Search Results (16)

A series of 3-azabicyclo[3.1.0]hexanes and cyclopropa[a]pyrrolizidines spiro-fused to acenaphthylene-1(2H)-one and aceanthrylene-1(2H)-one frameworks have been studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), melanoma (Sk-mel-2), osteosarcoma (U2OS), as well as murine melanoma (B16) cell lines. Using confocal microscopy, it was found that cultivation with the tested spiro-fused compounds led to the disappearance of stress fibers (granular actin was distributed diffusely in the cytoplasm in up to 56% of treated cells) and decrease in filopodia-like deformations (up to 69% after cultivation), which indirectly suggests a decrease in cell motility. The human melanoma cell line scratch test showed that these cells lose their ability to move after cultivation with the tested spiro-fused compounds and do not fill the scratched strip. This was also supported by docking simulations with actin-related targets (PDB ID: 8DNH, 2Q1N). Using flow cytometry, the impact on the mitochondrial membrane potential showed that the tested compounds led to a significant increase in the number of cells with decreased mitochondrial membrane potential from 10% for the control up to 55–80% for the cyclopropa[a]pyrrolizidine adducts. The obtained results support the antitumor effect of the tested spiro-compounds and encourage the extension of the study in order to improve their anticancer activity as well as reduce their toxicological risks. Full article

Background: A series of spiro-fused heterocyclic compounds containing cyclopropa[a]pyrrolizidine-2,3′-oxindole and 3-spiro[3-azabicyclo[3.1.0]-hexane]oxindole frameworks were synthesized and studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), acute T cell leukemia (Jurkat), melanoma (Sk-mel-2) and breast cancer (MCF-7) as well as mouse colon carcinoma (CT26) cell lines. Methods: Cell proliferation was evaluated in vitro by MTS assay. Confocal microscopy was used to study actin cytoskeleton structure and cell motility. Cell cycle analysis was evaluated by flow cytometry. Results: It was found that compounds 4, 8, 18 and 24 showed antiproliferative activity against the Jurkat, K-562, HeLa and Sk-mel-2 cell lines with IC₅₀ ranging from 2 to 10 μM (72 h). Evaluation of the impact on cell cycle progression showed that the tested compounds achieved significant cell-cycle perturbation with a higher accumulation of cells in the SubG1 and G0/G1 phases of the cell cycle, in comparison to the negative control. I Incubation with tested compounds led to the disappearance of stress fibers (granular actin was distributed diffusely in the cytoplasm in up to 38% of treated HeLa cells) and changes in the number of filopodia-like deformations (reduced from 93% in control cells to 64% after treatment). The impact on the Sk-mel-2 cell actin cytoskeleton structure was even greater: granular actin was distributed diffusely in the cytoplasm in up to 90% of treated cells while the number of filopodia-like deformations was reduced by up to 23%. A scratch test performed on the human melanoma cell line showed that these cells did not fill the scratched strip and lose their ability to move under treatment. Conclusions: The obtained results support the antitumor effect of the tested spiro-compounds and encourage the extension of this study in order to improve their anticancer activity as well as reduce their toxicological risks. Full article

Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using the recently proposed diffusion mixing technique, which led to ~5–15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. Full article

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC₅₀ = 1.09 mg/mL and IC₅₀ = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC₅₀ = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out. Full article

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC₅₀ 2.0 ± 0.5 μM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC₅₀ 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV. Full article

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI₂ is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH₂Cl or Boc₂O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH₂Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H₂O₂ or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2. Full article

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades. Full article

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths. Full article

A series of new spiro-heterocycles engrafted spirooxindole/pyrrolidine/thiochromene scaffolds was synthesized by the three-component 1,3-dipolar cycloaddition reactions in a fully controlled regio- and stereo-selective fashion. Condensation of several substituted isatin derivatives with L-proline generated the azomethine ylides which subsequently reacted with chalcones based thiochromene scaffold, and finally afforded the target spiro-compounds. This simple protocol furnished a structurally complex, biologically relevant spiro-heterocycles in good yields through a one-pot process. All synthesized chalcone-based thiochromene, along with the spirooxindole/pyrrolidine/thiochromene scaffolds, were tested for their anticancer activity against four cancer cell lines (PC3, HeLa, MCF-7, and MDA-MB231). Toxicity of these compounds was also evaluated against human fibroblast BJ cell line, and they appeared to be not cytotoxic. For the prostate cancer (PC3) cell line, the most active hybrid, among synthesized series, was compound (7f, IC₅₀ = 8.7 ± 0.7 µM). The most potent spirooxindole/pyrrolidine/thiochromene hybrid against cervical (HeLa) cancer cells was compound (7k, IC₅₀ = 8.4 ± 0.5 µM) having chlorine and p-trifluoromethyl substituents attached to phenyl rings. Finally, against the MCF-7 and MDA-MB231 breast cancer cell lines, compound (7d) was the most active member of this series (IC₅₀ = 7.36 ± 0.37, and 9.44 ± 0.32 µM, respectively). Full article

Attempted RCM of 2,2'-bis(allyloxy)-1,1'-binaphthyl resulted in a Claisen-type rearrangement of a postulated labile dioxacyclodecine proceeding at room temperature and followed by [2+2] cycloaddition. Structures of products were confirmed by X-ray crystallography. A mechanistic rationalisation based on relative stabilities of proposed intermediates and transition states is provided. Full article

Homophthalic anhydride reacts with different aromatic amines to produce N-substituted homophthalimides. Bromination of the latter produces 4,4-dibromo-homophthalimide derivatives that can be used as precursors for spiro-derivatives. The dibromo derivatives react with different binucleophilic reagents to produce several spiro-isoquinoline derivatives. Reaction of the dibromo derivatives with malononitrile produces dicyanomethylene derivatives which react with different binucleophiles to produce new spiro-derivatives. Structures of the newly synthesized compounds are proved using spectroscopic methods such as IR, ¹H-NMR and ¹³C-NMR. The newly synthesized compounds were tested for their antimicrobial and antioxidant activities, showing weak or no antimicrobial activity. On the other hand select compounds showed promising antioxidant activities. Full article

Di-D-fructose dianhydrides (DFAs) comprise a unique family of stereoisomeric spiro-tricyclic disaccharides formed upon thermal and/or acidic activation of sucroseand/ or D-fructose-rich materials. The recent discovery of the presence of DFAs in food products and their remarkable nutritional features has attracted considerable interest from the food industry. DFAs behave as low-caloric sweeteners and have proven to exert beneficial prebiotic nutritional functions, favouring the growth of Bifidobacterium spp. In the era of functional foods, investigation of the beneficial properties of DFAs has become an important issue. However, the complexity of the DFA mixtures formed during caramelization or roasting of carbohydrates by traditional procedures (up to 14 diastereomeric spiroketal cores) makes evaluation of their individual properties a difficult challenge. Great effort has gone into the development of efficient procedures to obtain DFAs in pure form at laboratory and industrial scale. This paper is devoted to review the recent advances in the stereoselective synthesis of DFAs by means of chemical and enzymatic approaches, their scope, limitations, and complementarities. Full article

The novel 3H-spiro[1-benzofuran-2-cyclopentan]-3-one skeleton has been madeaccessible by different routes. One- and two-step protocols lead to tricyclic and tetracyclicbenzofuranones 2 and 3, respectively. A four-step synthesis to spirocompound 4 isdescribed. The novel spirocyclic benzofuranones display modest to no inhibition of thehuman peptidyl prolyl cis/trans isomerase Pin1. Full article