Isoindolone Derivatives Research Articles

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.

Isoindolone derivatives as novel potential anti-Alzheimer’s candidates: synthesis, in silico, and AChE inhibitory activity evaluation

Isoindolone derivatives as novel potential anti-Alzheimer’s candidates: synthesis, in silico, and AChE inhibitory activity evaluation

Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2 C Receptors.

The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2CR. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2CR and high selectivity over 5-HT2A and 5-HT2B. [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2CR in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2C sites by PET.

Synthesis of novel isoindolone derivatives via cascade reactions. Contrasting diastereoselectivity under solution-phase vis-a-vis solvent-free ball-milling reaction conditions

The highly diastereoselective synthesis, crystallographic analysis, and full characterization of several novel heterocycle-fused isoindolones is described. The synthetic strategy involves a cascade Michael/aldol-like cyclization reaction between N-substituted phthalimides rac-1 or 2 and several α,β-unsaturated electrophiles to afford the tricyclic systems pyrrolo[2,1- a]isoindolone and tetrahydropyrido[2,1-a]isoindolone. This synthetic strategy offers a convenient alternative to existing procedures for the preparation of isoindolone derivatives fused to five- and six-membered rings. X-ray crystallographic analysis allowed the determination of relative configurations and revealed that the synthesized compounds exhibit significant structural distortion, especially in the five membered rings. Relevantly, the diastereomeric distribution of products depends substantially on whether the cascade reaction is carried out under solution vis-a-vis solvent-free conditions.

Stereoselective Synthesis of Functionalized Benzooxazepino[5,4-a]isoindolone Derivatives via Cesium Carbonate Catalyzed Formal [5 + 2] Annulation of 2-(2-Hydroxyphenyl)isoindoline-1,3-dione with Allenoates

In this work, we present a strategy for the stereoselective synthesis of functionalized benzooxazepino[5,4- a]isoindolone derivatives via a Cs2CO3-catalyzed domino β-addition and γ-aldol reaction of 2-(2-hydroxyphenyl)isoindoline-1,3-dione derivatives with allenoates, which offers an avenue for a combination of the structural unity between benzooxazepine and isoindolone motifs in synthetically useful yields with high stereoselectivities under mild conditions. Remarkably, it is the first example of highly stereoselective Cs2CO3-catalyzed formal [5 + 2] annulation of 2-(2-hydroxyphenyl)isoindoline-1,3-dione with allenoates.

Study of the Hetero-[4+2]-Cycloaddition Reaction of Aldimines and Alkynes. Synthesis of 1,5-Naphthyridine and Isoindolone Derivatives.

Both experimental and computational studies for the cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes where 1,5-naphthyridines are obtained are reported. The reaction of benzaldimine with a methoxycarbonyl group in position 2 with phenyl acetylene, styrene, and indene afforded polycyclic isoindolone derivatives. The mechanism of reaction of N-(3-pyridyl)aldimines with olefins can be explained by an asynchronous [4+2] cycloaddition; in the case of acetylenes, the obtained results suggest a stepwise mechanism through a 3-azatriene.

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition.

2-(4,6-Dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c) is one of isoindolone derivatives with antiproliferative activity against human umbilical vein endothelial cells (HUVECs). The aim of this study was to investigate its antitumor activity in vitro and anti-angiogenic effects in vitro and in vivo. K562 leukemic cells and HUVECs were used for in vitro studies. Cell viability was examined using MTT assay. Cell apoptosis and mitochondrial transmembrane potential (Δψm) were detected with flow cytometry. Tube formation and migration of HUVECs were studied using two-dimensional Matrigel assay and wound-healing migration assay, respectively. VEGF levels were analyzed with RT-PCR and Western blotting. A zebrafish embryo model was used for in vivo anti-angiogenic studies. The molecular mechanisms for apoptosis in K562 cells and antiangiogenesis were measured with Western blotting. In antitumor activity studies, QSN-10c suppressed the viability of K562 cells and induced apoptosis in dose- and time-dependent manners. Furthermore, QSN-10c dose-dependently decreased the Δψm in K562 cells, increased the release of cytochrome c and the level of Bax, and decreased the level of Bcl-2, suggesting that QSN-10c-induced apoptosis of K562 cells was mediated via the mitochondrial apoptotic pathway. In anti-angiogenic activity studies, QSN-10c suppressed the viability of HUVECs and induced apoptosis in dose dependent manners. QSN-10c treatment did not alter the Δψm in HUVECs, but dose-dependently inhibited the expression of VEGF, inhibited the tube formation and cell migration in vitro, and significantly suppressed the number of ISVs in zebrafish embryos in vivo. Furthermore, QSN-10c dose-dependently suppressed the phosphorylation of AKT and GSK3β in both HUVECs and K562 cells. QSN-10c is a novel antitumor compound that exerts both antitumor and anti-angiogenic effects via inhibiting the PI3K/AKT/GSK3β signaling pathway.

Antifungal and antiviral products of marine organisms

Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (-)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (-)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1-5 (TH 1-5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the aforementioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The prospects of employing them in clinical practice are promising in view of the wealth of these compounds from marine organisms. The compounds may also be used in agriculture and the food industry.

Synthesis of 3-alkylideneisoindolinones and isoindolones by a Horner–Wadsworth–Emmons reaction

A series of 3-alkylideneisoindolinones was prepared by a Horner–Wadsworth–Emmons (HWE) reaction of aromatic aldehydes with N-(ω-hydroxyalkyl)-substituted 3-phosphoisoindolin-1-ones, obtained in one-pot synthesis from 2-formylbenzoic acid. Additionally, the intramolecular HWE reaction of the N-(ω-formylalkyl)-substituted phosphoisoindolin-1-ones afforded the corresponding isoindolone derivatives.

ChemInform Abstract: Highly Fluorescent, π‐Extended Indenopyrido[2,1‐a]isoindolone Derivatives Prepared by a Palladium‐Catalyzed Cascade Reaction.

AbstractA new series of the title compounds is prepared and the photophysical properties in CH2Cl2 are determined.

Highly Fluorescent, π‐Extended Indenopyrido[2,1‐a]isoindolone Derivatives Prepared by a Palladium‐Catalysed Cascade Reaction

AbstractA new family of heterocyclic pentacyclic compounds have been prepared by a cascade reaction involving 2,5‐dihalopyridines and (2‐formylphenyl)boronic acids. Most of the compounds exhibit high quantum yields of fluorescence in dichloromethane. In some cases, small changes in the substitution pattern caused fluorescence quenching. To rationalize this effect, a detailed photophysical study combined with electrochemical and computational studies was performed on four representative derivatives. It appears that the fluorescence quenching is caused by a thermally activated non‐radiative deactivation process that can be prevented in a rigid matrix such as ethanol at 77 K or a PMMA polymer.

ChemInform Abstract: [3 + 2] Cycloaddition of Masked o‐Benzoquinones with Azomethine Ylides.

AbstractThe reaction leads to formation of isoindolone derivatives.

Copper-Catalyzed Synthesis of N-Heterocyclic Compounds

The synthesis of N-heterocyclic compounds is an important direction because of their diverse biological functions. Recently, there has been remarkable progress in copper-catalyzed cross couplings with inexpensive, readily available, insensitive-to-air and low-toxicity copper catalysts. This review summarizes recent advances in the copper-catalyzed synthesis of N-heterocyclic compounds. 1 Introduction and Background 2 Synthesis of Five-Membered Heterocycles with One Nitrogen Atom 2.1 Pyrrolidine and Pyrrole Derivatives 2.2 Indole Derivatives 2.3 Indolone and Isoindolone Derivatives 2.4 Oxazole, Isoxazole, Benzoxazole and Benzothiazole Derivatives 3 Synthesis of Five-Membered Heterocycles with Two Nitrogen Atoms 3.1 Imidazole Derivatives 3.2 Benzimidazole Derivatives 3.3 Benzimidazolone Derivatives 4 Synthesis of N-Sulfonyltriazoles 5 Synthesis of Six-Membered Heterocycles with One Nitrogen Atom 5.1 Piperidine and Pyridine Derivatives 5.2 Quinoline and Quinolinone Derivatives 5.3 Isoquinoline Derivatives 6 Synthesis of Six-Membered Heterocycles with Two Nitrogen Atoms 6.1 Quinazoline Derivatives 6.2 Quinazolinone Derivatives 7 Synthesis of N-Fused Heterocycles 8 Summary

3+2] Cycloaddition of Masked o-Benzoquinones with Azomethine Ylides

A simple and efficient access to highly functionalized isoindolone derivatives via a [3+2] cycloaddition process between in situ generated azomethine ylides with various stable (isolable) masked o-benzoquinones is described. This approach allows a rapid and general synthesis of isoindolones with substituents to further manipulate and elaborate the structural complexity.

Antiviral isoindolone derivatives from an endophytic fungus Emericella sp. associated with Aegiceras corniculatum

Chemical investigation of the endophytic fungus Emericella sp. (HK-ZJ) isolated from the mangrove plant Aegiceras corniculatum led to isolation of six isoindolones derivatives termed as emerimidine A and B and emeriphenolicins A and D, and six previously reported compounds named aspernidine A and B, austin, austinol, dehydroaustin, and acetoxydehydroaustin, respectively. Their structures were elucidated on the basis of NMR spectroscopic evidence while the anti-influenza A viral (H1N1) activities of eight compounds were also evaluated using the cytopathic effect (CPE) inhibition assay.

Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-amyloid fibrils

Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Abeta42 fibrils using [(125)I]TZDM. All the isoindolone derivatives showed very good binding affinities with K(i) values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (K(i)=0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (K(i)=0.52 nM) and PIB (K(i)=0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Abeta fibrils.

Unusual Synthesis of Dihydropyrido[2,1‐a]isoindolone Derivatives by Radical Cyclization of Enamides of Baylis—Hillman Adducts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Unusual synthesis of dihydropyrido[2,1- a]isoindolone derivatives by radical cyclization of enamides of Baylis–Hillman adducts

During the radical cyclization of enamide derivatives 4 we found unusual formation of dihydropyrido[2,1- a]isoindolone derivatives 5. The enamides were synthesized in four steps from the Baylis–Hillman adducts of ortho-bromobenzaldehydes.

Isoindolone derivatives, a new class of 5-HT 2C antagonists: Synthesis and biological evaluation

Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT 2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon–carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT 2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.

Synthesis, proton and 13C NMR and reaction mechanism studies of novel isoindolones derivatives, obtained through TAWERS procedure

A series of novel isoindolone derivatives ( 13– 18) were prepared in goods yields by applying the TAWERS methodology. A general approach for formation of isoindolones from the aza-Wittig reaction of iminophosphoranes with dialdehydes under neutral and mild conditions was realized. Using 1D NMR a [ 1, 3]-hydride migration was detected. The assignment of the structures and conformation behavior of the derivatives was achieved using 1D and 2D NMR (NOESY, DEPT, HMQC, and HMBC).