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Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4–11 cells at low picomolar concentrations (IC(50) = 3 pM; BRD4 DC(50) = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

The effect of glutarimide dioxime (H3A) on the fate of Tc in aqueous solution was studied, the results found that the distribution ratio of Tc between TBP and aqueous phase decreased by one order of magnitude with addition of H3A, due to the formation of low-valent Tc complexes with H3A. Further study of coordination mode between low-valent Tc and H3A was carried by using Re as substitute. Firstly, the low-valent Re complexes with H3A were prepared by reduction of Re(VII) using hydrazine in the presence of H3A, the results showed that pH 8.0, high CH3A and high Chydrazine are favorable for the formation of low-valent Re complexes, with a characteristic peak at 380 nm. Subsequently, the species of low-valent Re complexes were further studied by XPS, ESI–MS and EXAFS, low-valent Re is tetravalent and forms 1:1 (ReA) and 1:2 (ReA2) mononuclear complexes with H3A. The low-valent Re/Tc complexes are air-stable in aqueous solution.

Nowadays, pharmaceutical cocrystals are an alternative approach to the synthesis of new solids without altering active pharmaceutical ingredients of the drug. In this study, lamotrigine (LTG) theophylline (THP) cocrystal monohydrate (1:1:1) and LTG glutarimide (GLU) cocrystal (1:1) were synthesized and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and Fourier transform infrared analysis. The Hirshfeld surface and 2D fingerprint of the LTG molecule in LTG-THP-H2O and LTG-GLU indicated that the main intermolecular forces between two LTG cocrystals molecules are H•••N/N•••H and H•••O. Dissolution results and stability studies demonstrated that the properties of LTG were enhanced by cocrystal formation. Contrary to LTG-GLU, LTG-THP-H2O posed slower dissolution rate and higher stability capability, which can be ascribed to the hydrated structure in LTG-THP-H2O and the aminopyridine dimer structure in LTG-GLU. Hence, it is necessary to select the conformers purposefully as to improve the corresponding performance of LTG.

A LiOH-promoted hydrolysis selective C-N cleavage of twisted N-acyl glutarimide for the synthesis of primary amides under mild conditions has been developed. The reaction is triggered by a ring opening of glutarimide followed by C-N cleavage to afford primary amides using 2 equiv of LiOH as the base at room temperature. The efficacy of the reactions was considered and administrated for various aryl and alkyl substituents in good yield with high selectivity. Moreover, gram-scale synthesis of primary amides using a continuous flow method was achieved. It is noted that our new methodology can apply under both batch and flow conditions for synthetic and industrial applications.

Thalidomide is a drug that presents two enantiomers with markedly different pharmacological and toxicological activities. It is sadly famous due to its teratogenic effects mostly caused by the preferential docking of the (S)-enantiomer to the target protein cereblon (CRBN). To compare the structure of the bound CRBN thalidomide enantiomers with that of the isolated molecule, the rotational spectrum of laser-ablated thalidomide has been studied by chirp-pulsed Fourier transform microwave spectroscopy in supersonic jets complemented by theoretical computations. A new setup of the laser ablation nozzle used is presented. Two stable equatorial and axial conformers of thalidomide have been predicted corresponding to the two possible bent conformations exhibited by the glutarimide moiety. Only the most stable equatorial conformer has been detected. The comparison of its structure with those of the (S)- and (R)-enantiomers bound to CBRN shows that the bound (S) species is only slightly distorted. On the contrary, the bound (R)-enantiomer exhibits a highly distorted structure which affects the degree of puckering of the glutarimide ring and especially to the orientation of the phtalimide and glutarimide subunits. This is consistent with a less stable (R)-enantiomer and the known preference of (S)-thalidomide to bind CRBN, which starts the process leading to teratogenic effects.

A gene cluster encoding a cryptic trans‐acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters led to the identification of gladiostatin, the metabolic product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2‐acyl‐4‐hydroxy‐3‐methylbutenolide in addition to the glutarimide pharmacophore. An AfsA‐like domain at the C‐terminus of the PKS was shown to catalyze condensation of 3‐ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation., Genome mining enabled the discovery of gladiostatin, a novel glutarimide antibiotic from the cystic fibrosis associated bacterium Burkholderia gladioli. Gladiostatin contains an unusual 2‐acyl‐3‐hydroxy‐4‐methylbutenolide and exhibits promising activity against human cancer cells. The polyketide synthase responsible for its biosynthesis employs a novel mechanism for chain release, resulting in formation of a phosphorylated butenolide intermediate.

N-Acyl-glutarimides have emerged as the most reactive precursors for N-C(O) bond cross-coupling reactions to date, wherein the reactivity is driven by ground-state destabilization of the amide bond. Herein, we report a full study on the effect of a glutarimide ring on the structures, electronic properties, and reactivity of fully perpendicular N-acyl-glutarimide amides. Most notably, this report demonstrates the generality of deploying N-acyl-glutarimides to achieve full twist of the acyclic amide bond, and results in the discovery of N-acyl-glutarimide amide with an almost perfect twist value, τ = 89.1°. X-ray structures of five new N-acyl-glutarimides are reported. Reactivity studies in the Suzuki-Miyaura cross-coupling and transamidation reactions provide insight into the reactivity of N-acyl-glutarimides in metal-catalyzed and transition-metal-free reactions. The effect of distortion, structures, and rotational barriers around the N-C(O) axis is discussed. The ability to achieve full distortion of the amide bond significantly expands the range of reagents available for N-C(O) cross-coupling reactions.

Neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are a class of heterogeneous pathologies of the central nervous system (CNS) affecting millions of people worldwide. CNS-related pathologies represent a global health burden in developed and developing countries with no curative treatments currently available. Thus, the development of novel multitarget neuroprotective drugs is a health priority. In this work, a bioinspired methodology in solution-phase for the assembly and regioselective conjugation of Glypromate® neuropeptide with active pharmaceutical ingredients (APIs) is described. The main purpose is to design new hybrid molecules which may offer increased systemic resistance of Glypromate® towards proteases and/or allow the controlled release of both APIs and the neuroprotective peptide within CNS. For the synthesis of such peptide-hybrid compounds (R)-1-aminoindane, amantadine, and memantine were selected as APIs for conjugation with Glypromate®. Furthermore, capping strategies are explored to prepare Glypromate® conjugates with more favorable pharmacodynamic profiles by masking polar exposed groups. Overall, this synthetic approach led to the development of a small library of 12 conjugates with improved drug-like properties in comparison with Glypromate®, paving the way for the discovery of novel CNS multitarget drugs. Additionally, by exploring the bis-functionalization of glutamate, the formation of chiral glutarimides is disclosed for the first time employing TBTU as the coupling reagent. This unusual reactivity of TBTU with glutamate offers a new synthetic approach for the preparation of chiral glutarimide alkaloids.

A LC-MS-guided screening led to the isolation of two new streptimidone derivatives (2 and 3) containing a glutarimide ring and two glutarimide ring-opened compounds (4 and 5) along with a known glutarimide-containing polyketide, streptimidone (1) from Streptomyces sp. W3002 strain. Their structures were elucidated by MS and NMR spectroscopic analyses and by comparison with data from the literature. Compound 2 is a non-hydroxylated analog at the C-5 position of streptimidone. The structure of 3 was determined as a streptimidone derivative possessing the α, β-unsaturated ketone moiety at positions C-5 and C-6. Compound 4 had similar chemical shifts and splitting patterns with 3, but the glutarimide ring is opened. Compound 5 closely resembles that of 4 with the only difference being the existence of an additional methoxy group instead of an amide group. Streptimidone (1) and 3 showed weak cytotoxic activity against three human cancer cell lines, respectively.

Phthalimide analogues devoid of the glutarimide moiety exhibit multiple biological activities, thus making them candidates for the treatment of patients with different diseases, including those with inflammatory and painful disorders. In the present study, the activities of five phthalimide analogues devoid of the glutarimide moiety (N-hydroxyphthalimide, N-hydroxymethylphthalimide, N-3-hydroxypropylphthalimide, N-carboxy-3-methylphthalimide, N-carboxymethyl-3-nitrophthalimide) were evaluated in experimental models of acute and chronic inflammatory and neuropathic pain. The phthalimide analogues were administered per os (po) in Swiss mice or Wistar rats. Nociceptive response induced by formaldehyde and mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve or intraplantar (ipl) injection of complete Freund’s adjuvant (CFA) were used as experimental models of pain. N-carboxymethyl-3-nitrophthalimide (700 mg/kg, -1 h) inhibited the second phase of the nociceptive response induced by the intraplantar injection of formaldehyde in mice. N-3-hidroxypro-pylphthalimide (546 mg/kg, -1 h) inhibited both phases of the nociceptive response induced by formaldehyde. Treatment of rats with N-carboxymethyl-3-nitrophthalimide (700 mg/kg) or JV-3-hydroxypropylphthalimide (546 mg/kg) inhibited the mechanical allodynia induced by CCI of the sciatic nerve or ipl injection of CFA in rats. Intraperitoneal administration of the opioid antagonist naltrexone (10 mg/kg, -1.5h) attenuated the antinociceptive activity of N-carboxymethyl-3-nitrophthalimide (700 mg/kg) in the model of nociceptive response induced by formaldehyde. N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide, two phthalimide analogues devoid of the glutarimide moiety, exhibited activities in different experimental models of pain, including models of chronic inflammatory and neuropathic pain.

Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti-aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N-acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C11b. Cope elimination of the dibenzylamino group then converted the two diastereomers into enantiomers.

The nonenzymatic deamidation reactions of asparagine (Asn) and glutamine (Gln) residues in proteins are associated with protein turnover and age-related diseases. The reactions are also believed to provide a molecular clock for biological processes. Although Gln deamidation is assumed to occur through the glutarimide intermediate, the mechanisms for this are unclear because under normal physiological conditions, Gln deamidation occurs relatively less frequently and at a lower rate than Asn deamidation. We investigate the mechanisms underlying glutarimide formation from Gln residues, which proceeds in two steps (cyclization and deammoniation) catalyzed by phosphate and carbonate. We also compare these reactions with noncatalytic mechanisms and water-catalyzed mechanisms. The calculations were performed on the model compound Ace–Gln–Nme (Ace = acetyl, Nme = methylamino) using the density functional theory with the B3LYP/6-31+G(d,p) level of theory. Our results suggest that all the catalysts used in our study can mediate the proton relays required for glutarimide formation. We further determined that the calculated activation barriers of the reactions catalyzed by phosphate ions (115 kJ mol–1) and carbonate ions (112 kJ mol–1) are sufficiently low for the reactions to occur under normal physiological conditions. We also show that nucleophilic enhancement of Nme nitrogen is essential for the cyclization of Gln residues.

Two new glutarimide antibiotics, 9-methylstreptimidone 2-α-D-glucopyranoside (1), and hydroxyiso-9-methylstreptimidone (2), along with a known compound, 9-methylstreptimidone (3), have been isolated from the broth of Streptomyces sp. HS-NF-780. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. By modified Mosher's method and acid hydrolysis, the absolute configurations of compounds 1 and 2 were established. Compounds 1 and 2 exhibited moderate cytotoxic activity.

Long-lived proteins (LLPs) are susceptible to the accumulation of both enzymatic and spontaneous post-translational modifications (PTMs). A prominent PTM observed in LLPs is covalent protein–protein crosslinking. In this study, we examined aged human lenses and found several proteins to be crosslinked at Glu and Gln residues. This new covalent bond involves the amino group of Lys or an α-amino group. A number of these crosslinks were found in intermediate filament proteins. Such crosslinks could be reproduced experimentally by incubation of Glu- or Gln-containing peptides and their formation was consistent with an amino group attacking a glutarimide intermediate. These findings show that both Gln and Glu residues can act as sites for spontaneous covalent crosslinking in LLPs and they provide a mechanistic explanation for an otherwise puzzling observation, that a major fraction of Aβ in the human brain is crosslinked via Glu 22 and the N-terminal amino group.

A concise four step synthetic route for glutarimide alkaloids of high biological interest is presented. The scaffold is accessed via an Ugi four component reaction, hereby introducing two points of variation. This is followed by a hydrolysis, a cyclization under mild conditions, and an amine deprotection. The diastereomers of the cyclized intermediate can be easily separated, thus leading to optically pure alkaloids. By this route, four natural products and ten derivatives were synthesized. The scope and limitations of the synthetic methodology were investigated.

Unravelling the molecular basis of thalidomide embryotoxicity, which is remarkably species–specific, is challenging in view of its low toxicity in the mature animal. Employing data derived solely from proven sensitive primate species or susceptible strains of rabbit, the structure–activity relationship of over 50 compounds which are, arguably, congeners of thalidomide has been reviewed. The molecular requirement for ‘thalidomide-type’ teratogenicity was highly structure dependent. Both the phthalimide and glutarimide groups were essential for embryopathic activity, although minor substitutions in either or both rings could be tolerated without a loss of toxicity. An α-linkage between the two cyclic structures was essential; a β-link resulted in a complete loss of embryopathic activity. Crucially, this α-configuration provided a centre of asymmetry enabling the existence of stereoisomers. The thalidomide molecule is not a static entity and under physiological conditions it undergoes a number of intra- and inter-molecular reactions. Besides irreversible hydrolysis, its keto–enol tautomerism, base-assisted proton transfer and glutarimide ring rotation lead to rapid interconversion of the thalidomide enantiomers. These enantiomers form equilibria between themselves and also between both homochiral and heterochiral dimers. It is proposed that the more energetically favourable and stable heterochiral dimer of thalidomide is an active agent that possesses the structural features of the paired nucleotides of the double-stranded DNA. Its capacity to enter into hydrogen bonding interactions affects DNA expression in a chaotic manner without causing permanent mutations. This disruption may well be concentrated at nucleotide sites known to be involved in specific promoter regions of the genome.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Thalidomide was indicated as a sedative and antiemetic and prescribed for pregnant women. Its tragic teratogenic effects culminated in withdrawal from the market. Since the discovery of its anti-angiogenic and anti-inflammatory actions, thalidomide has been used in the treatment of leprosy and multiple myeloma, which justify studies of its stability. We investigated the effects of irradiation of thalidomide up to 100 kGy (fourfold the usual sterilizing dose for pharmaceutics). The β polymorph of thalidomide was obtained in an isothermal experiment at 270 °C. All samples underwent gamma irradiation for specific times. At different doses, decomposition of the pharmaceutical was not observed up to 100 kGy. The observed effect was angle turning between the phthalimide and glutarimide rings modulated by repulsion towards the carbonyl group, leading to a stable energetic configuration, as measured by the equilibrium in the torsion angle after irradiation. The thalidomide molecule has a center of symmetry, so a full turn starting from 57.3° will lead to an identical molecule. Further irradiation will start the process again. Samples irradiated at 30 and 100 kGy have more compact unit cells and a lower volume, which leads to an increase in the intermolecular hydrogen interaction within the unit cell, resulting in higher thermal stability for polymorph α.

A new strategy for the stereoselective synthesis of alkaloids with perhydro-9b-azaphenalene skeleton has been developed. The starting material is the substituted glutarimide derivative 1, readily available in either enantiomeric form through the palladium-catalyzed asymmetric allylic alkylation of glutarimide. The strategy relies on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been used in the first synthesis of (-)-9a- epi-hippocasine.

In contrast with the common belief that all the amino acid residues in higher organisms are l-forms, d-amino acid residues have been recently detected in various aging tissues. Aspartic acid (Asp) residues are known to be the most prone to stereoinvert via cyclic imide intermediate. Although the glutamic acid (Glu) is similar in chemical structure to Asp, little has been reported to detect d-Glu residues in human proteins. In this study, we investigated the mechanism of the Glu-residue stereoinversion catalyzed by water molecules using B3LYP/6-31+G(d,p) density functional theory calculations. We propose that the Glu-residue stereoinversion proceeds via a cyclic imide intermediate, i.e., glutarimide (GI). All calculations were performed by using a model compound in which a Glu residue was capped with acetyl and methylamino groups on the N- and C-termini, respectively. We found that two water molecules catalyze the three steps involved in the GI formation: iminolization, cyclization, and dehydration. The activation energy required for the Glu residue to form a GI intermediate was estimated to be 32.3 kcal mol-1 , which was higher than that of the experimental Asp-residue stereoinversion. This calculation result suggests that the Glu-residue stereoinversion is not favored under the physiological condition.

The development of new transamidation reactions for the synthesis of amides is an important and active area of research due to the central role of amide linkage in various fields of chemistry. Herein, we report a new method for transamidation of N-acyl-glutarimides with amines under mild, metal-free conditions that relies on amide bond twist to weaken amidic resonance. A wide range of amines and functional groups, including electrophilic substituents that would be problematic in metal-catalyzed protocols, are tolerated under the reaction conditions. Mechanistic experiments implicate the amide bond twist, thermodynamic stability of the tetrahedral intermediate and leaving group ability of glutarimide as factors controlling the reactivity of this process. The method further establishes the synthetic utility of N-acyl-glutarimides as bench-stable, twist-perpendicular, amide-based reagents in acyl-transfer reactions by a metal-free pathway. The origin of reactivity of N-acyl-glutarimides in metal-free and metal-catalyzed processes is discussed and compared.

As an extension of the boron enolate-based aldol reactions, the oxazolidinone-installed bisimide 1a from 3-(trifluoromethyl)glutaric acid was employed for Mannich reactions with tosylated imines 2 as electrophiles to successfully obtain the corresponding adducts in a stereoselective manner.

We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure–activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3–CRBN–GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.

A novel synthesis of anhydrides from twisted amides is reported. Sc(OTf)3 catalysis in the presence of water is used to synthesize anhydrides in one step from amides without external nucleophiles. Mechanistic studies indicate that the coordination of the catalyst is critical to induce the challenging N–C activation step. This process further highlights the utility of twisted amides in organic synthesis. Notably, the reaction indicates that twisted amides based on the glutarimide scaffold are more reactive than carboxylic acid anhydrides under the developed conditions, which opens the door to controlled sequential catalysis through amide N–C bond cleavage.

We present a novel route for the preparation of amino acid-derived cyclic imide dioxime derivatives. Readily accessible amino acids were conveniently converted to their corresponding cyclic imide dioximes in simple synthetic steps. The aim of this work was to describe and compare the iron-chelating and antioxidant properties of synthesized compounds in relation to their molecular structure, and in particular, which of those features are essential for iron(II)-chelating ability. The glutarimide dioxime moiety has been established as an iron(II)-binding motif and imparts potent anti-Fenton properties to the compounds. Compound 3 was shown to strongly suppress hydroxyl radical formation by preventing iron cycling via Fe-complexation. These findings provide insights into the structural requirements for achieving anti-Fenton activity and highlight the potential use of glutarimide dioximes as antioxidants.

Aspartic acid (Asp) residues are prone to non-enzymatic stereoinversion, and Asp-residue stereoinversion is believed to be mediated via a succinimide (SI) intermediate. The stereoinverted Asp residues are believed to cause several age-related diseases. However, in peptides and proteins, few studies have reported the stereoinversion of glutamic acid (Glu) residues whose structures are similar to that of Asp. We previously presumed that Glu-residue stereoinversion proceeds via a glutarimide (GI) intermediate and showed that the calculated activation barriers of SI- and GI-intermediate stereoinversion are almost equivalent in the gas phase. In this study, we investigated the stereoinversion pathways of the l-GI intermediate in the aqueous phase using B3LYP density functional methods. The calculated activation barrier of l-GI-intermediate stereoinversion in the aqueous phase was approximately 36 kcal&middot, mol&minus, 1, which was much higher than that in the gas phase. Additionally, as this activation barrier exceeded that of Asp-residue stereoinversion, it is presumed that Glu-residue stereoinversion has a lower probability of proceeding under physiological conditions than Asp-residue stereoinversion.

The imide functionality is ubiquitous in nature and found in many structurally diverse natural products. The imides themselves are most often cyclic and the natural products containing them tend to be bioactive. Some imides, such as glutarimide, appear so frequently in highly potent, naturally occurring antibiotics, that they have come to be considered privileged scaffolds. The imide natural products covered in this chapter are grouped by a combination of the overall structural similarity of both the molecule and the type of imide itself; the groups include bisindoles, glutarimides, maleimides, polyketides, succinimides, and tetramic acids. Each individual natural product is further broken down by isolation, biological activity, and synthesis, where applicable. This chapter is not intended to provide comprehensive and exhaustive coverage of all known imide-containing natural products. Rather, it will cover selected, representative natural products in a range of structural classes with initial isolation dates from the early 20th century up to 2018.

International audience; An enantioselective Michael addition-four-atom ring expansion cascade reaction involving cyclobutanones activated by a N-aryl secondary amide group and ortho-amino nitrostyrenes has been developed for the preparation of functionalized eight-membered benzolactams using bifunc-tional aminocatalysts. Taking advantage of the secondary amide activating group, the eight-membered cyclic products could be further rearranged into their six-membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion-ring contraction strategy.

A transition metal-free direct arylation of 2-substituted cyanoacetates with diaryliodonium salts was developed. With this approach, a wide range of α-tolunitrile derivatives has been synthesized in good to excellent yields of 45–92%. Furthermore, the practicability of this approach is further manifested in the synthesis of a related bioactive agent of glutarimide.

The multifunctional alkoxysilane precursor, 2,6-bis(propyl-trimethoxysilylurelene)pyridine (DPS) was designed and synthesized, envisaging a multiple hydrogen-bond interaction in the molecular imprinting of the drug aminoglutethimide (AGT). Imprinted xerogels were obtained in bulk and spherical formats. The spherical format was achieved by pore-filling onto spherical mesoporous silica, as a straightforward technique to generate the spherical format. The bulk gels presented better selectivity for the template against its glutarimide (GLU) analogue (selectivity factor: bulk 13.4; spherical 4.6), and good capacity (bulk 5521μmol/L; spherical 2679μmol/L) and imprinting factor parameters (bulk 11.3; spherical 1.4). On the other hand, the microspherical format exhibited better dynamic properties associated to chromatographic efficiency (theoretical plates: bulk 6.8; spherical 75) and mass transfer, due mainly to the existence of a mesoporous network, lacking in the bulk material. The performance of the imprinted xerogels was not as remarkable as that of their acrylic counterparts, previously described. Overall it was demonstrated that the use of designed new "breeds" of organo-alkoxysilanes may be a strategy to achieve satisfactory imprints by the sol-gel processes. DPS may in principle be applied even more effectively to other templates bearing better-matching spatially compatible acceptor-donor-acceptor arrays.

The studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn(II)-mediated intramolecular Horner-Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z-diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA-MB-231 breast cancer cells (GI50 =1-3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50-52 lacking the glutarimide side-chain were found to be significantly less toxic against human mammary epithelial cells.

Novel copper(II) nanocoordination complexes [LCuCl]Cl C1, [LCu(SCN)]SCN C2, and [LCu(NO3)]NO3C3 capped by bis-benzimidazole diamide ligand N1,N5-bis{(1H-benzo[d]imidazole-2-yl)methyl}glutarimide L were synthesized and characterized by spectroscopic methods viz. transmission electron microscopy (5–100 nm), dynamic light scattering, elemental analysis, EPR, and infrared spectroscopy. These complexes were also tested for their ability to inhibit nitric oxide release during culture. Lipopolysaccharide-induced superoxide production decreased most significantly for complex C2. Nanocoordination complex C2 also showed the most significant in vitro cytotoxicity against HeLa human cervical cancer cells, MCF-7 breast cancer cells, and U-87 glioblastoma cells, ranging from 50 μg ml−1 to 500 μg ml−1. In vivo study revealed an increase in body weight (11.5 g) for the tumour control groups, whereas in the case of the mouse groups treated with test sample C3, the difference in body weight as compared to the control was approximately 4.7 g. In further studies, it decreased to 2.2 g and 0.6 g in the case of mouse groups treated with nanocoordination complexes C1 and C2, respectively. The mean mouse survival time was 21 days, which increased to 100, 120, and 170 days for C3, C1, and C2, respectively.

The reintroduction of thalidomide in the pharmacotherapy greatly stimulated the interest in the synthesis and pharmacological evaluation of phthalimide analogs with new and improved activities and also greater safety. In the present study, we evaluated the activities of two phthalimide analogs devoid of the glutarimide ring, namely 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO), in experimental models of inflammatory pain and edema in male C57BL/6J mice. Intraplantar (i.pl.) injection of carrageenan (300 μg) induced mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-OH and PTD-NO (750 mg/kg) and also by thalidomide (500 or 750 mg/kg). The edema induced by carrageenan was also inhibited by previous p.o. administration of PTD-OH (500 and 750 mg/kg) and PTD-NO (125, 250, 500 or 750 mg/kg), but not by thalidomide. Carrageenan increased tumor necrosis factor (TNF)-α and CXCL1 concentrations and also the number of neutrophils in the paw tissue. Previous p.o. administration of PTD-NO (500 mg/kg) reduced all the parameters, while PTD-OH (500 mg/kg) reduced only the accumulation of neutrophils. Thalidomide, on the other hand, was devoid of effect on these biochemical parameters. Plasma concentrations of nitrite were increased after p.o. administration of the phthalimide analog coupled to a NO donor, PTD-NO (500 mg/kg), but not after administration of PTD-OH or thalidomide. In conclusion, our results show that small molecules, structurally much simpler than thalidomide or many of its analogs under investigation, exhibit similar activities in experimental models of pain and inflammation. Finally, as there is evidence that the glutarimide moiety contributes to the teratogenic effect of many thalidomide analogs, our results indicate that phthalimide analogs devoid of this functional group could represent a new class of analgesic and anti-inflammatory candidates with potential greater safety.

Four glutarimide-derived compounds including a new 3-[2-[2-hydroxy-3-methylphenyl-5-(hydroxymethyl)]-2-oxoethyl] glutarimide (1) and three known 3-[2-(2-hyroxy-3,5- dimethylphenyl)-2-oxoethyl] glutarimide (2, actiphenol), 3-hydroxy-3-[2-(2-hydroxy-3,5-dimethylphenyl)-2-oxoethyl] glutarimide (3) and 3-[2-[2-hydroxy-3-(hydroxymethyl)-5-methylphenyl]-2-oxoethyl] glutarimide (4), along with a known indole alkaloid 3-(hydroxyacetyl) indole (5), were isolated from ethyl acetate extract of the fermentation broth of the marine sponge-derived Streptomyces anulatus S71. Their structures were deduced by extensive studies of NMR and mass spectra.

Two novel compounds, alienusolin, a 4α-deoxyphorbol ester (1), crotonimide C, a glutarimide alkaloid derivative (2), and ten known compounds, julocrotine (3), crotepoxide (4), monodeacetyl crotepoxide (5), dideacetylcrotepoxide, (6), β-senepoxide (7), α-senepoxide (8), (+)-(2S,3R-diacetoxy-1-benzoyloxymethylenecyclohex-4,6-diene (9), benzyl benzoate (10), acetyl aleuritolic (11), and 24-ethylcholesta-4,22-dien-3-one (12) were isolated from the Kenyan Croton alienus. The structures of the compounds were determined using NMR, GCMS, and HRESIMS studies.

Chemical investigation of Croton pullei (Euphorbiaceae) collected in the Brazilian Amazon region was revisited. The chemical composition of the essential oils of leaves and stems was analyzed by GC/MS. It was found that both the oils comprise mainly terpenes, among which linalool was the major one (24.90 and 39.72%, respectively). Phytochemical investigation of the stem methanol extract led to the isolation of a new natural product from the glutarimide alkaloid group named N-[2,6-dioxo-1-(2-phenylethyl)-3-piperidinyl]-acetamide, confirming that C. pullei is a rich source of this class of alkaloids. The hexane and methanol extracts of the stems of C. pullei showed moderate antibacterial and antifungal activity and the highest inhibition was observed when the methanol extract was tested against Staphylococcus aureus CCMB 262 and CCMB 263.

In mass-spectrometry based peptide sequencing, formation of b- and y-type fragments by cleavage of the amide C–N bond constitutes the main dissociation pathway of protonated peptides under low-energy collision induced dissociation (CID). The structure of the b 2 fragment ion from peptides containing glutamine (Gln) and asparagine (Asn) residues is investigated here by infrared ion spectroscopy using the free electron laser FELIX. The spectra are compared with theoretical spectra calculated using density functional theory for different possible isomeric structures as well as to experimental spectra of synthesized model systems. The spectra unambiguously show that the b2-ions do not possess the common oxazolone structure, nor do they possess the alternative diketopiperazine structure. Instead, cyclic imide structures are formed through nucleophilic attack by the amide nitrogen atom of the Gln and Asn side chains. The alternative pathway involving nucleophilic attack from the side-chain amide oxygen atom leading to cyclic isoimide structures, which had been suggested by several authors, can clearly be excluded based on the present IR spectra. This mechanism is perhaps surprising as the amide oxygen atom is considered to be the better nucleophile; however, computations show that the products formed via attack by the amide nitrogen are considerably lower in energy. Hence, b2-ions with Asn or Gln in the second position form structures with a five-membered succinimide or a six-membered glutarimide ring, respectively. b2-Ions formed from peptides with Asn in the first position are spectroscopically shown to possess the classical oxazolone structure.

An approach to the enantiospecific syntheses of sesbanimide and its enantiomer is described; enantiomeric intermediates in the syntheses of both compounds possessing the required glutarimide and 1,3-dioxane rings are derived from D-glucose.

A transition metal-free direct arylation of 2-substituted cyanoacetates with diaryliodonium salts was developed. With this approach, a wide range of α-tolunitrile derivatives has been synthesized in good to excellent yields of 45–92%. Furthermore, the practicability of this approach is further manifested in the synthesis of a related bioactive agent of glutarimide.

The dearth of new antibiotics in the face of widespread antimicrobial resistance makes developing innovative strategies for discovering new antibiotics critical for the future management of infectious disease. Understanding the genetics and evolution of antibiotic producers will help guide the discovery and bioengineering of novel antibiotics. We discovered an isolate in Alaskan boreal forest soil that had broad antimicrobial activity. We elucidated the corresponding antimicrobial natural products and sequenced the genome of this isolate, designated Streptomyces sp. 2AW. This strain illustrates the chemical virtuosity typical of the Streptomyces genus, producing cycloheximide as well as two other biosynthetically unrelated antibiotics, neutramycin, and hygromycin A. Combining bioinformatic and chemical analyses, we identified the gene clusters responsible for antibiotic production. Interestingly, 2AW appears dissimilar from other cycloheximide producers in that the gene encoding the polyketide synthase resides on a separate part of the chromosome from the genes responsible for tailoring cycloheximide-specific modifications. This gene arrangement and our phylogenetic analyses of the gene products suggest that 2AW holds an evolutionarily ancestral lineage of the cycloheximide pathway. Our analyses support the hypothesis that the 2AW glutaramide gene cluster is basal to the lineage wherein cycloheximide production diverged from other glutarimide antibiotics. This study illustrates the power of combining modern biochemical and genomic analyses to gain insight into the evolution of antibiotic-producing microorganisms.

In order to elucidate the reason why glutamic acid residues have lesser racemisation reactivity than asparaginic acid, we investigated the racemisation energy barrier of piperidinedione, which is the presumed intermediate of the isomerisation reaction of L-Glu to D-Glu, by density functional theory calculations. In two-water-molecule-assisted racemisation, the activation barrier for keto–enol isomerisation was 28.1 kcal/mol. The result showed that the activation barrier for the racemisation of glutamic acid residues was not different from that for the racemisation of aspartic acid residues. Thus, glutamic acid residues can possibly cause the racemisation reaction if the cyclic intermediate stably exists.

The significance of the molecular chirality of drugs has been widely recognized due to the thalidomide tragedy. Most of the new drugs reaching the market today are single enantiomers, rather than racemic mixtures. However, many optically pure drugs, including thalidomide, undergo enantiomerization in vivo, thus negating the single enantiomers' benefits or inducing unexpected effects. A detailed atomic level understanding of chiral conversion, which is still largely lacking, is thus critical for drug development. Herein, we use first-principle density function theory (DFT) to explore the mechanism of enantiomerization of thalidomide. We have identified the two most plausible interconversion pathways for isolated thalidomide: 1) proton transfer from the chiral carbon center to an adjacent carbonyl oxygen atom, followed by isomerization and rotation of the glutarimide ring (before the proton hops back to the chiral carbon atom); and 2) a pathway that is the same as "1", but with the isomerization of the glutarimide ring occurring ahead of the initial proton transfer reaction. There are two remarkable energy barriers, 73.29 and 23.59 kcal mol(-1), corresponding to the proton transfer and the rotation of the glutarimide ring, respectively. Furthermore, we found that water effectively catalyzes the interconversion by facilitating the proton transfer with the highest energy barrier falling to approximately 30 kcal mol(-1), which, to our knowledge, is the first time that this important role of water in chiral conversion has been demonstrated. Finally, we show that the hydroxide ion can further lower the enantiomerization energy barrier to approximately 24 kcal mol(-1) by facilitating proton abstraction, which agrees well with recent experimental data under basic conditions. Our current findings highlight the importance of water and hydroxide ions in the enantiomerization of thalidomide and also provide new insights into the mechanism of enantiomerization at an atomic level.

Molecular probes based on 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide) were synthesized and assessed for inhibitory activity against LPS-induced NO production. Among the probes examined, several derivatives exhibited potential for use in determining the target proteins of DTCM-glutarimide.

Literature describes kinetics of reactions of alcohols, phenols, carboxylic acids, amines and amides with oxiranes such as ethylene oxide and propylene oxide. However, there is no information regarding kinetic of reaction of imides with oxiranes. In this article the kinetics of the reaction of cyclic monoimides: succinimide, phtalimide, and glutarimide, with ethylene and propylene oxides in presence of triethylamine in aprotic solvent was studied. The rate laws for those processes were established based upon on dilatometric measurements. I was said that cyclic monoimides react with oxiranes in presence of triethylamine to give N-(2-hydroxyalkyl)imides as major product. This product react further with oxiranes in consecutive reaction. The kinetics of the reaction of cyclic mono-imides with oxiranes obey the following rate law: V = k1/2 c1/2cat c3/2imide c1/2oxirane. Based upon kinetic data the following orders of reactivity of imides and oxiranes were obtained: phtalimide ≥ succinimide > glutarimide and ethylene oxide > propylene oxide. The solvent (DMF, DMSO and dioxane) effect was also studied. From temperature dependences the thermodynamic parameters: activation energy, enthalpy and entropy from linear Eyring plots were obtained.

Cyclic imides are a large class of compounds obtained by organic synthesis including several sub-classes (succinimides maleimide, glutarimide, phthalimides naphtalimides, and its derivatives). Recently, some cyclic imide derivatives have shown important results as potential antitumor agents, as a Mitonafide and Amonafide. Based on this fact, we have studied antitumoral properties of nine cyclic imide derivatives, four of which are unpublished compounds, against Murine Melanoma Cells (B16F10). Initially, the MTT assay was used to select the compound with the best cytotoxic potential. After this selection, the compound 2-benzyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (4), which showed the best cytotoxic effects, was evaluated by flow cytometry, and a significant increase was observed in the proportion of cells in the subG0/G1, S and G2/M phases accompanied by a significant decrease in the G0/G1 phases. Then the mechanism involved on the death route (necrosis or apoptosis) was evaluated the by bromide and acridine orange method and by an Annexin V-FITC Apoptosis Detection kit. These results confirm that the percentage of B16F10 cells observed in the sub G0/G1 phase were undergoing apoptosis. The biological effects observed in the current study for the cyclic imide derivatives suggested promising applications, especially for the prototype compound 4.

National Natural Science Foundation of China[20832005]; National Basic Research Program (973 Program) of China[2010CB833200]

Cyclic imides were synthesized from simple diols with primary amines in a single step using an in situ generated ruthenium catalytic system. The developed methodology is atom economical and operatively simple for the syntheses of succinimides, phthalimides, and glutarimides, which are important building blocks in natural products and drugs. Other recent approaches for the cyclic imide synthesis were also reviewed.

We have previously synthesized a novel piperidine compound, 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide), that inhibits LPS-induced NO production, and in the present research we studied further the anti-inflammatory activity of DTCM-glutarimide in a macrophage cell line and in mice bearing transplanted hearts. Mouse macrophage-like RAW264.7 cells were employed for the evaluation of cellular inflammatory activity. DTCM-glutarimide was synthesized in our laboratory. The AP-1 activity was measured by nuclear translocation and phosphorylation. For the heart transplantation experiment, male C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donor and recipient, respectively. DTCM-glutarimide was administered intraperitoneally. DTCM-glutarimide inhibited the LPS-induced expression of iNOS and COX-2 in macrophages; but, unexpectedly, it did not inhibit LPS-induced NF-κB activation. Instead, it inhibited the nuclear translocation of both c-Jun and c-Fos. It also inhibited LPS-induced c-Jun phosphorylation. Moreover, it inhibited the mixed lymphocyte reaction in primary cultures of mouse spleen cells; and furthermore, in mice it prolonged the graft survival in heart transplantation experiments. The novel piperidine compound, DTCM-glutarimide, was found to be a new inhibitor of macrophage activation, inhibiting AP-1 activity. It also inhibited graft rejection in mice, and thus may be a candidate for an anti-inflammatory agent.

The total synthesis of (-)-julocrotine (1) starting from l-glutamic acid in 41% overall yield is described. The methodology utilizes protection, deprotection, and regioselection (carbonyl differentiation via oxazolidinone) protocols, and glutarimide ring formation is the key step.

When synthesizing arylpiperazine library modified with N-acylated amino acid derivatives (e.g., cyclized aspartic acid, cyclized glutamic acid, proline) we wished to rapidly determine the way of cyclization of N-acylated glutamic acid derivatives. During concomitant cleavage and cyclization two alternative routes were possible—either formation of six-member imide (glutarimide) or five-member lactam. Application of MS/MS and 1H NMR method allowed us to establish that cyclization of N-acylated glutamic acid derivatives preceded to lactams—N-acylated pyroglutamic acid derivatives. Under acidic treatment the Lantern bound N-acylated glutamic acid derivatives underwent concomitant cleavage and cyclization. Herein, we studied two alternative cyclization routes—imides, lactams. It was found that cyclization of N-acylated glutamic acid derivatives yielded pyroglutamic acid derivatives (Structure C).