Spiroisoxazoline Derivatives Research Articles

Anti-cancer Activity Evaluation of Naphthalenonic and Chromanonic Spiroisoxazoline Derivatives as Selective COX-2 Inhibitors on HT29 Cell Lines

Background: Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be highly expressed in various types of cancer cells. On the other hand, it is well documented that chemical compounds with spiro scaffolds in their structure could be effective chemical agents against cancer types. Objective: In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing naphthalinone and chromanone spiro-bridge were investigated. Methods: The cytotoxicity effects of compounds 7a-7h were evaluated by performing the MTT assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney) cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected to analyze the cell cycle and apoptosis mechanism. Results: The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of compounds 7b (IC50 value: 1.07±0.28 µM) and 7f (IC50 value: 11.92±1.07 µM). None of the compounds had a toxic effect on normal HEK-293 cells, except for compound 7g with an IC50 value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin, known as anti-cancer agents. Subsequently, compound 7e with significant yield and cytotoxic activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound 7e induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells Conclusion: The selective COX-2 inhibitor compounds with spiroisoxazoline core structure could be suitable scaffolds for cytotoxic effects.

Design and Synthesis of C-8 spiro-isoxazoline analogues of 14-Deoxy-11,12-didehydroandrographolide (14-DDA) for dual targeting of CDK4 and BCL2 mediated anticancer activity

14-Deoxy-11,12-didehydroandrographolide (14-DDA, 3), a secondary metabolite found in Andrographis paniculata nees, has been synthetically modified into a new series of C-8 spiro-isoxazoline derivatives. Andrographolide and its derivatives were well reported for the anticancer activity so herein we have synthesised C-8 spiro-isoxazoline derivatives (4a-l) and screened for in vitro studies against four human cancer cell lines: breast (MCF-7), lung (A549), pancreatic (MiaPaCa-2), and prostate (PC-3). Most of the synthesized compounds exhibited better anti-cancer activities than the parent natural products andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (3) for different human cancer lines. Among all compounds, compound 4k displayed most potent cytotoxicity (IC50 =3 μM) in breast cancer cells (MCF-7). Further, mechanistic studies revealed that compound 4k affected the nuclear morphology of MCF-7 cells, increased the production of cellular and mitochondrial ROS, decreased the mitochondrial membrane potential (MMP), and inhibited the colony formation. The compound 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. The expression of Cdk-4 was also downregulated by 4k. The overall findings of this study indicate that the compound 4k exhibited significant anticancer activity with reduced toxicity in-vitro and might thus be a promising anti-cancer lead candidate.

Insights into the Corrosion Inhibition Performance of Three 2-Isoxazoline-γ-Lactones for Carbon Steel in Acidic Medium: Linking Molecular and Experimental-Level Information with Microscopic-Scale Modeling

The corrosion inhibition properties of three spiro-isoxazoline derivatives, namely 3,4-diphenyl-1,7-dioxa-2-azaspiro[4.4]non-2-en-6-one (DDA), 3-phenyl-4-(p-tolyl)-1,7-dioxa-2-azaspiro[4.4]non-2-en-6-one (PDA) and 4-(4-methoxyphenyl)-3-phenyl-1,7-dioxa-2-azaspiro[4.4]non-2-en-6-one (MDA) on carbon steel in 1.0 mol/L HCl acid medium were experimentally and computationally investigated. The experimental results showed that the inhibitory efficiency reached remarkable values of 76.26, 80.31, and 82.91%, respectively, for DDA, PDA and MDA at a maximum concentration of 10−3 mol/L. The potentiodynamic polarization curves (PPCs) showed that investigated compounds had a mixed type character, controlling both anodic and cathodic corrosion reactions. In addition, electrochemical impedance spectroscopy (EIS) indicated that the addition of increasing concentration of tested compounds to HCl solutions led to a significant increase in the polarization resistance of the carbon steel, which was accompanied with a simultaneous decrease in the double layer capacitance. On the other hand, the morphological study of the metal surface by scanning electron microscope (SEM) and energy dispersive X-ray (EDX) confirmed the effective protection of the carbon steel by the inhibitors against corrosion through the formation of a protective film on its surface. The adsorption characteristics of investigated compounds on carbon steel were assessed at microscopic level using Density Functional Based Tight Binding (DFTB) simulation, which revealed the formation of covalent bonds between inhibitors’ atoms and Fe atoms. Furthermore, additional insights into the compounds’ reactivity and adsorption configurations on steel surface were obtained from global reactivity descriptors and Monte Carlo simulation. The present work’s outcomes are interesting for further design and performance evaluation of effective organic corrosion inhibitors for acid environments.

Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents

ObjectiveA new family of 3′-(Mono, di or tri-substituted phenyl)-4′-(4-(methylsulfonyl) phenyl) spiroisoxazoline derivatives containing indanone spirobridge was designed, synthesized, and evaluated for their selective COX-2 inhibitory potency and cytotoxicity on different cell lines. MethodsA synthetic reaction based on 1,3-dipolar cycloaddition mechanism was applied for the regiospecific formation of various spiroisoxazolines. The activity of the newly synthesized compounds was determined using in vitro cyclooxygenase inhibition assay. The toxicity of the compounds was evaluated by MTT assay. In addition, induction of apoptosis, and expression levels of Bax, Bcl-2 and caspase-3 mRNA in MCF-7 cells were evaluated following exposure to compound 9f. The docking calculations and molecular dynamics simulation were performed to study the most probable modes of interactions of compound 9f upon binding to COX-2 enzyme. ResultsThe docking results showed that the synthesized compounds were able to form hydrogen bonds with COX-2 involving methyl sulfonyl, spiroisoxazoline, meta-methoxy and fluoro functional groups. Spiroisoxazoline derivatives containing methoxy group at the C-3′ phenyl ring meta position (9f and 9g) showed superior selectivity with higher potency of inhibiting COX-2 enzyme. Furthermore, compound 9f, which possesses 3,4-dimethoxyphenyl on C-3′ carbon atom of isoxazoline ring, exhibited the highest COX-2 inhibitory activity, and also displayed the most potent cytotoxicity on MCF-7 cells with an IC50 value of 0.03 ± 0.01 µM, comparable with that of doxorubicin (IC50 of 0.062 ± 0.012 µM). The results indicated that compound 9f could promote apoptosis. Also, compared to the control group, the mRNA expression of Bax and caspase-3 significantly increased, while that of Bcl-2 significantly decreased upon exposure to compound 9f which may propose the activation of mitochondrial-associated pathway as the mechanism of observed apoptosis. ConclusionIn vitro biological evaluations accompanied with in silico studies revealed that indanone tricyclic spiroisoxazoline derivatives are good candidates for the development of new anti-inflammatory and anticancer (colorectal and breast) agents.

Synthesis of novel spiro-pyrazole and spiro-isoxazoline derivatives of 9α- and 9β-hydroxyparthenolide

A series of novel spiropyrazoles and spiroisoxazolines was efficiently synthesized. Structural modifications were performed at the C-9 and C-13 positions of 9α- and 9β-hydroxyparthenolide, which were isolated from the aerial parts of Anvillea radiata. The structures and stereochemistry of the cycloadducts were fully established by spectroscopic methods including X-ray diffraction data.

Design, synthesis and biological evaluation of new tricyclic spiroisoxazoline derivatives as selective COX-2 inhibitors and study of their COX-2 binding modes via docking studies

A new series of 3′-(4-substitutedphenyl)-4′-(4-(methylsulfonyl)phenyl) spiroisoxazoline derivatives containing naphthalenone and chromanonespiro-bridge were synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. A synthetic reaction based on the 1,3-dipolar cycloaddition mechanism was used for the regiospecific formation of various spiroisoxazolines. One of the analogs, i.e., compound 7h, as the representative of the series was recrystallized and characterized structurally by single-crystal X-ray diffraction method. Moreover, the 3D structures of the synthesized compounds were docked into the COX-2 binding site to determine their most probable binding modes once the drug-receptor complexes are formed.

Synthesis and investigation of novel spiro-isoxazolines as anti-cancer agents

A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 values ranging from 43μM to 56μM.

In-silico Investigation of Tubulin Binding Modes of a Series of Novel Antiproliferative Spiroisoxazoline Compounds Using Docking Studies.

Interference with microtubule polymerization results in cell cycle arrest leading to cell death. Colchicine is a well-known microtubule polymerization inhibitor which does so by binding to a specific site on tubulin. A set of 3', 4'-bis (substituted phenyl)-4'H-spiro [indene-2, 5'-isoxazol]-1(3H)-one derivatives with known antiproliferative activities were evaluated for their tubulin binding modes. 3D structures of the derivatives were docked into the colchicine binding site of tubulin using GOLD 5.0 program under flexible ligand and semi-flexible receptor condition. The spiroisoxazoline derivatives bind tubulin in a similar manner to colchicine by establishing at least a hydrogen bonding to Cys(241) as well as hydrophobic interactions with Leu(255), Ile(378) and Lys(254) and few other residues at the binding pocket. It can be concluded that the spiroisoxazoline core structure common to the studied derivatives is a suitable scaffold for placing the antitubulin pharmacophoric groups in appropriate spatial positions required for tubulin binding activity.

Synthesis of resorcinol derived spironitronates.

Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide novel spiroisoxazoline derivatives.

Theoretical study of reaction mechanism and regioselectivity of spiro-isoxazoline derivatives synthesized by intermolecular 1,3-dipolar cycloaddition

The reaction mechanism and regioselectivity of spiro-isoxazoline derivatives synthesized by an intermolecular 1,3-dipolar cycloaddition reaction between 2,6-dichlorobenzonitrile oxide and 3-(4-chlorobenzylidene)dihydrofuran-2-one were studied using density functional theory and ab initio theory. Two possible reaction channels, which are related to the formation of isoxazoline-5-spiro-cyclic (Channel 1) and isoxazoline-4-spiro-cyclic (Channel 2) are investigated using natural bond orbital analysis, geometrical parameters analysis, energy analysis and frontier molecular orbital (FMO) analysis. The energy analysis shows that both the activation energy and reaction energy for Channel 2 are higher than those for Channel 1. The larger activation energy prevents the formation of isoxazoline-4-spiro-cyclic. Therefore, isoxazoline-5-spiro-cyclic is formed as the energetically favored product. The FMO analysis shows that the regioselectivity of this reaction is controlled by the LUMO dipole–HOMO dipolarophile interaction, and the reaction proceeds via Channel 1 which agrees with the experimental results. The natural bond order analysis shows the reaction follows a concerted mechanism with two bonds formed at about the same time.

Stereochemistry of some spiropyrazolines and spiroisoxazolines

The stereochemistry and conformational behaviour of spiropyrazoline and spiroisoxazoline derivatives (2–5) obtained by regio- and stereoselective cycloaddition of 1 (2-arylidene-1-tetralone, 3-arylidene-1-thiochromanone, -chromanone and -flavanone) to C-2-(5-nitrofuryl)-N-methylnitrile imine, C-2-(5-nitrofuryl)-N-phenylnitrile imine, C-(4-nitrophenyl)-N-methylnitrile imine and 4-nitrobenzonitrile oxide were investigated by one- and two-dimensional 1H, 13C and 15N NMR spectroscopy. The sites of the conformational equilibria were also evaluated.

ChemInform Abstract: Oxidative Cyclization of o‐Phenolic Oxime‐Acid Derivatives Using Phenyliodonium Diacetate: Synthesis of Spiroisoxazoline Derivatives.

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Oxidative cyclisation of o-phenolic oxime-acid derivatives using phenyliodonium diacetate: Synthesis of spiroisoxazoline derivatives

An efficient formation of spiroisoxazoline ring system by intramolecular oxidative cyclisation of o-phenolic oxime-esters and oxime-amides using phenyliodonium diacetate (PIDA) is described. The intramolecular oxidative cyclisation of various o-phenolic oxime-acid derivatives in acetonitrile at 0 °C proceeded smoothly to afford spiroisoxazolines in good yields. Synthesis of o-phenolic oxime-esters and oxime-amides was also described.

Formation of Novel Isoxazoline Spiro Compounds by a Reaction of Aryl Substituted a-Nitroacrylates with Titanium Tetrachloride and Toluene

New spiroisoxazoline derivatives were synthesized via novel cyclization of arylsubstituted α-nitroacrylates (naphthyl and phenanthryl analogues) with TiCl 4 and toluene. The structural determination by single crystal X-ray analysis is reported