Investigation of drug product and container-closure interactions: A case study of diluent containing prefilled syringe.

Prefilled syringes (PFS) constitute a widely used medical device for drug delivery particularly for the drugs of biological origin. Interactions between the product contents and the components of the PFS play a critical role in determining the suitability of selected PFS. A diluent (with benzyl alcohol/BzOH as a preservative) containing PFS used for reconstitution of the lyophilized product revealed a systematic decrease in the BzOH content during accelerated and stress stability program.

Selective Targeting of Integrin αvβ8 by a Highly Active Cyclic Peptide.

Integrins play important roles in physiological and pathophysiological processes. Among the RGD-recognizing integrin subtypes, the αvβ8 receptor is emerging as an attractive target because of its involvement in various illnesses, such as autoimmune diseases, viral infections, and cancer. However, its functions have, so far, not been investigated in living subjects mainly because of the lack of a selective αvβ8 ligand.

Oxyluciferin Derivatives: A Toolbox of Environment-Sensitive Fluorescence Probes for Molecular and Cellular Applications.

In this work, we used firefly oxyluciferin (OxyLH) and its polarity-dependent fluorescence mechanism as a sensitive tool to monitor biomolecular interactions. The chromophores, OxyLH, and its two analogues, 4-MeOxyLH and 4,6'-DMeOxyL, were modified trough carboxylic functionalization and then coupled to the N-terminus part of Tat and NCp7 peptides of human immunodeficiency virus type-1 (HIV-1). The photophysical properties of the labeled peptides were studied in live cells as well as in complex with different oligonucleotides in solution.

A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins.

Integrins, a diverse class of heterodimeric cell surface receptors, are key regulators of cell structure and behaviour, affecting cell morphology, proliferation, survival and differentiation. Consequently, mutations in specific integrins, or their deregulated expression, are associated with a variety of diseases. In the last decades, many integrin-specific ligands have been developed and used for modulation of integrin function in medical as well as biophysical studies.

In Vivo PET Imaging of the Cancer Integrin αvβ6 Using Ga-Labeled Cyclic RGD Nonapeptides.

Expression of the cellular transmembrane receptor αvβ6 integrin is essentially restricted to malignant epithelial cells in carcinomas of a broad variety of lineages, whereas it is virtually absent in normal adult tissues. Thus, it is a highly attractive target for tumor imaging and therapy. Furthermore, αvβ6 integrin plays an important role for the epithelial-mesenchymal interaction and the development of fibrosis.

Bioinspired Molecular Lantern: Tuning the Firefly Oxyluciferin Emission with Host-Guest Chemistry.

Fireflies generate flashes of visible light via luciferase-catalyzed chemiexcitation of the substrate (luciferin) to the first excited state of the emitter (oxyluciferin). Microenvironment effects are often invoked to explain the effects of the luciferase active pocket on the emission; however, the exceedingly complex spectrochemistry and synthetic burdens have precluded elucidation of the nature of these interactions. To decipher the effects of microenvironment on the light emission, here the hydrophobic interior of cucurbit[7]uril (CB7) is used to mimic the nonpolar active pocket of luciferase.

Small Cause, Great Impact: Modification of the Guanidine Group in the RGD Motif Controls Integrin Subtype Selectivity.

Due to its unique role as a hydrogen-bond donor and its positive charge, the guanidine group is an important pharmacophoric group and often used in synthetic ligands. The chemical modification of the guanidine group is often considered to destroy its function. Herein, we show that the N-methylation, N-alkylation, or N-acylation of the guanidine group can be used to modify the receptor subtype specificity of the integrin ligand cilengitide.

Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6-Selective Integrin Ligands.

The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide.

Emission properties of oxyluciferin and its derivatives in water: revealing the nature of the emissive species in firefly bioluminescence.

The first systematic steady-state and time-resolved emission study of firefly oxyluciferin (emitter in firefly bioluminescence) and its analogues in aqueous buffers provided the individual emission spectra of all chemical forms of the emitter and the excited-state equilibrium constants in strongly polar environment with strong hydrogen bonding potential. The results confirmed the earlier hypothesis that excited-state proton transfer from the enol group is favored over proton transfer from the phenol group. In water, the phenol-keto form is the strongest photoacid among the isomers and its conjugate base (phenolate-keto) has the lowest emission energy (634 nm).

Vibrational spectra of chemical and isotopic variants of oxyluciferin, the light emitter of firefly bioluminescence.

The chemical complexity of oxyluciferin (OxyLH2), the light-emitting molecule in the bioluminescence of fireflies, originates from the possibility of keto/enol tautomerism and single or double deprotonation. Herein, we present detailed infrared spectroscopic analysis of OxyLH2 and several of its chemical isomers and isotopomers. To facilitate the future characterization of its biogenic forms, we provide accurate assignments of the solid-state and solution FTIR spectra of OxyLH2 based on comparison to six isotopically labeled variants ([2-(13)C]-OxyLH2, [3-(15)N]-OxyLH2, [4-(13)C]-OxyLH2, [5-(13)C]-OxyLH2, [2'-(13)C]-OxyLH2, [3'-(15)N]-OxyLH2), five closely related structural analogues, and theoretically computed spectra.

Synthesis of Soai aldehydes for asymmetric autocatalysis by desulfurative cross-coupling.

Palladium-catalyzed dehydrosulfurative Liebeskind-Srogl coupling of terminal alkynes with 2-mercapto-1,3-pyrimidine-5-carbaldehyde under base-free conditions provides 2-(alkynyl)-1,3-pyrimidine-5-carbaldehydes, which are substrates for autocatalytic amplification of chirality according to Soai et al. The mercapto aldehyde acceptor is obtained by condensation of Arnold's vinamidinium salt with thiourea.

Why is firefly oxyluciferin a notoriously labile substance?

The chemistry of firefly bioluminescence is important for numerous applications in biochemistry and analytical chemistry. The emitter of this bioluminescent system, firefly oxyluciferin, is difficult to handle. The cause of its lability was clarified while its synthesis was reinvestigated.

On the influence of water on the electronic structure of firefly oxyluciferin anions from absorption spectroscopy of bare and monohydrated ions in vacuo.

A complete understanding of the physics underlying the varied colors of firefly bioluminescence remains elusive because it is difficult to disentangle different enzyme-lumophore interactions. Experiments on isolated ions are useful to establish a proper reference when there are no microenvironmental perturbations. Here, we use action spectroscopy to compare the absorption by the firefly oxyluciferin lumophore isolated in vacuo and complexed with a single water molecule.

Chiral ionic liquid/ESI-MS methodology as an efficient tool for the study of transformations of supported organocatalysts: deactivation pathways of Jørgensen-Hayashi-type catalysts in asymmetric Michael reactions.

The deactivation pathways of Jørgensen-Hayashi-type organocatalysts modified with an ionic liquid fragment in asymmetric Michael reactions of α,β-enals with C- (nitromethane, dimethylmalonate) or N-nucleophiles (N-carbobenzyloxyhydroxylamine) that involved an iminium-ion formation step were studied for the first time by the electrospray ionization mass spectrometry (ESI-MS). "Parasitic" side reactions and undesirable cation intermediates that poisoned the catalysts were identified in accordance with their m/z values as well as their relation to the reported mechanisms of Michael reactions in the presence of O-TMS-α,α-diarylprolinol (TMS=trimethylsilyl) derivatives. The proposed approach may be useful for the study of transformations of other types of organocatalysts modified with ionic groups in various organocatalytic reactions and for the development of novel robust catalysts and processes that would be suitable for large-scale industrial applications.