100,427 research outputs found
Click 1,2,3-triazoles in drug discovery and development: From the flask to the clinic?
No full textAfter 20 years since its conception, click chemistry has come of age and we believe the time has come to evaluate if the copper-catalyzed azide alkyne cycloaddition (CuCAAC) reaction deserves to be considered the perfect transformation in medicinal chemistry campaigns and to weigh up the concrete results that have been produced in terms of drugs approved and clinical candidates in development. After a description of the properties of the triazole nucleus in terms of both pharmacokinetic and pharmacodynamic profile, a practical guide for the best approaches to be used for the synthesis of triazoles is provided, capitalizing on our 20-year hands-on experience in this chemistry. Finally, we describe those molecules displaying the 1,2,3-triazole nucleus that have entered the market or are, at least, in clinical trials. Only four 1,2,3-triazole-bearing drugs have been launched so far. Among them the recently approved antibody drug conjugate sacituzumab govitecan was discovered thanks to click chemistry. Nevertheless, to the best of our knowledge, there are a dozen 1,2,3-triazoles in clinical development and it is likely that we will witness the launch on the market of at least some of them, encouraging medicinal chemists to further use this approach, not only as a route to early-stage discoveries, but also as a means to developing successful drugs
Deuterium in drug discovery: progress, opportunities and challenges
No full textSubstituting a hydrogen atom with its heavy isotope deuterium may improve the pharmacokinetic and/or toxicity profile of a drug compared with its non-deuterated counterpart. This article highlights milestones in the field of deuteration in drug discovery and development, and discusses recent examples of its application, which have shifted towards deuteration of novel drug candidates instead of developing deuterated analogues of marketed drugs.Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Transition-Metal-Free Synthesis of 2-Arylimidazolones via Cascade Reaction between Arynes and α,α′-Disubstituted α-Isocyanoacetamides
No full textThe reaction between arynes and secondary α,α′-disubstituted α-isocyanoacetamides was developed to access 2-arylimidazolones of structural diversity and complexity in a straightforward manner
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
The 115 year old multicomponent Bargellini reaction: Perspectives and new applications
No full text: Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929-1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
Tritylamine as an ammonia surrogate in the ugi reaction provides access to unprecedented 5-sulfamido oxazoles using burgess-type reagents
No full textStarting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position. The synthetic procedure employs readily available starting materials and proceeds smoothly under mild reaction conditions with good tolerance for a variety of functional groups, coming to fill a gap in the field of oxazole compounds
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
A rotational investigation of the three isomeric forms of cyanoethynylbenzene (HCC-C6H4-CN): benchmarking experiments and calculations using the “Lego brick” approach
No full textWe report the study of three structural isomers of phenylpropiolonitrile (3-phenyl-2-propynenitrile, C6H5-C3N) containing an alkyne function and a cyano group, namely ortho-, meta-, and para-cyanoethynylbenzene (HCC-C6H4-CN). The pure rotational spectra of these species have been recorded at room temperature in the millimeter-wave domain using a chirped-pulse spectrometer (75-110 GHz) and a source-frequency modulation spectrometer (140-220 GHz). Assignments of transitions in the vibrational ground state and several vibrationally excited states were supported by quantum chemical calculations using the so-called “Lego brick” approach [A. Melli, F. Tonolo, V. Barone and C. Puzzarini, J. Phys. Chem. A, 2021, 125, 9904-9916]. From these assignments, accurate spectroscopic (rotational and centrifugal distortion) constants have been derived: for all species and all observed vibrational states, predicted rotational constants show relative accuracy better than 0.1%, and often of the order of 0.01%, compared to the experimental values. The present work hence further validates the use of the “Lego brick” approach for predicting spectroscopic constants with high precision
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