Intramolecular through-space NMR spectroscopic effect of steric compression on H NMR spectroscopy.

The intramolecular through-space NMR spectroscopic effect of steric compression is related to intramolecular through-space van der Waals repulsion. The electron cloud of a proton can be pushed away by the electron cloud of a nearby proton or functional group. As the electron population of the sterically compressed proton is decreased (therefore deshielded), the chemical shift sharply moves downfield, which may result in ambiguity for the proton signal assignment.

α-Methylacyl-CoA Racemase from -Detailed Kinetic and Structural Characterization of the Active Site.

α-Methylacyl-CoA racemase in (MCR) has an essential role in fatty acid metabolism and cholesterol utilization, contributing to the bacterium's survival and persistence. Understanding the enzymatic activity and structural features of MCR provides insights into its physiological and pathological significance and potential as a therapeutic target. Here, we report high-resolution crystal structures for wild-type MCR in a new crystal form (at 1.

Evaluation of chemical disposition in skin by stimulated Raman scattering microscopy.

Tracking drug disposition in the skin in a non-destructive and at least semi-quantitative fashion is a relevant objective for the assessment of local (cutaneous) bioavailability. Confocal Raman spectroscopy has been shown potentially useful in this regard and, importantly, recent advances have enabled the presence of applied chemicals in the viable epidermis below the stratum corneum (SC) to be determined without ambiguity and having addressed the challenges of (a) background signals from endogenous species and noise and (b) signal attenuation due to absorption and scattering. This study aimed to confirm these observations using a different vibrational spectroscopy approach - specifically, stimulated Raman scattering (SRS) microscopy - and the more conventional in vitro skin penetration test (IVPT).

Analysis of enzyme reactions using NMR techniques: A case study with α-methylacyl-CoA racemase (AMACR).

α-Methylacyl-CoA racemase (AMACR; P504S) catalyzes the conversion of R-2-methylacyl-CoA esters into their corresponding S-2-methylacyl-CoA epimers enabling their degradation by β-oxidation. The enzyme also catalyzes the key epimerization reaction in the pharmacological activation pathway of ibuprofen and related drugs. AMACR protein levels and enzymatic activity are increased in prostate cancer, and the enzyme is a recognized drug target.

Confocal Raman Spectroscopic Characterization of Dermatopharmacokinetics Ex Vivo.

Confocal Raman spectroscopy is being assessed as a tool with which to quantify the rate and extent of drug uptake to and its clearance from target sites of action within the viable epidermis below the skin's stratum corneum (SC) barrier. The objective of this research was to confirm that Raman can interrogate drug disposition within the living layers of the skin (where many topical drugs elicit their pharmacological effects) and to identify procedures by which Raman signal attenuation with increasing skin depth may be corrected and normalized so that metrics descriptive of topical bioavailability may be identified. It was first shown in experiments on skin cross-sections parallel to the skin surface that the amide I signal, originating primarily from keratin, was quite constant with depth into the skin and could be used to correct for signal attenuation when confocal Raman data were acquired in a "top-down" fashion.

Practical Synthesis of Antimicrobial Long Linear Polyamine Succinamides.

There are many severe bacterial infections notorious for their ability to become resistant to clinically relevant antibiotics. Indeed, antibiotic resistance is a growing threat to human health, further exacerbated by the lack of new antibiotics. We now describe the practical synthesis of a series of substituted long linear polyamines that produce rapid antibacterial activity against both Gram-positive and Gram-negative bacteria, including meticillin-resistant .

Quantification of Chemical Uptake into the Skin by Vibrational Spectroscopies and Stratum Corneum Sampling.

Evaluation of the bioavailability of drugs intended to act within the skin following the application of complex topical products requires the application of multiple experimental tools, which must be quantitative, validated, and, ideally and ultimately, sufficiently minimally invasive to permit use in vivo. The objective here is to show that both infrared (IR) and Raman spectroscopies can assess the uptake of a chemical into the stratum corneum (SC) that correlates directly with its quantification by the adhesive tape-stripping method. Experiments were performed ex vivo using excised porcine skin and measured chemical disposition in the SC as functions of application time and formulation composition.

Practical Synthesis of Polyamine Succinamides and Branched Polyamines.

Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram-positive and Gram-negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4-Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines.

Antibacterial activity of novel linear polyamines against .

New therapeutic options are urgently required for the treatment of infections. Accordingly, we sought to exploit the vulnerability of to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine.

Design and synthesis of hybrid compounds as novel drugs and medicines.

The development of highly effective conjugate chemistry approaches is a way to improve the quality of drugs and of medicines. The aim of this paper is to highlight and review such hybrid compounds and the strategies underpinning their design. A variety of unique hybrid compounds provide an excellent toolkit for novel biological activity, anticancer and non-viral gene therapy (NVGT), and as templates for killing bacteria and preventing antibiotic drug resistance.

The H NMR Spectroscopic Effect of Steric Compression Is Found in [3.3.1]Oxa- and Azabicycles and Their Analogues.

The through-space H NMR effect of steric compression by the lone-pair electrons of O- and N-atoms is shown in synthetic [3.3.1]oxa- and azabicycles.

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition.

Racemases and epimerases catalyse changes in the stereochemical configurations of chiral centres and are of interest as model enzymes and as biotechnological tools. They also occupy pivotal positions within metabolic pathways and, hence, many of them are important drug targets. This review summarises the catalytic mechanisms of PLP-dependent, enolase family and cofactor-independent racemases and epimerases operating by a deprotonation/reprotonation (1,1-proton transfer) mechanism and methods for measuring their catalytic activity.

A neoclerodane orthoester and other new neoclerodane diterpenoids from Teucrium yemense chemistry and effect on secretion of insulin.

Teucrium yemense, a medicinal plant commonly grown in Saudi Arabia and Yemen, is traditionally used to treat infections, kidney diseases, rheumatism, and diabetes. Extraction of the dried aerial parts of the plant with methanol, followed by further extraction with butanol and chromatography, gave twenty novel neoclerodanes. Their structures, relative configurations and some conformations were determined by MS and 1-D and 2-D NMR techniques.

Multinuclear Nuclear Magnetic Resonance Spectroscopy Is Used to Determine Rapidly and Accurately the Individual p Values of 2-Deoxystreptamine, Neamine, Neomycin, Paromomycin, and Streptomycin.

Unambiguous assignments have been made for each individual p value of the amino group and guanidine substituents on 2-deoxystreptamine, neamine, neomycin, paromomycin, and streptomycin by pH-titration evaluation of their H, C, and N (by H-N heteronuclear multiple-bond correlation (HMBC) spectra) NMR chemical shifts (δs) as the reporter nuclei. These data require minor revisions of the literature data in terms of the assignment order for neomycin and paromomycin. In situ titrations and NMR spectroscopy are shown to be a powerful combination for rapidly (minutes) obtaining each distinct p value of the similar amine and guanidine functional groups, which decorate aminoglycoside antibiotics.

Individual p Values of Tobramycin, Kanamycin B, Amikacin, Sisomicin, and Netilmicin Determined by Multinuclear NMR Spectroscopy.

NMR spectroscopy is a powerful technique for separating and measuring each distinct p value of the amino groups around aminoglycoside antibiotics. Unambiguous assignments were made for each individual amine substituent on 2-deoxystreptamine, tobramycin, kanamycin B, amikacin, sisomicin, and netilmicin using variations in the NMR spectroscopic chemical shift (δ) with H, C, and N HMBC; the individual p values of netilmicin are reported for the first time.

Impacts of Steric Compression, Protonation, and Intramolecular Hydrogen Bonding on the N NMR Spectroscopy of Norditerpenoid Alkaloids and Their Piperidine-Ring Analogues.

H-N HMBC spectra of norditerpenoid alkaloids and their synthetic azabicyclic analogues were obtained to investigate the impacts of the through-space effect of steric compression, protonation, and formation of intramolecular hydrogen bonding on the N NMR spectroscopy of these natural products and their piperidine-containing analogues. A rare N NMR effect of steric compression is demonstrated in half-cage A/E-rings of norditerpenoid alkaloid free bases and their synthetic azabicyclic analogues, in which the distribution of the lone pair of electrons of the tertiary amine -atom is sterically restricted by bridged cycloalkanes, e.g.

Prediction of Drug Loading in the Gelatin Matrix Using Computational Methods.

The delivery of drugs is a topic of intense research activity in both academia and industry with potential for positive economic, health, and societal impacts. The selection of the appropriate formulation (carrier and drug) with optimal delivery is a challenge investigated by researchers in academia and industry, in which millions of dollars are invested annually. Experiments involving different carriers and determination of their capacity for drug loading are very time-consuming and therefore expensive; consequently, approaches that employ computational/theoretical chemistry to speed have the potential to make hugely beneficial economic, environmental, and health impacts through savings in costs associated with chemicals (and their safe disposal) and time.

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships.

α-Methylacyl-CoA racemase (AMACR; P504S; EC 5.1.99.

Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents.

α-Methylacyl-CoA racemase (AMACR; P504S) catalyses an essential step in the degradation of branched-chain fatty acids and the activation of ibuprofen and related drugs. AMACR has gained much attention as a drug target and biomarker, since it is found at elevated levels in prostate cancer and several other cancers. Herein, we report the synthesis of 2-(phenylthio)propanoyl-CoA derivatives which provided potent AMACR inhibitory activity (IC = 22-100 nM), as measured by the AMACR colorimetric activity assay.

A simple H NMR based assay of total capsaicinoid levels in Capsicum using signal suppression in non-deuterated solvent.

Background: The heat of Capsicum fruits is routinely assayed using high-performance liquid chromatography (HPLC) to determine capsaicin (CA) and dihydrocapsaicin (DHC) levels. The assay can be time consuming, with each HPLC run typically lasting 10 min. Nuclear magnetic resonance (NMR) is eminently suitable for quantification of fruit extracts, although it has been largely ignored for quantitative chilli analysis.

Structure-activity relationships of rationally designed AMACR 1A inhibitors.

α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the 'racemisation' reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure-activity relationship study has been performed. This paper describes the first structure-activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated.

A novel colorimetric assay for α-methylacyl-CoA racemase 1A (AMACR; P504S) utilizing the elimination of 2,4-dinitrophenolate.

α-Methylacyl-CoA racemase (AMACR; P504S) regulates branched-chain fatty acid degradation, activates Ibuprofen and is a recognised cancer drug target. A novel, facile colorimetric assay was developed based on elimination of 2,4-dinitrophenolate. The assay was used to test 5 known inhibitors, determining IC and K values, reversibility and characterizing irreversible inhibition.

A study on the AMACR catalysed elimination reaction and its application to inhibitor testing.

α-Methylacyl-CoA racemase (AMACR; P504S) catalyses a key step in the degradation of branched-chain fatty acids and is important for the pharmacological activation of Ibuprofen and related drugs. Levels of AMACR are increased in prostate and other cancers, and it is a drug target. Development of AMACR as a drug target is hampered by lack of a convenient assay.

Metal influence on the iso- and hetero-selectivity of complexes of bipyrrolidine derived salan ligands for the polymerisation of -lactide.

In this paper we have prepared a series of Ti(iv), Hf(iv) and Al(iii) complexes based on bipyrrolidine salan pro-ligands. The Hf(iv) complexes have all been characterised in the solid-state, the chiral ligands coordinate to Hf(iv) in an α- manner whereas the ligand coordinates in a β- geometry. The Hf(iv) complexes are all active for the ROP of -lactide in the melt, with the fluxional complex affording a strong isotactic bias = 0.