Alkylamine Side Chain Research Articles

Influence of Lipid Composition on Membrane Activity of Antimicrobial Phenylene Ethynylene Oligomers

Host defense peptides (HDPs), part of the innate immune system, selectively target the membranes of bacterial cells over that of host cells. As a result, their antimicrobial properties have been under intense study. Their selectivity strongly depends on the chemical and mostly structural properties of the lipids that make up different cell membranes. The ability to synthesize HDP mimics has recently been demonstrated. To better understand how these HDP mimics interact with bilayer membranes, three homologous antimicrobial oligomers (AMOs) 1-3 with an m-phenylene ethynylene backbone and alkyl amine side chains were studied. Among them, AMO 1 is nonactive, AMO 2 is specifically active, and AMO 3 is nonspecifically active against bacteria over human red blood cells, a standard model for mammalian cells. The interactions of these three AMOs with liposomes having different lipid compositions are characterized in detail using a fluorescent dye leakage assay. AMO 2 and AMO 3 caused more leakage than AMO 1 from bacteria membrane mimic liposomes composed of PE/PG lipids. The use of E. coli lipid vesicles gave the same results. Further changes of the lipid compositions revealed that AMO 2 has selectively higher affinity toward PE/PG and E. coli lipids than PC, PC/PG or PC/PS lipids, the major components of mammalian cell membranes. In contrast, AMO 3 is devoid of this lipid selectivity and interacts with all liposomes with equal ease; AMO 1 remains inactive. These observations suggest that lipid type and structure are more important in determining membrane selectivity than lipid headgroup charges for this series of HDP mimics.

Chromatographic and Mass Spectral Studies on Methoxy Methyl Methamphetamines Related to 3,4-Methylenedioxymethamphetamine

The methoxy methyl methamphetamines are a unique set of compounds having an isobaric relationship with the controlled drug substance 3,4-methylenedioxymethamphetamine (3,4-MDMA or Ecstasy). The various isomeric forms of the methoxy methyl methamphetamines have mass spectra essentially equivalent to 3,4-MDMA, all have molecular weight of 193 and major fragment ions in their electron ionization mass spectra at m/z 58 and 135/136. Mass spectral differentiation of 3,4-MDMA from some of the methoxy methyl methamphetamines was possible after formation of the perfluoroacyl derivatives, pentafluoropropionamides (PFPA) and heptafluorobutyramides (HFBA). Perfluoroacyl derivatization provided unique and characteristic mass spectral fragment ions when the methoxy group is substituted at the 2- or 4-position of the aromatic ring relative to the alkylamine side chain group. Perfluoroacyl derivatization did not offer any characteristic ions for discrimination of 3,4-MDMA from the 3-methoxy ring substituted methyl methamphetamines. Gas chromatographic separation on non-polar stationary phases successfully resolved subsets of the methoxy methyl methamphetamines, based on ring position of the methoxy group, from 2,3- and 3,4-MDMA as the PFPA and HFBA derivatives.

Polarizabilidade atômica efetiva alfad pode ditar a ionização de radioligantes 99Tc m - diaminoditiol alquilamínicos?

Polarizability correlates well with organic ion stabilization in solution and can be defined as a measure of the relative ease of the distortion of the electronic cloud of a dipolar system exposed to an external electric field. The effective atomic polarizability, ad, has a fundamental influence on chemical reactivity in the gas phase and in solution. In terms of chemical reactivity the charge is generated within the molecule as a positive charge due to protonation, ionization or resulting from the attack of a nucleophilic anion. In this paper, lipoidal diaminedithiol (DADT) perfusion radioligands based on 99Tcm and possessing an alkylamine side chain have been used to check the influence of ad on their brain uptake. Some new DADT derivatives, respectively DADT-DIPA (diaminedithiol - diisopropylamine), DADT DIBA (diaminedithiol diisobutylamine), DADT-PR (diaminedithiol - branched pyperidine), have been designed to have high nitrogen alkylamine ad values. In spite of the fact of higher ad values having been correlated to higher brain uptakes, there isn't a clear mechanism able to trap these radioligands into the brain space.

Facially amphiphilic phenylene ethynylenes

AbstractFacially amphiphilic poly(phenylene ethynylenes) were synthesized with various non‐polar alkyl and polar amine side chains by Sonogashira‐Hagihara coupling conditions. para‐Phenylene ethynylene derivatives with pentoxy and tertiary amine side chains were dissolved in organic solvent, such as toluene or 1,2,4‐trichlorobenzene, and introduced into an acidic, aqueous environment. The polymer molecules were found to self‐assemble and stabilize these oil‐water interfaces as visualized by confocal scanning laser microscopy. meta Derivatives containing dodecyl and primary amine side chains were also prepared and found to be active at the air‐water interface. When analyzed by Langmuir trough experiments, this polymer was found to have an area of approximately 45 Å2 per repeat unit, which correlates to an edge‐on orientation at the air‐water interface where the polar groups are immersed in the water sub‐phase and both the hydrocarbon backbone and dodecyl chains extend away from the interface. Due to the facially amphiphilic architecture and large hydrocarbon side chains, these polymers were found to self‐assemble from aqueous solutions into large aggregates with some order. Copyright © 2005 John Wiley & Sons, Ltd.

Photophysical and photochemical properties of amitriptyline and nortriptyline hydrochloride: a 266 nm nanosecond laser flash and theoretical study

Amitriptyline (AMI) and nortriptyline (NT) hydrochlorides were studied by 266 nm laser transient absorption spectroscopy and quantum theoretical calculations. Both drugs photoionize through a biphotonic mechanism producing a radical cation and the solvated electron. A triplet excited state in a twisted conformation around the exocyclic bond is proposed as the intermediate state in the photoionization process. The solvated electron reacts with the ground state drug molecules with rate constants of 6.5 and 5.5×10 9 M −1 s −1 to form electron adducts, that absorb in the same wavelength region as the radical cation. Photosensitization experiments using thioxanthone triplet state as the sensitizer demonstrated that AMI or NT quenches this state by a mechanism that depends on the protonation of the amino group in the alkylamine side chain. The protonated species favors energy transfer, while the unprotonated species produces the tricyclic antidepressive radical cation of these drugs and the thioxanthone ketyl radical. These results follow the Rehm–Weller equation for an electron transfer mechanism. Quantum theoretical calculations indicate that ground and excited singlet states photophysical properties of these molecules are determined by the 1,2-diphenylethane system with little participation of the exocyclic double bond. The presence of these primary radicals could explain the reported Type I photodamaging effects for these drugs.

Synthesis and evaluation of new oxamniquine derivatives

Oxamniquine derivatives were synthesized and evaluated as novel schistosomicide agents. Oxamniquine (1,2,3,4-tetrahydro-2-[[(1-methylethyl)amino]methyl]-7-nitro-6-quinolinemethanol) was submitted to the Mannich reaction, using formaldehyde, paraformaldehyde and acetaldehyde as reagents, and gave three unexpected products: two of them were cyclized on the alkylamine side chain and another etherified on the aminequinolinemethanol group. The three compounds were biologically evaluated using mice infected with Schistosoma mansoni and showed promising activities, but had higher toxicities. For studies on structure–activity relationships, results demonstrate that the side alkylamine group can be modified with preserved activity, but that this modification is associated with increased toxicity.

Recognition in the minor groove of double-stranded DNA by microgonotropens.

Microgonotropens consist of a minor groove binding moiety functionalized with alkylamine side chains which are protonated and positively charged at neutral pH and capable of forming electrostatic bonds with the negatively charged phosphodiester backbone of DNA. We have investigated the interactions between microgonotropens and double-stranded DNA by a combination of fluorescence, ultraviolet, and nuclear magnetic resonance spectroscopy. Our work reveals why microgonotropens are such potent inhibitors of the binding of transcription factors to their DNA binding sites.

Synthesis and biological evaluation of DNA targeting flexible side-chain substituted β-carboline derivatives

A series of 3-substituted-β-carboline derivatives was synthesized from l-tryptophan. The intercalating binding mode of these compounds with DNA, the effects of the flexible alkylamine side chain on the intercalating ability and their antitumor activity were studied, which agreed well with the molecular modeling results.

Structure-activity relationship studies of (+/-)-terbutaline and (+/-)-fenoterol on beta3-adrenoceptors in the guinea pig gastric fundus.

(+/-)-Terbutaline and (+/-)-fenoterol are both arylethanolamine analogs that have tertbutyl and aryliso-propyl substituents respectively at the a position on the nitrogen of the ethanolamine side chain. In the present study, we have investigated the structure-activity relationships of (+/-)-terbutaline and (+/-)-fenoterol as beta3-adrenoceptor agonists in the guinea pig gastric fundus. (+/-)-Terbutaline and (+/-)-fenoterol induced concentration-dependent relaxation of the precontracted gastric fundus with pD2 values of 4.45+/-0.10 and 5.90+/-0.09, and intrinsic activities of 1.00+/-0.03 and 0.99+/-0.01 respectively. The combination of the selective beta1-adrenoceptor antagonist (+/-)-atenolol (100 microM), and the selective beta2-adrenoceptor antagonist (+/-)-butoxamine (100 microM), produced a 2 and 6 fold rightward shift of the concentration-response curves for (+/-)-terbutaline and (+/-)-fenoterol respectively, without depressing the maximal responses. The order of potency of these agonists was (pD2 value): (+/-)-fenoterol (5.09+/-0.10) > (+/-)-terbutaline (4.13+/-0.08). In the presence of (+/-)-atenolol and (+/-)-butoxamine, however, the non-selective beta1, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol caused a concentration-dependent rightward shift of the concentration-response curves for (+/-)-terbutaline and (+/-)-fenoterol. Schild plot analyses of the effects of (+/-)-bupranolol against these agonists gave pA2 values of 6.21+/-0.07 ((+/-)-terbutaline) and 6.37+/-0.06 ((+/-)-fenoterol) respectively, and the slopes of the Schild plot were not significantly different from unity (p>0.05). These results suggest that the relaxant responses to (+/-)-terbutaline and (+/-)-fenoterol are mainly mediated through beta3-adrenoceptors in the guinea pig gastric fundus. The beta3-adrenoceptor agonist potencies of arylethanolamine analogs depend on the size of the end of the alkylamine side chain.

Transmembrane Domain I Contributes to the Permeation Pathway for Serotonin and Ions in the Serotonin Transporter

Mutation of a conserved Asp (D98) in the rat serotonin (5HT) transporter (rSERT) to Glu (D98E) led to decreased 5HT transport capacity, diminished coupling to extracellular Na+ and Cl-, and a selective loss of antagonist potencies (cocaine, imipramine, and citalopram but not paroxetine or mazindol) with no change in 5HT Km value. D98E, which extends the acidic side chain by one carbon, affected the rank-order potency of substrate analogs for inhibition of 5HT transport, selectively increasing the potency of two analogs with shorter alkylamine side chains, gramine, and dihydroxybenzylamine. D98E also increased the efficacy of gramine relative to 5HT for inducing substrate-activated currents in Xenopus laevis oocytes, but these currents were noticeably dependent on extracellular medium acidification. I-V profiles for substrate-independent and -dependent currents indicated that the mutation selectively impacts ion permeation coupled to 5HT occupancy. The ability of the D98E mutant to modulate selective aspects of substrate recognition, to perturb ion dependence as well as modify substrate-induced currents, suggests that transmembrane domain I plays a critical role in defining the permeation pathway of biogenic amine transporters.

Liquid Chromatographic and Mass Spectral Methods of Identification for Regioisomeric Dimethoxyamphetamines and Brominated Dimethoxyamphetamines

The six regioisomeric dimethoxyamphetamines are prepared from the commercially available dimethoxybenzaldehydes. The dimethoxyamphetamines show very similar mass spectra, and chromatographic methods must be used to differentiate the positional isomers. Bromination of the six isomeric dimethoxyamphetamines yields a monobromination product as the major component in all cases except for 3,5dimethoxyamphetamine, which yields the 2,6-dibrominated species as the major product. Mass spectrometric analysis readily divides the regioisomeric bromodimethoxyamphetamines into two groups of three compounds each. Only those isomers having a bromine substituent ortho- to the alkylamine side-chain show a major fragment at m/z from loss of bromine from the molecular ion. The major drug of abuse 4-bromo-2,5-dimethoxyamphetamine (DOB) is one of three compounds that do not yield the m/z ion. Though the mass spectra for the three non-m/z 194 isomers show some subtle differences, these compounds are best differentiated by a reversed-phase liquid chromatographic system.

Spectroscopy of Neurotransmitters and Their Clusters. 1. Evidence for Five Molecular Conformers of Phenethylamine in a Supersonic Jet Expansion

The neurotransmitter molecule phenethylamine (PEA) is studied by fluorescence excitation, mass-resolved excitation, hole burning, and dispersed emission spectroscopies. The excitation spectrum of PEA exhibits a group of five transition bands in the S1 ← region. This group of transitions appears repetitively with the same spectral separations and intensity pattern in the higher energy regions up to 1000 cm-1 above the origin. The hole burning spectra of these five bands show different independent spectral hole depletion features. With the observation of no blue shifted emission bands higher than the excitation energy in the dispersed emission spectra, these five transition bands can be assigned to five different molecular conformers of PEA. These molecular conformers are distinguished from each other in their alkylamine side chain conformations and the amino group spatial orientations. With the assistance of ab initio calculations, we are able to identify the conformations of these five isomers. The effects of the alkylamino chain conformation, as well as the amino group orientation, on the relative potential energies of these conformers are discussed. The significance of this work for future studies of PEA/solvent molecule clusters and the other neurotransmitters is demonstrated by the amphetamine (AMP) excitation spectrum. The conformation of the alkylamine side chain is found to have little impact on in-plane vibrational modes of the phenyl ring such as ν6b and ν12.

DNA triple-helix specific intercalators as antigene enhancers: Unfused aromatic cations

Triple-helical structures involving the interaction of an oligonucleotide third strand with a duplex nucleic acid sequence have recently gained attention as a therapeutic strategy in the "antigene" approach [cf. Helene, C. (1991) Eur. J. Cancer 27, 1466-1471]. This method utilizes the triple helix formed from the cellular duplex and an added third strand to directly regulate the activity of a selected gene. The limited stability of nucleic acid triple-helical interactions, particularly if the third strand has backbone modifications such as methylphosphonate or phosphorothioate substitutions, is a limiting condition for the use of this approach. We have designed and synthesized compounds, on the basis of the following three criteria, that we feel should provide selective interactions and significant stabilization of triplexes: appropriate aromatic surface area for stacking with triplex bases in an intercalation complex, positive charge, and limited torsional freedom in the aromatic system to match the propeller twist of the triple-base interactions in the triplex. A series of quinoline derivatives with an alkylamine side chain at the 4-position and with different aryl substituents at the 2-position has been synthesized as our first compounds. A 2-naphthyl derivative provides significant and selective stabilization of the triplex. In a 0.2 M NaCl buffer, the naphthyl derivative increased the Tm for the triplex (triplex to duplex and third strand transition) by approximately 30 degrees C more than the Tm increase for the duplex (duplex to single strands transition). Spectral changes and energy-transfer results indicate that the naphthyl compound and related derivatives bind to the triplex by intercalation.(ABSTRACT TRUNCATED AT 250 WORDS)

A molecular orbital treatment of the electronic spectra of some tryptamines

AbstractThe electronic absorption spectra of tryptamine, 5‐methoxytryptamine, 6‐fluorotryptamine, N‐acetyl‐5‐hydroxytryptamine, gramine, and melatonin were investigated. The observed transitions were π–π*, and the values of band maxima and intensity reflected an extent of interaction between the indole ring and the alkylamine side chain. Molecular orbital calculations at the level of INDO/S–CI were performed on all the studied molecules. State functions and transition energies were calculated. The correspondence between the experimental and theoretical results was satisfactory. © 1992 John Wiley & Sons, Inc.

Molecular Mechanics Study on the Folded Conformation of Semotiadil, a Ca2+ Antagonist Having a Benzothiazine Skeleton.

The conformation of semotiadil (1) was investigated by the molecular mechanics method. The analysis of energy components of the stable conformations suggested that stabilities are principally under the control of van der Waals and torsional energy terms. Two major van der Waals interactions were found between the 2-phenyl and the methylene-dioxyphenyl rings, and between the alkylamine side chain and the benzothiazine ring. The torsional energy term was caused mainly by the alkylamino side chain conformation. Stable conformations would be useful when considering possible solution conformations of 1.

Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity.

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.

Synthesis of 2-pyrrylalkylamines

Abstract Fyrroles substituted with an alkylamine side chain attached to the nitrogen, or at the 2, or 3 positions of the pyrrole ring represent potentially useful intermediates for the construction of a variety of novel heterocyclic systems.

Specificity of guinea pig liver transglutaminase for amine substrates.

The amine specificity of guinea pig liver transglutaminase, a model enzyme for endo-gamma-glutamine:epsilon-lysin transferases, was explored with the aid of synthetic substrates of high apparent affinities. As exemplified by dansyl- (5-dimethylamino-1-naphthalenesulfonyl), (2,4-dinitrobenzenesulfonyl)-, and (2,4,6-triisopropylbenzenesulfonyl)-cadaverines--each of which showed affinities of approximately 4 x 10(7) M-1--the best amine substrates carried a large hydrophobic substituent attached to an alkylamine side chain of about 7.2 A in length. Altogether, our results point to the importance of a hydrophobic binding region in the enzyme from where the alkyl side chain reaches into a narrow crevice toward the active center and positions the primary amine of the substrate for attacking the carbonyl group of the acyl enzyme intermediate.

Substrate specificity of caeruloplasmin. Phenylalkylamine substrates

Several phenylalkylamines have been examined as substrates for the copper-containing oxidase caeruloplasmin and it has been shown that the compounds most readily oxidized by this enzyme are those which contain a 3,4-dioxygenation pattern in the aromatic ring. Of these two oxygen atoms, one must be present as a free hydroxy group; the other may be either a hydroxy or methoxy group. A primary amino group may be substituted for one of these oxygen functions without loss of substrate activity. Monophenols are poor substrates for caeruloplasmin. Although the alkylamine side chain is essential for high substrate activity the distance between the basic group of the side chain and the aromatic nucleus is not critical, the higher homologues of dopamine being very good substrates for this enzyme. Monosubstitution at the α-carbon atom of the side chain has relatively little effect on substrate activity but disubstitution at this point markedly reduces substrate activity.

The Synthesis of Linearly Annelated Polycyclic Ketones by Friedel-Crafts Rearrangements of Their Angular Isomers

Abstract Derivatives of 5H-dibenzo[a, d]cycloheptene carrying an alkylamine side chain at position 5 serve as useful drugs in the chemotherapy of mental diseases.1–2 During a study of the effect of annelation on the activity of these psychopharmacological agents of the amitryptyline type, it was deemed necessary to synthesize the linear 13,14-dihydro-6H-cyclohepta-[1,2-b:4,5-b']dinaphthalen-6-one (I). The method of approach was the general synthesis of the polycyclic skeleton of amitryptyline, in which the seven-membered ring is constructed by a Friedel-Crafts (F - C) intramolecular acylation.3–4 Ketone I, however, contains two 2,3-disubstituted naphthalene moieties condensed to the central seven-membered ring.