Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-ß, and Oxidative Stress in Alzheimer's Disease.

The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-ß (Aß) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure-reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Aß sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Aß aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Aß, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.

Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands.

A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as antiproliferation agents. The biologic activity of the acridone compounds against leukemia CCRF-CEM cells demonstrated that some of the compounds displayed good antiproliferative activity, among which compound 6a containing dimethylamine substituents at the terminal C2 and C7 positions exhibited the highest cytotoxicity with IC50 at 0.3µM. In addition compound 6a showed little toxicity against normal 293T cells proliferation with IC50 more than 100µM. Further study indicated that compound 6a had strong binding activity to human telomeric G-quadruplex DNA, as detected by mass spectrometry, CD spectroscopy, UV absorption, FRET and fluorescence quenching assays. Our data suggested that the activity of 6a might be associated with its stabilization of G-quadruplex DNA, which can be developed as potent antitumor agent.

Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents.

A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 µM for AChE and 0.82-11.45 µM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aß aggregation inhibitory activity at 20 µM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease.

TDAE strategy for the synthesis of 2,3-diaryl N-tosylaziridines.

We report herein an original and rapid synthesis of 2,3-diaryl N-tosylaziridines by TDAE strategy starting from ortho- or para-nitro(dichloromethyl)benzene derivatives and N-tosylimines. A mixture of cis/trans isomers was isolated from 1-(dichloromethyl)-4-nitrobenzene, whereas only trans-aziridines were obtained from ortho-nitro derivatives.

Role of surface-bound intermediates in the oxygen-assisted synthesis of amides by metallic silver and gold.

A general mechanism for the oxygen-assisted synthesis of amides over metallic gold and silver surfaces has been derived from the study of acetaldehyde and dimethylamine in combination with previous work, allowing detailed comparison of the two surfaces' reactivities. Facile acetylation of dimethylamine by acetaldehyde occurs with high selectivity on oxygen-covered silver and gold (111) crystals via a common overall mechanism with different rate-limiting steps on the two metals. Adsorbed atomic oxygen activates the N-H bond of the amine leading to the formation of an adsorbed amide, which attacks the carbonyl carbon of the aldehyde, forming an adsorbed hemiaminal. Because aldehydes are known to form readily from partial oxidation of alcohols, our mechanism also provides insight into the related catalytic coupling of alcohols and amines. The hemiaminal ß-H eliminates to form the coupled amide product. On silver, ß-H elimination from the hemiaminal is rate-limiting, whereas on gold desorption of the amide is the slow step. Silver exhibits high selectivity for the coupling reaction for adsorbed oxygen concentrations between 0.01 and 0.1 monolayer, whereas gold exhibits selectivity more strongly dependent on oxygen coverage, approaching 100% at 0.03 monolayer. The selectivity trends and difference in rate-limiting steps are likely due to the influence of the relative stability of the adsorbed hydroxyl groups on the two surfaces. Low surface coverages of oxygen lead to the highest selectivity. This study provides a general framework for the oxygen-assisted coupling of alcohols and aldehydes with amines over gold- and silver-based catalysts in either the vapor or the liquid phase.

Preparation and in vitro photodynamic activity of amphiphilic zinc(II) phthalocyanines substituted with 2-(dimethylamino)ethylthio moieties and their N-alkylated derivatives.

Treatment of 4,5-dichlorophthalonitrile with 2-(dimethylamino)ethanethiol hydrochloride and K(2)CO(3) afforded 4,5-bis[2-(dimethylamino)ethylthio]phthalonitrile or a heterocycle-fused phthalonitrile depending on the reaction temperature. The latter has been spectroscopically and structurally characterized. Both compounds underwent mixed cyclization with 3equiv of unsubstituted phthalonitrile in the presence of Zn(OAc)(2).2H(2)O and 1,8-diazabicyclo[5.4.0]undec-7-ene to give the corresponding 2,3-disubstituted zinc(II) phthalocyanines. N-methylation or pentylation of the bis[2-(dimethylamino)ethylthio] substituted analogue resulted in the formation of the respective dicationic phthalocyanines. For comparison, the octa-substituted analogues were also prepared by base and zinc-promoted self-cyclization of 4,5-bis[2-(dimethylamino)ethylthio]phthalonitrile followed by N-methylation. The spectroscopic and basic photophysical properties of these di- and octa-substituted phthalocyanines were examined in N,N-dimethylformamide. All of them remained essentially non-aggregated, showed moderate fluorescence emission, and could generate singlet oxygen, except the heterocycle-fused analogue, of which the singlet excited state was reductively quenched by the amino substituent. The photocytotoxicity of these compounds was also evaluated against HepG2 human hepatocarcinoma cells and HT29 and T84 human colon adenocarcinoma cells. The disubstituted amphiphilic phthalocyanines are particularly potent with IC(50) values down to 0.08microM. Fluorescence microscopic studies revealed that the non-ionic derivative has selective affinity to the mitochondria of HT29 cells, while its di-N-methylated analogue shows preferential localization in the cell membrane.

Behenamidopropyl Dimethylamine: unique behaviour in solution and in hair care formulations.

SYNOPSIS: The rise of ecological awareness among consumers and industry has impacted the cationic surfactants market. The most used cationic surfactants present some drawbacks in this sense. Therefore, new molecules are being studied and developed which fulfil eco-toxicological requirements without losing performance. One of these surfactants is Behenamidopropyl Dimethylamine (BAPDMA). This biodegradable amidoamine, which converts into a cationic surfactant at acidic pH, shows outstanding water solubility, despite its very long alkyl chain. Its behaviour in solution has been exhaustively studied. The conditioning performance of this product is superior to that of commonly used cationic surfactants, providing a superior sensorial profile and improved combing force reductions on hair. Moreover, other applications for this product in the non-ionic form have been studied, such as conditioning agent in 2 in 1 shampoos, where it also shows colour protection effects, and as gelling agent in hair colouration creams. This multifunctional and high performance profile, together with an improved biodegradation and aquatic toxicity compared with currently used cationic surfactants, make this product a very interesting eco-friendly alternative for the hair care market.

Novel N,N '-diacyl-1,3-diaminopropyl-2-carbamoyl bivalent cationic lipids for gene delivery--synthesis, in vitro transfection activity, and physicochemical characterization.

Novel N,N'-diacyl-1,3-diaminopropyl-2-carbamoyl bivalent cationic lipids were synthesized and their physicochemical properties in lamellar assemblies with and without plasmid DNA were evaluated to elucidate the structural requirements of these double-chained pH-sensitive surfactants for potent non-viral gene delivery and expression. The highest in vitro transfection efficacies were induced at +/-4:1 by the dimyristoyl, dipalmitoyl and dioleoyl derivatives 1,3lb2, 1,3lb3 and 1,3lb5, respectively, without inclusion of helper lipids. Transfection activities were reduced in the presence of either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine alone or in combination with cholesterol for all derivatives except 1,3lb5, which maintained reporter gene expression levels at +/-4:1 and yielded increased lipofection activity at a lower charge ratio of +/-2:1. Ethidium bromide displacement indicated efficient plasmid DNA binding and compaction by the transfection-competent analogs. Dynamic light-scattering and electrophoretic mobility studies revealed lipoplexes of the active lipids with large particle sizes (mean diameter>or=500 nm) and zeta potentials with positive values (low ionic strength) or below neutrality (high ionic strength). Langmuir film balance studies showed high in-plane elasticity of these derivatives in isolation. In agreement with the monolayer experiments, fluorescence polarization studies verified the fluid nature of the highly transfection-efficient amphiphiles, with gel-to-liquid crystalline phase transitions below physiological temperature. The active compounds also interacted with endosome-mimicking vesicles to a greater extent than the poorly active derivative 1,3lb4, as revealed by fluorescence resonance energy transfer experiments. Taken together, the results suggest that well-hydrated and highly elastic cationic lipids with increased acyl chain fluidity and minimal cytotoxicity elicit high transfection activity.

[11C]-dimethylamine as a labeling agent for PET biomarkers.

The dimethylamine functional group is a common component of the chemical structure of numerous drugs. The most commonly used synthetic route for carbon-11 labeled radiopharmaceuticals which contain the dimethylamine group is via C-11 methylation of the monomethyl amine precursors. Here we describe the radiosynthesis of [11C]dimethylamine (1) and its application in the direct labeling of several positron emission tomography (PET) imaging agents by-passing the preparation of the monomethyl amine precursors.

A knot polymer mediated non-viral gene transfection for skin cells.

A knot polymer, poly[bis(2-acryloyl)oxyethyl disulphide-co-2-(dimethylamino) ethyl methacrylate] (DSP), was synthesized, optimized and evaluated as a non-viral vector for gene transfection for skin cells, keratinocytes. With recessive dystrophic epidermolysis bullosa keratinocytes (RDEBK-TA4), the DSP exhibited high transfection efficacy with both Gaussia luciferase marker DNA and the full length COL7A1 transcript encoding the therapeutic type VII collagen protein (C7). The effective restoration of C7 in C7 null-RDEB skin cells indicates that DSP is promising for non-viral gene therapy of recessive dystrophic epidermolysis bullosa (RDEB).

Synthesis and antiallergy activity of N-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamide derivatives.

A series of N-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamides was synthesized and evaluated for antiallergy activity. Several derivatives had activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity, but no derivative tested had activity at 10 mg/kg in the guinea pig anaphylaxis (GPA) assay. One analogue, N-[2-(dimethylamino)ethyl]-4-(4-fluorophenyl)-1-piperazinecarboxamide , had an IC50 = 310 nM for inhibition of tritiated mepyramine binding to H1 histaminic receptors isolated from guinea pig cerebral cortex.

Synthesis and evaluation of novel alkylpiperazines as potential dopamine antagonists.

Several alkylpiperazines, monocyclic subfragments of known tricyclic neuroleptic agents, were evaluated as dopamine antagonists in the isolated rabbit ear artery preparation. Compound prepared and evaluated are of the general structure Ar-X-(CH2)n-Y, where X = C, O, and N, n = 1-3, and Y, for the most part, was 4-methylpiperazine. Those compounds where X - NH, n = 3, and X = (Z)-CH - CH, n = 2, with an electron-withdrawing group meta to the side chain, possess dopamine antagonist activity comparable to that of clozapine. It is concluded that the entire tricyclic structure of phenothiazine-like agents (or at least more than a monocyclic ring system) is necessary for optimal activity as a dopamine antagonist in the receptor preparation used in this study.

Conformationally restricted analogs of histamine H1 receptor antagonists: trans and cis-1-benzyl-3-dimethylamino-6-phenylpiperidine.

The syntheses of trans- and cis-1-benzyl-3-dimethylamino-6-phenylpiperidine (1 and 2) are described. Compounds 1 and 2 were found to be inhibitors to histamine, acetylcholine, and barium chloride induced contractions of the isolated guinea pig ileum. Compounds 1 and 2 do not exhibit appreciable stereoselectivity in their ability to inhibit smooth muscle contractions. The cis compound 2 is a more effective inhibitor of histamine N-methyltransferase than the trans isomer 1.

Chemistry and biological activities of N,N-dimethylaminoethyl acrylate, a choline acetyltransferase inhibitor.

N,N-Dimethylaminoethyl acrylate (acryl-DMA) was synthesized as a tertiary nitrogen choline acetyltransferase (ChAc) inhibitor which would be able to penetrate biological membranes to inhibit ChAc in the nerve terminal. The synthesis from dimethylaminoethanol and acrylyl chloride was described and the hydration with times in an aqueous medium measured by NMR spectroscopy was presented. The autohydrolysis in water was found to be 1.75 x 10(-8) mol/min at pH 7.4 and 5.0 mM concentration. The enzymatic hydrolysis was unaffected by cholinesterases. Acryl-DMA was capable of inhibiting ChAc extracted from rat brain with I50 of 5.02 x 10(-4) M. The inhibition was reversible and displayed uncompetitive kinetics with respect to both substrates, choline and acetyl-CoA. Neither the hydrolysis nor the hydration products of acryl-DMA could inhibit ChAc. Although acryl-DMA was hydrated rapidly and completely within 1 hr at high pH (9.0), the time course of inhibition ability of acryl-DMA in aqueous medium at physiological pH was found to decrease rather slowly and by 36% in 1 hr, indicating that acryl-DMA can survive from hydration at physiological pH. Acryl-DMA was also tested for its ability to block electrically induced muscle contractions in both isolated skeletal and smooth nerve-muscle preparations. The ED50's obtained were less than 5 x 10(-4) M in both cases.

6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents.

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.

A [2 + 2] cycloaddition route to dimethylaminomethylene vinamidinium salts.

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).

Evaluation of commercial and newly-synthesized amine accelerators for dental composites.

The characteristics of newly synthesized tertiary aromatic amines as accelerators for restorative resins have been evaluated. Comparison of the composites prepared with these and presently used accelerators indicate that resins formulated with 4-N,N-dimethylaminophenylacetic acid, its methyl ester or N,N-dimethylaminoglutethimide have properties generally better than comparable resins prepared with commercially used amines.

Some effects of 1-(2,4-Dichlorophenyl)-4-dimethylamino-methyl-1-nonen-3-one hydrochloride on Escherichia coli GK-19.

1-(2,4-Dichlorophenyl)-4-dimethylaminomethyl-1-nonen-3-one hydrochloride (Id) was shown to inhibit the growth of Escherichia coli GK-19 at a concentration of 50 micrograms/mL in a medium of pH 6.5. Maximal antibacterial activity was found during the logarithmic growth phases rather than at the early stationary phase. Electron microscopy revealed that Id caused lysis, and inhibition of respiration and retardation of RNA and protein syntheses occurred in the bacteria with this compound at 50 micrograms/mL.

Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase.

A series of nine dimethylamino-chalcone derivatives (1,3-diaryl-propenones) was synthesized and screened as potential inhibitors of NO and PGE(2) production in the RAW 264.7 macrophage cell line. 4-Dimethylamino-2',5'-dimethoxychalcone (6) was found to be the most potent and dual inhibitor (IC(50s) in the submicromolar range) of NO and PGE(2) production. 2',6'-Dimethoxylation appeared to be an effective requirement for selective and potent inhibition of nitric oxide synthase induction as it was confirmed by Western blot analysis. Chalcone (6) at 25 mg kg(-1) by oral route, inhibited significantly the formation of oedema in the carrageenan-induced model of inflammation in mice.

Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells.

1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T-lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4-chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2-acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5-fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies.