex salt. The UV-Vis spectra are dominated by the typical π-π* transitions of the Pc^2? ligand at approximately 15100 (B), 28300 (Q₁) und 33500 cm^?1 (Q₂), only fairly dependent of the axial ligands. v(C? O) is observed at 1927 (X = I), 1930 (Cl, Br), 1936 (N₃, NCO) 1948 cm^?1 (NCS), v(C? N) at 2208 cm^?1 (NCO), 2093 cm^?1 (NCS) and v(N? N) at 2030 cm^?1 only in the MIR spectrum. v(Ru? C) coincides in the FIR spectrum with a deformation vibration of the Pc ligand, but is detected in the resonance Raman(RR) spectrum at 516 (X = Cl), 512 (Br), 510 (N₃), 504 (I), 499 (NCO), 498 cm^?1 (NCS). v(Ru? X) is observed in the FIR spectrum at 257 (X = Cl), 191 (Br), 166 (I), 349 (N₃), 336 (NCO) and 224 cm^?1 (NCS). Only v(Ru? I) is RR-enhanced.     

O-Protonation of α-Diazoketones in Super-strong Acids

Primary diazoketones, R? CO? CHN₂, are O-protonated in HF? SbF₅? SO₂ or FSO₃H? SbF₅? SO₂ at ?60°, as observed by NMR. The OH-proton resonates at 9.3–9.6 δ and is coupled with H? C 1 (J = 1–2.5 Hz). Secondary diazoketones, R? CO? C(N₂)? R, when protonated, give an OH-singlet at 8.85 δ. The assignments are corroborated by use of deuterated diazoketones, R? CO? CDN₂, or deuterated acid, FSO₃D. Primary diazoketones react with FSO₃H at ?60° to ?15°, giving products assigned the fluorosulfate structure, R? CO? CH₂? OSO₂F; they do not exchange H? C 1 with solvent before or during decomposition. Intermediate C-protonated diazonium ions and α-oxo-carbonium ions (vinyl carbonium ions) have not been identified. 3-Diazo-4-methyl-2-pentanone (VIII) reacts with FSO₃H at ?15°, eliminating N₂ and giving protonated mesityl oxide by a strictly intramolecular hydride shift.     

MEM(TCNQ)2 at room temperature and 10 K,and the absence of a spin‐Peierls transition

Precise X‐ray determinations of the crystal structure of the 1:2 complex of N‐ethyl‐N‐methyl­morpholinium and 7,7,8,8‐tetra­cyano‐p‐quinodi­methanide, abbreviated as MEM–TCNQ or MEM(TCNQ)₂ (C₇H₁₆NO⁺·2C₁₂H₄N₄^0.5?), have been performed at 293 and at 10 K. Evidence for the expected spin‐Peierls transition at 19 K is not found, and this may follow from radiation damage to the crystal or from insufficient equipment sensitivity.     

Synthesis of 4‐Aryl‐4,6‐dihydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐diones from Biginelli Compounds

Biginelli compounds 1 were first brominated at Me? C(6) with 2,4,4,6‐tetrabromocyclohex‐2,5‐dien‐1‐one to give Br₂CH? C(6) derivatives 2 . The hydrolysis of the 6‐(dibromomethyl) group of 2c to give the 6‐formyl derivative 3c in the presence of an expensive Ag salt followed by reaction with N₂H₄?H₂O yielded tetrahydropyrimido[4,5‐d]pyridazine‐2,5(1H,3H)‐dione ( 4c ; Scheme 1). However, treatment of the 6‐(dibromomethyl) derivatives 2 directly with N₂H₄?H₂O led to the fused heterocycles 4 in better overall yield (Schemes 1 and 2; Table).     

Synthesis,crystal structure and characterization of a series of complexes constructed from coordinated Lanthanides(III) and the heteropolyanion [SiMo12O40]4−

The reaction of α-[SiMo₁₂O₄₀]^4? with trivalent cations Ln³⁺ and N-methyl-2-pyrrolidone leads to a series of complexes of formula [Ln(NMP)₄(H₂O) _n ]H[SiMo₁₂O₄₀]?·?2NMP?·?mH₂O [where Ln?=?La (1), Pr (2), Nd (3), Sm (4), Gd (5), n?=?4, Ln?=?Dy (6), Er (7), n?=?3. NMP?=?N-methyl-2-pyrrolidone]. The syntheses, X-ray crystal structures, IR, and ESR spectra and thermal properties of the complexes 1, 2, 4, 6, 7 have been reported previously. Here, we report X-ray crystal structures, IR, UV, ESR spectra and thermal properties of the complexes [Nd(NMP)₄(H₂O)₄]H[SiMo₁₂O₄₀]?·?2NMP?·?1.5H₂O (3), and [Gd(NMP)₄(H₂O)₄]H[SiMo₁₂O₄₀]?·?2NMP?·?H₂O (5). In addition, the electrochemical behaviour of this series of complexes in aqueous solution and aqueous-organic solution has been investigated and systematic comparisons have been made. All these complexes exhibit successive reduction process of the Mo atoms.     

Oxidation of thiosulfate by manganese(III) and nickel(III) complexes: A kinetic and mechanistic investigation

The kinetics of the oxidation of thiosulfate ion by [Mn(Y)]^? (H₄Y = trans-cyclohezane-1,2-dimine-N,N,N′,N′-tetraacetic acid) and [Ni(L¹)]²⁺ (HL¹ = 15-amino-3-methyl-4,7,10,13-tetraazapentadec-3-en-2-one oxime) have been investigated at 20.0, 30.0, and 40.0°C in aqueous solution and found to follow the general rate law ?d/dt [complex] = k_ox[S₂O₃^2?] [complex]. The large negative entropy (ΔS?) of activation for the reactions and the results of Marcus calculation provide support for inner-sphere mechanism to be operative. © 1995 John Wiley & Sons, Inc.     

Association equlibria in acetonitrile solution of tetracyanoquinodimethanides

Trimetric ion (TCNQ)^2?₃ has been discovered in mixed solutions of TCNQ and LiTCNQ in acetonitrile. The estimated association constant isK_T = 5.6 × 10¹⁰ øl² mol^?2.     

Lanthanide complex of 1-phenyl-3-methyl-5-hydroxypyrazole-4-carbaldehyde-(isonicotinoyl) hydrazone: crystal structure and DNA-binding properties

A Schiff-base ligand derived from 1-phenyl-3-methyl-4-formyl-2-pyrazolin-5-one (PMFP) and isoniazid was prepared and its La(III) complex was characterized by X-ray single crystal diffraction. The La(III) is nine-coordinate in a space group P2₁/n. DNA-binding was investigated by UV-Vis, fluorescence titration, ethidium bromide displacement experiments, and viscosity measurements, which indicated that the ligand and La(III) complex strongly binds to calf thymus DNA presumably via groove binding and intercalation. The intrinsic binding constants of the ligand and La(III) complex were 0.86?×?10⁵ and 2.46?×?10^5?mol?L^?1, respectively. Antioxidant data from hydroxyl radical scavenging experiments in vitro suggest that the La(III) complex possesses higher scavenging ratio than the free ligand, metallic salt, and some standard antioxidants like mannitol.     

Radical polymerization of methyl methacrylate initiated by an enolizable ketone–carbon black system

The polymerization of methyl methacrylate (MMA) initiated by an enolizable ketone (R₁? CO? CH₂? CO? R₂)-carbon black system was investigated. Although enolizable ketone itself could not do so, the polymerization of MMA was initiated by enolizable ketone in the presence of carbon black. In addition, a chloranil-enolizable ketone system was able to initiate the polymerization of MMA. It was found that the enol form of the ketone and quinonic oxygen groups on the carbon black surface played an important role in the initiation system; namely, it was considered that the polymerization was begun by the ketone radical (R₁? CO? CH? CO? R₂) formed by a one-electron transfer reaction from enolate ion to quinonic oxygen groups. The effect of solvent on the process was also studied. The rate of the polymerization increased, depending on the solvent used, in the following order: benzene < 1,4-dioxane < dimethyl sulfoxide < N,N-dimethylformamide < N-methyl-2-pyrrolidone. Furthermore, it became apparent that during the polymerization poly(methyl methacrylate) was grafted onto the carbon black surface (grafting ratio was ca. 40% when benzene was used as solvent) and the carbon black obtained gave a stable colloidal dispersion in organic solvent.     

Reaction of a 2H-1,2,3-Diazaphosphole with Ethane-1,2-Dithiol

Abstract

Reaction of 2-acetyl-5-methyl-2H-1,2,3-diazaphosphole with ethane-1,2-dithiol at ?30°C leads to the formation of 2-acetyl-3-(β-mercaptoethylthio)-5-methyl-1,2,3-diaza-phospholene. On heating, this product forms 2-(β-mercaptoethylthio)-1,3,2-dithia-phospholane, 1,2-bis(1,3,2-dithiaphospholanyl)-dithioethane, and N-acetyl-N′-isopropilidene-hydrazine.     

Chemical stability and electroconductivity of 7,7,8,8-tetracyanoquinodimethane salts containing polycation polymers

The chemical and electrical stabilities of 7,7,8,8-tetracyanoquinodimethane (TCNQ) salts composed of neutral TCNQ (TCNQ^?), anion radicals of TCNQ(TCNQ^?·), and polycation polymers were studied by measuring their electronic spectra and resistivities (ρ). The results of spectral and chemical analyses confirmed that TCNQ^?· in TCNQ salts was decomposed to α,α-dicyano-p-toluoylcyanide (DTC^?) as the final product by the intermediate formation of TCNQ^? and p-phenylenediamalononitrile (H₂TCNQ) and that H₂O played an important part in the reaction. From these results it was concluded that TCNQ salts are decomposed by two reaction processes: The resistivity of TCNQ salts increases with the decomposition of TCNQ^?·. Studies on electroconductivity of TCNQ salts assume that the change in resistivity arises from the loss of unpaired electrons which become conduction carriers and also from the disintegration of the TCNQ^? and TCNQ^?· complex which forms the conduction path.     

DR. Maurits Dekker: A Pioneer in Scientific Publishing

Abstract

Organic salts as initiators [A? ⁺B^?: Ph?₃C⁺ClO^? ₄, Ph?₃C⁺SbCl^? ₆, (?)Sp? ⁺ClO^? ₄, and (?)(Sp)?₂ ³⁺(ClO₄)^? ₃] and catalysts [A ⁺B?^?: (+)CSA?; A? ⁺B?^?: ph?₃C⁺(+)CSA?^? and (?)Sp?⁺(+)CSA?^?] are prepared and characterized by the dissociation constant (K _d), fraction of free ions (α), and specific rotation. The asymmetrically stereoselective induction of the initiators and catalysts in the polymerization of N-vinylcarbazole is in the order A? ⁺B?^? > A ⁺B?^? > A? ⁺B^?. The specific rotations of the poly(N-vinylcarbazole) (PVCZ)s obtained are generally in this order.     

12α-hydroxy-N-demethyl-sauroxine,a lycodane type alkaloid from Phlegmariurus saururus

Abstract

12α-hydroxy-N-demethyl-sauroxine (1), another new Lycopodium alkaloid from the Lycodane group, was isolated from Phlegmariurus saururus (Lam.) B. Øllg. (Lycopodiaceae). Elucidation of the chemical structure and relative stereochemistry were stated by spectroscopic data and chemical correlation. In addition, the inhibitory activity on acetylcholinesterase for 1 was determined as well as for N-methyllycodine (2), a derivative with the same nucleus, previously identified in P. saururus (IC₅₀ = 33.8?±?0.8?μM and 547.5?±?0.5?μM, respectively) and N-demethylsauroxine (3) whose inhibition in the actual conditions was better than the previously informed.     

First report of anti-inflammatory chromenyl derivatives from the spineless cuttlefish Sepiella inermis

Abstract

The spineless cuttlefish Sepiella inermis encompasses a major share in the marine fisheries sector, and represents as a culinary delicacy in many cultures. Bioactivity-guided fractionation of methanol:ethyl acetate (MeOH:EtOAc, 1:1) extract of the edible parts of the species ensued in identification of two hexahydro chromenyl analogues namely, methyl 7-ethyl-hexahydro-8a-methyl-2H-chromene-4-carboxylate (1) and methyl 1-acetoxy-hexahydro-3-methyl-3-propyl-1H-isochromene-4-carboxylate (2). The isolated metabolites were checked for their radical scavenging and anti-inflammatory potentials by selective in vitro models. The isochromenyl derivative exhibited potential 2,2-diphenyl-1-picryl-hydrazil and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (IC₅₀?<?0.45?mg mL^?1) radical-scavenging capacities along with pro-inflammatory cyclooxygenase-2 (COX-2) (IC₅₀ 0.75?mg mL^?1) and 5-lipoxygenase (5-LOX) (IC₅₀ 0.77?mg mL^?1) inhibitory activities. The titled compounds displayed the selectivity indices (IC₅₀ anti-COX-1/IC₅₀ anti-COX-2) greater than 1.25, in comparison with synthetic anti-inflammatory drug ibuprofen (0.44), which attributed to their greater selectivity towards inducible pro-inflammatory enzyme COX-2.     

Reactions of <Emphasis Type="Italic">N</Emphasis>-and <Emphasis Type="Italic">C</Emphasis>-Alkenylanilines: VII. Synthesis of Indole Heterocycles from Products of Reaction between <Emphasis Type="Italic">N</Emphasis>-Mesyl-2-(1-alken-1-yl)anilines and Halogens

N-Mesyl-2-(1-methyl-1-butenyl)-6-methylaniline reacted with Br₂ to afford N-mesyl-2-(3-bromo-1-penten-2-yl)aniline that under treatment with NH₃ or amines underwent cyclization into N-mesyl-7-methyl-3-methylene-2-ethylindoline. The reaction of N-mesyl-2-(1-methyl-1-buten-1-yl)-4-methyl- and 2-(1-methyl-1-buten-1-yl)aniline with Br₂ gave rise to the corresponding N-mesyl-2-(2-bromo-1-methyl-1-buten-1-yl)anilines. Under the similar conditions N-tosyl-2-(1-cyclohexen-1-yl)aniline was converted into N-tosyl-2-(6-bromo-1-cyclohexen-1-yl)aniline that under treatment with NH₃ furnished N-tosyl-1,2,3,9a-tetrahydrocarbazole. The reaction of N-mesyl-1,2,3,9a-tetrahydrocarbazole with CuBr₂ in MeOH afforded N-mesyl-4-methoxy-1,2,3,4-tetrahydrocarbazole. N-Mesyl-6-methyl-2-(1-cyclopenten-1-yl)aniline in reaction with Br₂ in the presence of NaHCO₃ was oxidized into the corresponding cyclopentenone, and with NBS it gave N-mesyl-2-(2-bromo-1-cyclopenten-1-yl)aniline.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 730–737.Original Russian Text Copyright © 2005 by Gataullin, Sotnikov, Spirikhin, Abdrakhmanov.