Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water-and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features-related to elements found to be powerful in phenotypic screening. File list (2) download file view on ChemRxiv strained_allenes-preprint.pdf (184.62 KiB) download file view on ChemRxiv strained_allenes-SI.pdf (2.14 MiB)

A new approach towards the synthesis of glycosides based upon a (formal) insertion of glycosylidene carbenes into 0-H bonds is presented. The synthesis and characterization of the glycosylidene-derived diazirines 25-28, precursors of glycosylidene carbenes, are described.

Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners. ll

Dedicated to Duilio Arigoni on the occasion of his 65th birthday (1.X.93)In the context of the hypothesis postulating a heterolytic cleavage of a C-N bond during thermolysis of alkoxydiazirines (Scheme I ) , we report the preparation of the diazirines4,5,7, and 8, the kinetic parameters for the thermolysis in MeOH of the diazirines 1 and 4-9, and the products of their thermolysis in an aprotic environment. The diazirines 4,5,7, and 8 (Schemes 2-5) were prepared from the known hemiacetals 10,19,34 (prepared from 31 in an improved way), and 42 according to an established method. The oximes 11,20,35, and 43 were obtained from the corresponding hemiacetals as (E/Z)-mixtures; 43 was formed together wlth the cyclic hydroxylamine 44. Oxidation of 11,35, and 43 (N-chlorosuccinimide/l,8-diazabicyclo[5.4.0]undec-7-ene (NCS/DBU) or NaIO,) gave good yields of the (Z)-hydroximolactones 12, 36, and 45, while the oxime 20 led to a mixture of the (E)-and (2)-hydroximolactones 21 and 22, which adopt different conformations. Their configuration was assigned, inter alia, by a comparison with the enol ethers 28 and 29, which were obtained, together with 30, from the reaction of the diazirine 5 with benzaldehyde and PBu,. Treatment of the hydroximolactone 0-sulfonates 13,23,37, and 46 with NH,/MeOH afforded the diaziridines 15,25,38, and 47 in good yields, while the (E)-sulfonate 24 decomposed readily. Oxidation of the diaziridines gave 4, 5, 7, and 8, respectively. Thermolysis of the diazirines 1 and 4-9 in MeOH yielded the anomeric methyl glycosides 50/51,16/17,26/27,52/53,39/40,48/49, and 54/55, respectively. A comparison of the kinetic data of the thermolysis at four different temperatures shows the importance of conformational and electronic factors and is compatible with the hypothesis of a heterolytic cleavage of a C-N bond. An early transition state is evidenced by the absence of torsional strain by an annulated 1,3-dioxane ring. Thermolysis of 1 in MeCN at 23" led mostly to the diastereoisoineric (Z,Z)-, (E,E)-, and (E,Z)-lactone azines 56, 57, and 58 (Scheme 6), which convert to 56 under mild conditions, and to 59 (3%). The benzyloxyglucal59 was obtained in higher yields (IS%), together with 44% of 5658, by thermolysis of solid 1. Similarly, thermolysis at higher temperatures of4 in toluene, THF, or dioxane and of 9 in CH2C12 or THF yielded the (Z,Z)-lactone azines 60 and 61, respectively, the latter being accompanied by the dihydro-oxazole 62.Introduction. -Diazirines [I] are important precursors of carbenes, and the mechanism of their thermolysis attracted considerable attention, which focused on the concertedness of the cleavage of the two C-N bonds and the homo-or heterolytic nature of the bond breaking [2-71. The mechanism and the kinetics of the thermolysis of (a1koxy)alkyldiazirines (see [8] and earlier papers of the series [9-131) have not been studied, but we hypothesized that thermolysis of 1-azisugars, such as 1, i.e. cyclic (alkoxy)alkyldiazirines, is initiated by heterolysis of one of the C( 1)-N bonds, accord-