PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.

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In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

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A new method for the calorimetric characterization of high-energetic, fast reactions in flow mode was developed. The use of an engineered flow reactor in combination with a process modeling software allowed the deconvolution of the reaction enthalpy from space-resolved temperature profiles. The new procedure was verified in a comparison with a conventional batch calorimeter and subsequently implemented for the thermal characterization of an organolithium flow process. The information collected for this reaction successfully supported a scale-up to the pilot plant. Overall, the new approach resulted in being superior when compared with established procedures, enabling the generation of precise calorimetric data in an accurate scale-down flow device.

A platform for conducting organolithium chemistry in continuous flow mode, covering the scales from medicinal chemistry to later phase process development, is described. The use of this flow setup, which mimics the concept of f lash chemistry on scale, has been demonstrated by the exemplary, large-scale preparation of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Furthermore, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab environment to higher productivity are highlighted.

Hydrogen peroxide is showcased in a range of oxidations, operating in continuous-flow equipment to deliver practical and risk-minimized procedures.

The BF(3).Et(2)O-induced decomposition of ethyl 2-diazo-3-hydroxy-3,3-diarylpropanoates, prepared by the addition of a series of benzophenones to ethyl diazo(lithio)acetate, is reported and studied. By using acetonitrile as a solvent, the corresponding N-acyl beta-enamino ester derivatives are obtained in good yields and with a diverse regioselectivity as the result of 1,2-aryl migration in the vinyl cation intermediates. The factors that govern the migratory aptitude as well as the mechanistic aspects of the reaction are discussed.