Late-Stage Functionalization by Chan–Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors

© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim A late-stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper-catalysed diversification of a boronate ester by amination (Chan–Lam reaction) that can be carried out on a complex β-aryl-β-amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high-throughput-array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug-like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire

On DABAL-Me₃ promoted formation of amides

The range and utility of DABAL-Me3 couplings of methyl esters and free carboxylic acids with primary and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared for a significant range of coupling partners of relevance to the preparation of amides of interest in pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives. The influence of microwave energy on the reaction system was shown to be typically related to thermal effects (over-pressuring and superheating)

The alumni of the Scots colleges abroad, 1575-1799

The small cemetery is all that remains ofthe Snow Kirk! in Old Aberdeen. The church itself fell into ruin in the eighteenth century having been used bythe Catholic community since the Reformation? The churchyard, however, continued to be used ' for Catholic burials into the twentieth century. Two wall plaques record the burial there ofthe brothers, John and James Sharp both priests who had worked on the mission in Scotland for many years? The funeral monuments attest to their piety and in John's case state that he hadbeen educated at the colleges at Scalan in Upper Glenlivet and Valhido'lid in Spain.4 Praise follows for his great learning and for his personal culture and manners:s the implicatIOn being that he owed these qualities to .. his education at the colleges. It is particularly charming that,the epitaph pll\~es equal emphasis on learning and urbanity. He had been trained at a Scots College abroad in the penal times when it was illegal to receive such an education in Scotland. While his . . memorial tablet commemorates his achievements the majority of Scots Catholics who attended the colleges abroad during the penal times have gone unrecorded.6 This dissertation will attempt to identify those students who through their contributions to cultural life of Scotland and elsewhere deserve greater academic attention. Historians have written on aspects of Catholic history during these times. Alphons Bellesheim7 , J F S Gordon8 and William Forbes-Leith9 have produced histories ofthe Catho~.ic Church in Scotland. Their accounts, though ofgreat value, are more than a century old with consequent short-comings. Bellesheim, the German historian, wrote his four volumes on the history ofthe Church in Scotland from the earliest times. Volume 4 deals with post-Reformation history and concentrates on missionary work, particularly that of the Jesuits, in Scotland. The style is anecdotal and his approach is hagiographical. Gordon wrote his history in anticipation of the reestablishment ofthe Scottish hierarchy in 1878. The main part of his text is devoted to ', supporting this and the Penal Times are covered only in an extensive foreword in which he attempts a broad sweep ofthe subject and like Bellesheim relies heavily on unreferenced source material. Both ofForbes-Leith's major works are heavily dependent on the accounts ofthe troubles of Catholic individuals from the late sixteenth to the eighteenth century. In nature they are family histories dominated by a small number ofnorthern families including:tJordon, Forbes and Leith. In all these histories passing reference is made to the Scots colleges abroad but no asse~~mentof their impact is attempted. More recently Mark DilworthlO , Maurice Taylorll and Brian M Halloranl2 have produced histories of individual Scots colleges and an anthology ofessays on the Pontifical Scots College in Rome was produced to' celebrate its 400th anniversary.13 The Innes Review continues to produce scholarly articles on many aspects of Scottish CathoIicism.14 However, the vast majority ofthese accounts are focused exclusively on religious matters as is unsurprising since almost all ofthe historians involved are ordained priests, secular and regular, and therefore writing from a professional or vocational perspective. IS The impact ofthe Scots Catholic colleges in Europe during ,' this period has not yet been addressed as a whole, either in terms ofsecular history or ofthe wider influence ofthe alumni ofthe colleges. This dissertation has two foci. The first is a statistical analysis ofthe prosopographical information contained in the college registers ofstudents. Together with other archival material this gives a view ofpatterns of attendance and trends sustained over time. The main details covered with regard to the students are age, family background (social and occupational), geographical origin and relationships with wider Catholic and Scottish networks. This is all original work based on primary sources.16 The last comprehensive review ofthis college material was organised by P J Anderson17 more than a century ago and consisted ofthe assembly ofprimary material without translation or analysis. More recent attempts at prosopography have been those ofHalloran (a partial reconstruction ofthe missing Paris college records) . and Dilworth (a listing ofthe known members ofthe Wiirzburg Schottenkloster). In neither case was any analysis ofthe data attempted. My data base ofstudents was produced after rigorous examination or re-examination of original college archival material surviving in Scotland and on the continent. Wherever possible corroborative cross referencing was made with other archives - particularly those ofthe Society of Jesus18 and the Congregation ofPropaganth'FideJ9 in Rome - and therefore represents a significant advance on any earlier work attempted in the field.• , A second focus ofthe dissertation is on the cultural impact that the colleges achieved through their alumni. In the compass of a doctoral dissertation it is simply impossible to give a full account of the cultural or political activities ofso many individuals active over such a geographical area and a span ofcenturies. The overview attempted is only indicative ofthe scope and degree of influence achieved and in no way intended to be comprehensive or definitive. It is supported quantitatively, however, by the statistical analysis ofthe data base which establishes the minimum numbers of Scottish alumni active in various fields such as the Church, military and state service, commerce, academic research, humanities, art and architecture A number ofthe most famous students ofthe colleges have been evaluated .already as contributors to their own field of endeavour either in biographies21 or within general histories.22 In each case they have been treated as individuals with little suggestion that they belonged to a corpus ofalumni that benefited from the unique privileges which attendance at a Scots college conferred. This omission becomes more regrettable when an assessment is made ofthe other students ofthe colleges in more than two centuries who have escaped the attention of historians or have received only the most peremptory ofaccounts. In a preliminary way this dissertation attempts to sketch some ofthe connections which emerge when these individuals are viewed in context. Again the constraints of space have limited the background which I have been able to provide. What is offered is inte.tfded only to aid the reader in having some .A sense ofthe world in which the Scots alumni existed. It is in .no way . primar;:.to the dissertation or fundamental to its purpose or claims. In my researches I have had access to a number of archives of primary materials. As well as those ofthe Jesuits and Propaganda Fide already mentioned were the MadridlValladolid College (now in Salamanca) and the Roman College: also the Archivio Segreto Vaticano and Biblioteca Apostolica Vaticana were examined for relevant material. The University of WUrzburg kindly allowed me access to surviving manuscripts from that city's Schottenkloster. I have made extensive use ofthe Scottish Catholic Archives in Edinburgh and found valuable material in the Special Collections ofthe University ofAberdeen and in the City ofAberdeen's archives.. ,. The methodology which I have adopted in constructing this dissertation is to have discussed in order the following: the founding ofthe colleges; the basis oftheir academic success; the numbers and backgrounds ofstudents who attended; their contributions to the Catholic mission in Scotland; further contributions to the wider Catholic Church; those alumni who took up significant positions in Military or State service; those who were prominent in scholarly or academic life; and those noted for scientific, business or.artistic excellence. In all cases, where relevant, statistical analysis ofthe data base has been used to support any conclusions drawn. One more point requires to be made in this preface: to declare my personal viewpoint. By confession I am a Catholic, Scottish but ofIrish ancestry. This has driven much ofmy interest in this research but I have striven to avoid it colouring my objectivity. I sta~ed the research in a state of almost complete ignorance and was driven by curiosity which only intensified the more I learned. If! have weighed evidence more lightly or exaggerated outcomes more than a totally objective commentator from a wholly secular background might have done then in my defence I might claim that I have done no more than partially to rectify the imbalance shown by past historians in their almost total neglect or denial ofthe substantial contributions to cultural developments achieved by the Scots Colleges abroad.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Unusual Undergraduate Training in Medicinal Chemistry in Collaboration between Academia and Industry

Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design–synthesize–test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds. Considerable emphasis is placed on standard design properties used within industry. The modules are popular with the students and usually oversubscribed. An unexpected benefit has been the opportunities that have emerged with research and commercial potential. Graduate and postgraduate training of medicinal chemists at GSK is also briefly described

Active search for computer-aided drug design

We consider lead discovery as active search in a space of labelled graphs. In particular, we extend our recent data-driven adaptive Markov chain approach, and evaluate it on a focused drug design problem, where we search for an antagonist of an av integrin, the target protein that belongs to a group of Arg-Gly-Asp integrin receptors. This group of integrin receptors is thought to play a key role in idiopathic pulmonary fibrosis, a chronic lung disease of significant pharmaceutical interest. As an in silico proxy of the binding affinity, we use a molecular docking score to an experimentally determined avb6 protein structure. The search is driven by a probabilistic surrogate of the activity of all molecules from that space. As the process evolves and the algorithm observes the activity scores of the previously designed molecules, the hypothesis of the activity is refined. The algorithm is guaranteed to converge in probability to the best hypothesis from an a priori specified hypothesis space. In our empirical evaluations, the approach achieves a large structural variety of designed molecular structures for which the docking score is better than the desired threshold. Some novel molecules, suggested to be active by the surrogate model, provoke a significant interest from the perspective of medicinal chemistry and warrant prioritization for synthesis. Moreover, the approach discovered 19 out of the 24 active compounds which are known to be active from previous biological assays

Relative Binding Affinities of Integrin Antagonists by Equilibrium Dialysis and Liquid Chromatography–Mass Spectrometry

The integrin α_vβ₆ is a potential target for treatment of idiopathic pulmonary fibrosis (IPF). Equilibrium dialysis (ED) was investigated for its ability to report ligand binding in an α_vβ₆ inhibitor screening assay. As a preliminary experiment, an established peptidomimetic inhibitor of the integrin was dialyzed against α_vβ₆, and the fraction bound (<i>f</i>_b) and percentage saturation determined by liquid chromatography–mass spectrometry (LC-MS) analysis. Quantitation of the inhibitor in the two chambers of the ED cartridge revealed an uneven distribution in the presence of α_vβ₆, corresponding to near saturation binding to the protein (93 ± 3%), while the control (without integrin) showed an equal partitioning of the inhibitor on either side of the dialysis membrane. A competitive ED assay with a 12 component mixture of antagonists was conducted, and the results compared with an established cell adhesion assay for quantifying α_vβ₆ inhibition of individual antagonists. Compounds clustered into three groupings: those with p<i>IC</i>₅₀ values between ca. 5.0 and 5.5, which possessed ED <i>f</i>_b values indistinguishable from the controls, those with p<i>IC</i>₅₀s of 6.5 ± 0.2, which exhibited detectable integrin binding (<i>f</i>_b 13–25%) in the ED assay, and a single compound of p<i>IC</i>₅₀ 7.2 possessing an <i>f</i>_b value of 38%. A good correlation between ED-derived <i>f</i>_b and p<i>IC</i>₅₀ was observed despite the two assays utilizing quite different outputs. These results demonstrate that ED with LC-MS detection shows promise as a rapid α_vβ₆ integrin antagonist screening assay for mixtures of putative ligands

Structure Activity Relationships of α_v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents

Antagonism of α_vβ₆ is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an α_vβ₃ antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved α_vβ₆ activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds <b>33S</b> and <b>43E1</b> are pan α_v antagonists having <i>ca.</i> 100 nM potency against α_vβ_3, α_vβ_5, α_vβ₆, and α_vβ₈ in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC₅₀ values between the integrins in question) for α_vβ₃ and α_vβ₅