1,721,097 research outputs found
4-Substituted prolines, useful reagents in enantioselective synthesis and conformational restraints in bioactive peptidomimetics design
No full textAmong the substituted prolines, 4-substituted ones deserve particular attention. The ring conformation and the puckering preference of the prolyl ring is strongly affected by insertion of the substituent and a great number of peptides containing this non-canonical amino acids have been investigated in the last five years. Moreover, the distance of the substituent from the functions involved in peptide chain formation, create a minimum steric hindrance thus offering the opportunity for conjugation with other chemical objects with low perturbation of the peptide chain
alpha-Bromo-beta,gamma-unsaturated Ketenes as Valuable Intermediates in the Synthesis of alpha-Amino-beta,gamma-Unsaturated Acids
No full textThe synthesis of alpha-benzylamino-beta,gamma-unsaturated acids has been developed starting from a-bromo-a,b-unsaturated
chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the deconjugated
ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine,
followed by acid hydrolysis, allowed to us obtain enantiomerically enriched a-benzylamino-b,c-unsaturated acids
A Review of Strategies for the Development of Alkyl Prolines in Drug Discovery
No full textAmong all natural α-amino acids, proline represents a singularity. Due to the presence of the pyrrolidine ring, proline includes a secondary amino group, that does not contain a hydrogen atom when involved in an amide bond. A variety of synthetic analogues have been developed in the last years, based on ring substitutions, incorporation of heteroatoms into the ring, expansion or contraction of the pyrrolidine ring. The present review focuses on chemical synthesis of mono substituted derivatives of proline containing leucine, isoleucine, valine side chains, and other alkyls, including the contribution of literature from 2004 to 2015 or earlier where necessary
Can integrin agonists have cards to play against cancer? A literature survey of small molecules integrin activators.
Full text linkThe ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out the cells. A tight regulation of the integrin signalling is paramount for normal physiological functions such as migration, proliferation, and differentiation and a misregulated integrin activity could be associated with several pathological conditions. Because of the important roles of integrins and their ligands in biological development, immune responses, leukocyte traffic, haemostasis, and cancer, their potential as therapeutic tools is now widely recognized. Nowadays extensive efforts have been made to discover and develop small molecule ligands as integrin antagonists whereas less attention has been payed to agonists. In recent years, it has been recognized that integrin agonists could open up novel opportunities for therapeutics, which gain benefits to increase rather than decrease integrin-dependent adhesion and transductional events. For instance, a significant factor in chemo-resistance in melanoma is a loss of integrin-mediated adhesion; in this case, stimulation of integrin signalling by agonists significantly improved the response to chemotherapy. In this review, we overview results about small molecules which revealed an activating action on some integrins, especially those involved in cancer, and to examine from a medicinal chemistry point of view their structure and behavior
Conjecturing about Small-Molecule Agonists and Antagonists of α4β1 Integrin: From Mechanistic Insight to Potential Therapeutic Applications
Full text linkIntegrins are heterodimeric cell-surface receptors that regulate cell–cell adhesion and cellular functions through bidirectional signaling. On the other hand, anomalous trafficking of integrins is also implicated in severe pathologies as cancer, thrombosis, inflammation, allergies, and multiple sclerosis. For this reason, they are attractive candidates as drug targets. However, despite promising preclinical data, several anti-integrin drugs failed in late-stage clinical trials for chronic indications, with paradoxical side effects. One possible reason is that, at low concentration, ligands proposed as antagonists may also act as partial agonists. Hence, the comprehension of the specific structural features for ligands’ agonism or antagonism is currently of the utmost interest. For α4β1 integrin, the situation is particularly obscure because neither the crystallographic nor the cryo-EM structures are known. In addition, very few potent and selective agonists are available for investigating the mechanism at the basis of the receptor activation. In this account, we discuss the physiological role of α4β1 integrin and the related pathologies, and review the few agonists. Finally, we speculate on plausible models to explain agonism vs. antagonism by comparison with RGD-binding integrins and by analysis of computational simulations performed with homology or hybrid receptor structures
Synthesis and evaluation of the affinity toward mu-opioid receptor of atypical, lipophilic ligands based on the sequence c[Tyr-Pro-Trp-Phe-Gly-].
No full textAn ultimate and general model describing the interaction between opioid ligands and mu-opioid receptors is not available yet, so the mode of action of atypical peptide analogues or peptidomimetics is worthy of investigation. In this context, the peptide c[-Tyr-d-Pro-d-Trp-Phe-Gly-] was observed to act as an agonist toward mu-opioid receptors with appreciable potency, albeit deprived of a protonable nitrogen. This compound was synthesized as a member of a library of diastereo- or enantiomeric cyclic peptides based on the sequence of endomorphin-1, aiming to obtain lipophilic peptide ligands active at the mu-opioid receptors, having good performances in terms of resistance to enzymatic degradation and permeation of biological barriers
New isoxazolidinone and 3,4-dehydro-β-proline derivatives as antibacterial agents and MAO-inhibitors: A complex balance between two activities
No full textAmong the different classes of antibiotics, oxazolidinone derivatives represent important drugs, since their unique mechanism of action overcomes commonly diffused multidrug-resistant bacteria. Anyway, the structural similarity of these molecules to monoamino oxidase (MAO) inhibitors, like toloxatone and blefoxatone, induces in many cases loss of selectivity as a major concern. A small library of compounds based on isoxazolidinone and dehydro-β-proline scaffold was designed with the aim to obtain antibacterial agents, evaluating at the same time the potential effects of structural features on MAO inhibitory behaviour. The structural modification introduced in the backbone, starting from Linezolid model, lead to a significant loss in antibiotic activity, while a promising inhibitory effect could be observed on monoamino oxidases. These interesting results are also in agreement with docking experiments suggesting a good binding pose of the synthesized compounds into the pocket of the oxidase enzymes, in particular of MAO-B
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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