ABSTRACT
Hair is exposed every day to a range of harmful effects such as sunlight, pollution, cosmetic treatments, grooming practices and cleansing. The UV components of sunlight damage human hair, causing fibre degradation. UV-B attacks the melanin pigments and the protein fractions (keratin) of hair and UV-A produces free radical/reactive oxygen species (ROS) through the interaction of endogenous photosensitizers. Hair was dyed and the efficacy of two antioxidant formulations was demonstrated after UV exposure by evaluating, surface morphology, protein and amino acid degradation, lipidic peroxidation, colour and shine changes and strength/relaxation properties. UV treatment resulted in an increase in protein and lipid degradation, changes in colour and shine and in adverse consequences for the mechanical properties. Natural antioxidants obtained from artichoke and rice applied to pretreated hair improved mechanical properties and preserved colour and shine of fibres, coating them and protecting them against UV. Furthermore, the lipidic peroxidation of the protein degradation caused by UV was reduced for some treated fibres, suggesting an improvement in fibre integrity. This was more marked in the case of the fibres treated using the artichoke extract, whereas the rice extract was better preserving shine and colour of hair fibres.
Subject(s)
Antioxidants/metabolism , Hair/metabolism , Chemistry, Pharmaceutical , Coloring Agents/chemistry , Coloring Agents/pharmacology , Cosmetics/chemistry , Hair/drug effects , Hair/radiation effects , Humans , Keratins/chemistry , Keratins/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxidation/radiation effects , Pigmentation/drug effects , Pigmentation/radiation effects , Tensile Strength/drug effects , Tensile Strength/radiation effects , Tryptophan/chemistry , Tryptophan/metabolism , Ultraviolet Rays/adverse effectsABSTRACT
Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual kappa/mu opioid receptor antagonist devoid of delta opioid receptor affinity against cloned human receptors: K(i) (2)=3.8nM (kappa), 30nM (mu); IC(50) ([(35)S]GTPgammaS binding)=140nM (kappa), 21nM (mu). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at kappa and mu, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3-10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed K(i) values ranging from 14 to 220nM against the kappa opioid receptor with mu/kappa ratios of 0.45-3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH(2)16 and Ac-Phe-trp-Phe-pro-NH(2)17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent mu ligands: K(i) (16)=340nM (mu); K(i) (17)=360nM (mu).
Subject(s)
Peptides, Cyclic/chemistry , Receptors, Opioid, kappa/antagonists & inhibitors , Computer Simulation , Crystallography, X-Ray , Humans , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/antagonists & inhibitors , Receptors, Opioid, mu/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of opioid peptide ligands containing modified N-terminal tyrosine (Tyr) residues was prepared and evaluated against cloned human mu, delta, and kappa opioid receptors. This work extends the recent discovery that (S)-4-carboxamidophenylalanine (Cpa) is an effective tyrosine bioisostere. Amino acids containing negatively charged functional groups in place of tyrosine's phenolic hydroxyl lacked receptor affinity, while exchange of Tyr for (S)-4-aminophenylalanine was modestly successful. Peptides containing the new amino acids, (S)-4-carboxamido-2,6-dimethylphenylalanine (Cdp) and (S)-beta-(2-aminobenzo[d]thiazol-6-yl)alanine (Aba), displayed binding (K(i)) and functional (EC(50)) profiles comparable to the parent ligands at the three receptors. Cdp represents the best performing Tyr surrogate in terms of overall activity, while Cpa and Aba show a subtle proclivity toward the delta receptor.
Subject(s)
Chemistry, Pharmaceutical/methods , Peptides/chemistry , Receptors, Opioid/chemistry , Tyrosine/chemistry , Cloning, Molecular , Drug Design , Humans , Hydrogen Bonding , Kinetics , Ligands , Models, Chemical , Molecular Conformation , Receptors, Opioid, delta/chemistry , Receptors, Opioid, kappa/chemistry , Receptors, Opioid, mu/chemistryABSTRACT
The microwave-assisted solid-phase synthesis of piperazines, 3,9-diazaspiro[5.5]undecanes and 2,9-diazaspiro[5.5]undecanes is reported. The synthesis relies on the direct annulation of primary amines with resin-bound bismesylates. Critical to the success of this chemistry was the development of alpha-methyl benzyl carbamate resin linker. This resin permits the cleavage of the heterocycles under mildly acidic conditions, free of contaminating linker-derived N-alkylated byproducts.
Subject(s)
Amines/chemistry , Aza Compounds/chemical synthesis , Combinatorial Chemistry Techniques/methods , Piperazines/chemical synthesis , Resins, Synthetic/chemistry , Spiro Compounds/chemical synthesis , Aza Compounds/chemistry , Carbamates/chemistry , Magnetic Resonance Spectroscopy , Mesylates/chemistry , Molecular Structure , Piperazines/chemistry , Spiro Compounds/chemistryABSTRACT
Heterocyclic demonstration libraries for agrochemical screening were prepared from the common intermediates 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (1), using standard solution-phase techniques. A total of 18 screening libraries were prepared in good to excellent yields. Several members of these libraries were active in the first level of agrochemical screening, especially in the fungicide screen.
Subject(s)
Chemistry, Pharmaceutical , Combinatorial Chemistry Techniques , Heterocyclic Compounds/chemical synthesis , Nitriles/chemistry , Pyridones/chemistry , Cyclization , Drug Evaluation, Preclinical , Fungicides, Industrial/analysis , Fungicides, Industrial/pharmacology , Molecular Weight , StereoisomerismABSTRACT
(S)-4-(Carboxamido)phenylalanine (Cpa) is examined as a bioisosteric replacement for the terminal tyrosine (Tyr) residue in a variety of known peptide ligands for the mu, delta and kappa opioid receptors. The Cpa-containing peptides, assayed against cloned human opioid receptors, display comparable binding affinity (Ki), and agonist potency (EC50) to the parent ligands at the three receptors. Cpa analogs of delta selective peptides show an increase in delta selectivity relative to the mu receptor. Cpa is the first example of an amino acid that acts as a surrogate for Tyr in opioid peptide ligands, challenging the long-standing belief that a phenolic residue is required for high affinity binding.