Imide Functions Research Articles

(S)-trans-cyclohexane-1,2-dicarboximide.

The molecule of the title compound, C(8)H(11)NO(2), contains a strained bicyclic system with a significantly twisted imide chromophore. The five-membered ring fragment containing the imide function is strongly puckered and adopts a half-chair conformation. The six-membered ring has a slightly distorted chair conformation. The molecules are joined by strong N-H.O and weak C-H.O hydrogen bonds into infinite chains.

Plasma stability of two glycosyl indolocarbazole antitumor agents

In recent years, several glycosyl indolocarbazole derivatives have been developed as antitumor agents targeting the topoisomerase I-DNA complex and a few of them were evaluated in clinical trials. The lead drug in the series is compound A which bears a formylamino substituent on the N-imide F-ring. This compound has shown promising antitumor activities in vivo and was tested clinically but it has been recently replaced with a more active analogue, J-107088, bearing a (hydroxymethyl-2-hydroxy) ethylamino substituent on the N-imide F-ring. We have compared the plasma stability of two molecules in this series, compounds A and D, which only differ by the nature of the group on the imide ring. The conversion of the compounds into the anhydride species B was studied by HPLC and the resulting metabolite, formed both in human plasma ultrafiltrate and in water, was characterized by NMR and mass spectrometry. Absorption measurements provided a facile method to follow the conversion of compounds A and D into their metabolite product B. Altogether, the experimental data demonstrate that the replacement of the NHCHO substituent of compound A with a hydrophilic NHCH(CH 2OH) 2 chain preserves the intact imide function that is known to be essential for topoisomerase I inhibition and cytotoxicity. The transformation of compound A into the anhydride metabolite B (or its diacid open form) occurs much more slowly compared to compound D. Half-life parameter t 1/2 of 67 and 245 min −1 were calculated for compounds A and D, respectively. A molecular modeling analysis, performed to compare the conformation and electronic properties of compounds A and D, offers a rational explanation for the gain of chemical stability of the indolocarbazole derivative D. The data provide important information for the rational design of antitumor indolocarbazole derivatives.

Fluorescence sensing of ionic analytes in water: from transition metal ions to vitamin B13.

The fluorescence chemosensor ATMCA has been realised by appending an anthrylmethyl group to an amino nitrogen of TMCA (2,4,6-triamino-1,3,5-trimethoxycyclohexane), a tripodal ligand selective for divalent first-row transition metal ions in water. The ATMCA ligand can act as a versatile sensor for ZnII and CuII ions. Its sensing ability can be switched by simply tuning the operating conditions. At pH 5, ATMCA detects copper(II) ions in aqueous solutions by the complexation-induced quenching of the anthracene emission. Metal ion concentrations < 1 microM can be readily detected and very little interference is exerted by other metal ions. At pH 7, ATMCA signals the presence of ZnII ions at concentrations < 1 microM by a complexation-induced enhancement of the fluorescence. Again the sensor is selective for ZnII over several divalent metal ions, with the exception of CuII, CoII and HgII. Most interestingly, the [ZnII(atmca)]2+ complex can act as a fluorescence sensor for specific organic species, notably selected dicarboxylic acids and nucleotides, by the formation of ternary ligand/zinc/substrate complexes. The oxalate anion is detected in concentrations <0.1 mM; however, no effects on the system's fluorescence is observed in the presence of monocarboxylic acids and long-chain dicarboxylic acids. Among the nucleotides, those containing an imide or amide function are readily detected and an unprecedented high sensitivity for guanine derivatives allows the determination of this nucleotide for 0.05-0.5 mM solutions. Moreover, [ZnII(atmca)]2+ is a very effective and selective sensor in the case of vitamin B13 (orotic acid) in sub-micromolar concentrations. The operative features of the systems investigated are also clearly suitable for intracellular analyses. The factors at the source of organic substrate recognition, here briefly discussed, are of paramount importance for further developments in the applicability of these sensing systems.

Zinc carbenoid-mediated chain extension of β-keto amides

The reaction of β-keto amides with ethyl(iodomethyl)zinc provides access to a wide variety of γ-keto amides, including primary, secondary, and tertiary amides. Although the reaction of α-substituted β-keto amides are in many cases unsatisfactory, the method can be applied to a broad spectrum of substrates that possess imide and olefinic functionality.

Frankiamide, a highly unusual macrocycle containing the imide and orthoamide functionalities from the symbiotic actinomycete Frankia.

Frankiamide, a highly unusual macrocycle containing the imide and orthoamide functionalities from the symbiotic actinomycete Frankia.

Fluorescent and electroactive cyclic assemblies from perylene tetracarboxylic acid bisimide ligands and metal phosphane triflates.

Tetraaryloxy-substituted perylene tetracarboxylic acid bisimides with one or two 4-pyridyl receptor substituents at the imide functionality were synthesized and employed in transition metal directed self-assembly with Pd(II) and Pt(II) phosphane triflates. Upon mixing of the components, quantitative formation of functional molecular square-type complexes containing four dye molecules and model complexes of a 2:1 (perylene bisimide ligand:transition metal ion) stoichiometry was observed. The isolated metallosupramolecular squares were characterized by 1H and 31P [1H] NMR spectroscopy as well as conventional electrospray ionization (ESI) and ESI-FTICR mass spectrometry, which gave evidence for the structure and the high stability of these giant cyclic dye assemblies (molecular weight (3a) 8172, Pt-Pt corner diagonal ca. 3.4 nm). Studies of the optical absorption and fluorescence properties and the electrochemistry and spectroelectrochemistry of both the perylene bisimide ligands and the perylene bisimide metal complexes show that Pt(II) coordination does not interfere with the optical and electrochemical properties of the perylene bisimide ligands; this gives squares with high fluorescence quantum yields (phiF (3a)=0.88) and three fully reversible redox couples. The latter could be unambiguously related to quantitative formation of perylene bisimide radical cations (E1/2 = +0.93 V vs. Fc/Fc+), radical anions (E1/2= - 1.01 V vs. Fc/Fc+), and dianions (E1/2 = -1.14 V vs. Fc/Fc+); these redox reactions change the charge state of the cyclic assembly from +12 to zero. In contrast, Pd(II) coordination influenced the electrochemical properties of the assembly because of an irreversible palladium reduction at E1/2= -1.15 V versus Fc/Fc+. Finally, dynamic ligand exchange processes between different metallosupramolecular assemblies were investigated by multinuclear NMR and electrospray mass spectrometry. These studies confirmed the reversible nature of the pyridine-Pt(II)/Pd(II) coordination process.

Covalently bonded heparin to alter the pericardial calcification.

Calcification is the leading cause of failure of a wide spectrum of cardiovascular and non-cardiovascular medical devices. In this study our aim was to immobilize polyethylene glycol (PEG) and heparin on multiple crosslinked bovine pericardium with Glutaraldehyde (GA) and carbodiimide. Grafting of PEG and heparin through an intermediate tissue bound substrate containing aldehyde and imide functional groups showed reduction in calcification. In this experimental protocol, we used Golomb and Wagner's in vitro model for studying pericardial calcification and a diffusion cell with two compartments for evaluating the diffusion of calcium across the BP. The results showed that heparin immobilization on the surface reduces calcification independent of its concentration in the incubating medium. It is conceivable that inactivation of unpaired aldehydic moieties present in pericardium after exposure to GA act as potential site for PEG grafting and imide functionalities of EDC can covalently bind heparin, would be the key step in the prevention of calcification. It is well-established fact that heparin has a potent antithrombotic effect. But the exact role of heparin in the anticalcification process of bioprostheses still remain elusive.

Amphiphilic 3-Arm Star Block Polymers by Living Cationic Polymerization

Via living cationic polymerization with a trifunctional initiator, amphiphilic tri-armed star block copolymers were synthesized, where each arm consisted of an AB-block copolymer with a hydrophobic and soft vinyl ether segment and a hydrophilic (amine-containing) and hard styrene segment. The sequential living polymerization was initiated first for 2-chloroethyl vinyl ether (CEVE) with the trifunctional HCl-adduct (1) of a trivinyl ether in conjunction with SnCl4 in the presence of n-Bu4NCl and 2.6-di-tert-butyl-4-methylpyridine (DTBMP) in CH2Cl2 at −78 °C, followed by block polymerization of p-(phthalimidemethyl)styrene (ImSt). The polymers had 3 arm chains with controlled molecular weights and compositions and with narrow molecular weight distributions (Mw/Mn∼1.3). Similar star amphiphiles were prepared by “one-shot” living cationic block polymerizations of CEVE and ImSt with 1/SnCl4/DTBMP in CH2Cl2 at −15 °C, due to the large reactivity difference between the two monomers (CEVE >> ImSt). Hydrazinolysis of the imide functions gave tri-armed amphiphilic block copolymers consisting of a hydrophobic poly(CEVE) soft segment and a hydrophilic hard polystyrene segment with pendant primary amino groups, soluble in dimethyl sulfoxide, methanol, water, and 0.5N HCl. Besides the soft-hard (CEVE–ImSt) version, the soft-soft tri-armed polymers were also prepared, consisting of an amino-functionalized hydrophilic soft poly(vinyl ether) segment and a hydrophobic poly(CEVE) segment. The surface tension of the tri-armed polymers was smaller than that of the linear block (or arm) polymers. Small angle light scattering measurement showed that these tri-armed copolymers exit as unimers in water.

A Convenient Route to Quinolone-Fused Imides and Lactams: Synthesis of Pyrrolo[3,4-b]quinoline-3,9-diones and 1,3,9-triones by Oxidation of Indole Derivatives

Pyrrolo[3,4-b]quinoline-3,9-diones have been obtained by Winterfeldt's oxidation (O2, t-BuOK, DMF) of readily available N(b)-substituted tetrahydropyrido[3,4-b]indol-1-ones (tetrahydrocarbazol-1-ones). Surprisingly, the oxidation using N(b)-unsubstituted analogue as starting material afforded under the same conditions pyrrolo[3,4-b]quinoline-1,3,9-trione. The difference in reactivity was interpreted. Two unknown pyrrolo[3,4-b]quinoline-1,9-dione derivatives have been synthesized by regioselective reduction of the imide function.

Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin

The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3–6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.

Syntheses and biological evaluation of indolocarbazoles, analogues of rebeccamycin, modified at the imide heterocycle.

A series of 10 indolocarbazole derivatives, analogues to the antitumor antibiotic rebeccamycin, bearing modifications at the imide heterocycle were synthesized. They bear an N-methyl imide, N-methyl amide, or anhydride function instead of the original imide. Their inhibitory potencies toward topoisomerase I were examined using a DNA relaxation assay and by analyzing the drug-induced cleavage of 32P-labeled DNA. Protein kinase C (PKC) inhibition and interaction with DNA were also studied together with the in vitro antiproliferative activities against B16 melanoma and P388 leukemia cells. The antimicrobial activities against two Gram-positive bacteria (Bacillus cereus and Streptomyces chartreusis), a Gram-negative bacterium (Escherichia coli), and a yeast (Candida albicans) were tested as well as their antiviral activities toward HIV-1. The efficiency of the anhydride compounds was compared to that of the parent compound rebeccamycin and its dechlorinated analogue. All the compounds studied were inactive against PKC. The structural requirements for PKC and topoisomerase I inhibition are markedly different. In sharp contrast with the structure-PKC inhibition relationships, we found that an anhydride function does not affect topoisomerase I inhibition, whereas a methyl group on the indole nitrogen prevents the poisoning of topoisomerase I. The compounds exhibiting a marked toxicity to P388 leukemia cells had little or no effect on the growth of P388CPT5 cells which are resistant to the topoisomerase I inhibitor camptothecin. This study reinforces the conclusion that the DNA-topoisomerase I cleavable complex is the primary cellular target of the indolocarbazoles and significantly contributes to their cytotoxicity and possibly to their weak but noticeable anti-HIV-1 activities. The structure-activity relationships are also discussed.

Electron Transport in Vapor-Deposited Naphtlalene Dicarboximide Glasses

Electron mobilities have been measured in vapor-deposited layers of N-(1,2-dimethylpropyl)benzo[k,l]thioxanthene-3,4-dicarboximide-7,7-dioxide (BTDD) and N,N′-bis(1,2-dimethylpropyl)-1,4,5,8-naphthalenetetracarboxylic diimide (NTDI). BTDD is a highly polar acceptor molecule that incorporates both an imide and a sulfone electronegative functionality. NTDI is a weakly polar acceptor molecule that contains two imide functionalities. The results are described by a formalism based on disorder, due to Bässler and coworkers. The formalism is based on the assumption that transport occurs by hopping through a manifold of localized states that are distributed in energy. The key parameter of the formalism is σ, the energy width of the hopping site manifold. The width is described by a model based on dipolar disorder. The model is premised on the argument that the width is comprised of a dipolar component σ d and a van der Waals component σ vdW. Describing the dipolar component by an expression due to Young yields σ d=0.133 eV for BTDD and 0.009 eV for NTDI. The van der Waals component for both molecules is 0.092 eV. The difference in the dipolar component is the principal reason for the large difference in mobility of these molecules.

Chemistry and reactivity of carboxylic acid-containing surfaces

Polymer surface modification techniques, such as corona, plasma, and ultraviolet treatments, promote adhesion to polymer surfaces through introduction of specific functional groups that interact with subsequent coating layers. Carboxylic acid groups formed during corona and plasma treatments may play a significant role in adhesion promotion, so such groups have been chosen for model surface chemistry studies. Thin films (<30 nm) of the potassium salt of poly(acrylic acid) (PAA) and poly(vinyl methyl ether-co-maleic acid) (VME-MA) copolymer were analyzed before and after surface protonation by dilute acid solution. The reactive nature of the acid groups was probed using infrared reflection absorbance spectroscopy (IRRAS) to analyze the entire thin film and high-resolution electron energy loss spectroscopy (HREELS) to analyze the top 1-2 nm. The HREELS results show that it is possible to obtain surfaces enriched in carboxylic acid groups by protonation of the potassium salts of PAA and VME-MA. Anhydride formation, followed as a function of temperature, went to completion quickly (5-10 min) at the surface, whereas complete conversion did not occur in the bulk thin film even after 4 h. PAA formed anhydride at 160°C, as compared to 100°C for VME-MA. The large difference between the temperature for anhydride formation in PAA and VME-MA may be a result of the adjacent acid groups available for forming anhydride in VME-MA, or the high Tg of PAA (105°C) relative to that of VME-MA (80°C). IRRAS and HREELS show that PAA and VME-MA form imide functionalities following butylamine exposure and heating at 125°C. The reactive nature of PAA and VME-MA at elevated temperatures suggests that acid-containing surfaces are good candidates for reaction with organic materials containing primary amine groups, an example being gelatin, which is the binder used in photographic emulsions.

Syntheses and Reactions of 1′,2′‐Unsaturated 2′,3′‐Seconucleoside Analogues

AbstractThe 1′,2′‐unsaturated 2′,3′‐secoadenosine and 2′,3′‐secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′‐ditosylates, 2 and 18, respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to HC(4′). The retained (tol‐4‐yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′‐azido, 3′‐chloro, and 3′‐hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr2 in dry CH2Cl2 was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid‐sensitive, ketene‐derived N,O‐ketal function. In the uridine series, base‐promoted regioselective elimination (→19), nucleophilic displacement of the tosyl group by azide (→20), and debenzylation of the protected N(3)‐imide function gave 1′,2′‐unsaturated 5′‐O‐trityl‐3′‐azido‐secouridine derivative 21. The same compound was also obtained by the elimination performed on 2,2′‐anhydro‐3′‐azido‐3′‐azido‐3′‐deoxy‐5′‐O‐2′,3′‐secouridine (22) that reacted with KO(t‐Bu) under opening of the oxazole ring and double‐bond formation at C(1′).

N-aryl-N'-benzylpiperazines as potential antipsychotic agents.

N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.

Photochemistry of 1,2 : 4,5-Benzenebis(dicarboximide). Insertion of Alkenes into the C-N Bond of N,N′-Dihexyl-1,2 : 4,5-benzenebis(dicarboximide)

Abstract In the photolyses of acetonitrile solutions of N,N′-dihexyl-1,2 : 4,5-benzenebis(dicarboximide) (1) and alkenes, insertion of the double bond in the alkenes into the C–N bond of the imide function of 1 was observed. The insertion reaction proceeded along with a retention of the stereochemistry of the alkenes in reactions with trans- and cis-2-butene.

Regioselective Allylations of Pyrimidine Ribonucleosides Using Pd(0) Catalyst

Abstract A novel procedure for regiospecific O-allylation of pyrimidine ribonucleosides is reported by using Pd(PPh3)4–allyl ethyl carbonate reagent to synthesize 2′-O-allyluridine and 2′-O-allylcytidine. 3-N-allylation of the pyrimidine ring is prevented by protection of uridine imide function by 4-O-(2,5-dimethylphenyl) group which can be transformed to 4-oxo function of uridine or exocyclic amino function of cytidine.

New functional polyamides derived from citric acid and L‐lysine: Synthesis and characterization

AbstractNew functional aliphatic polyamides bearing pendant carboxylic acid and tertiary alcohol groups have been synthesized by step‐growth polymerization of protected citric acid in the diacyl chloride activated form and protected L‐lysine using the interfacial method. It has been found that a secondary reaction occurs during polymerization and leads to the formation of intramolecular imide cycles. Cleavage of protecting groups and partial or total hydrolysis of imide functions were carried out stepwisely. Resulting structural changes are discussed on the basis of IR and 13C NMR data.

Synthesis of a Series of Functionalized Bis-Crown Ethers

A new series of bis-crown ethers bearing either acid, alcohol and amine side chains as well as imide and lactam functions have been synthesized.

(S,S)-diphenyl-ethanediamine (DPEDA) derivatives as chiral selectors Part I. Undecenoyl bound dinitrobenzoyl-DPEDA as a broadly applicable chiral stationary phase

The synthesis of optically pure (S,S)-N-3,5-dinitrobenzoyl-1,2-diphenylethane-1,2-diamine (DNB-DPE-DA) immobilized via an undecenoyl spacer onto silica gel and the resolving power of this new chiral stationary phase (CSP) for normal phase HPLC are described. The phase shows good enantioselectivity for various chiral compounds containing amide (imide) functionality and π-donor type aromatic subsitutents, and also for some alcohols and sulfoxides. The influence of protic and nonprotic mobile phase components on the enantioselectivity has also been examined.