DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions ...have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C–N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C–N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.
Herein we describe a method to orthogonally remove on-DNA N-Cbz, N-Alloc, N-Allyl, O-Bn, and O-Allyl protecting groups in the presence of other common protecting groups to afford free amines and ...carboxylic acids, respectively. The developed method uses NaBH4 as the source of hydrogen in the presence of Pd(OAc)2 under DNA aqueous conditions. In addition, under the developed conditions we were able to successfully hydrogenate triple and double bonds to totally saturated compounds. Furthermore, we introduce a new alternative procedure to reduce azides and aromatic nitro compounds to primary amines.
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The output of an affinity selection screening results in a huge amount of valuable data that, after conducting the appropriate analysis, lead to the correct identification of the ...compounds enriched in the target of interest. The approach chosen to perform these analyses has become a key step in the development of a successful DNA Encoded Library platform.
In this paper, we describe the combination of High Performance Liquid Chromatography purification during the library production with the Next Generation Sequencing analysis of the libraries to assess the yield of the chemical reactions prior to the affinity selection. This process allows us, apart from achieving higher quality libraries, to enable a normalization analysis of the affinity selection output, thus minimizing the bias induced by the chemical yield of each reaction as a misleading factor within the analysis and subsequent compound short-listing for off-DNA synthesis.
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and ...apolipoprotein(a) (apo(a))
. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K
) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs.
). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K
7-8. We identify compounds that bind to apo(a) K
7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
The synthesis of a wide structural variety of enantiopure 1-phosphino-2-sulfenylferrocene ligands 1 possessing exclusively planar chirality is described. In the case of the readily available ...tert-butylsulfenyl derivatives very high enantioselectivities were obtained in the palladium-catalyzed allylic substitution of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate (ee's up to 97%) and nitrogen nucleophiles (ee's up to 99.5%). Palladium complexes of these ferrocenes were characterized by NMR and X-ray diffraction, revealing the P,S-bidentate character of the ligands 1 and the formation of a single epimer on the stereogenic sulfur atom resulting from the complexation with palladium. A model justifying the observed asymmetric induction exerted by this novel family of chiral ferrocenes, supported by solution NMR studies on a palladium allylic complex, is discussed.
A simple and modulable access to a structural variety of enantiopure amino-substituted ferrocenyl sulfoxides and their use as chiral catalysts in the asymmetric addition of diethylzinc to aromatic ...aldehydes is described. Moderate to high enantioselectivities (up to 96% ee) were obtained in the case of the arylsulfonamide ligands (R Fc, R S)-4h and (R Fc, R S)-4i. It has been demonstrated that the planar chirality of the ferrocene unit is the decisive chiral element involved in the reaction.
The first detailed study of the palladium-catalyzed amination of aryl nonaflates is reported. Use of ligands 2−4 and 6 allows for the catalytic amination of electron-rich and -neutral aryl nonaflates ...with both primary and secondary amines. With use of Xantphos 5, the catalytic amination of a variety of functionalized aryl nonaflates resulted in excellent yields of anilines; even 2-carboxymethyl aryl nonaflate is effectively coupled with a primary alkylamine. Moderate yields were obtained when coupling halo-aryl nonaflates with a variety of amines, where in most cases the aryl nonaflate reacted in preference to the aryl halide. Overall, aryl nonaflates are an effective alternative to triflates in palladium-catalyzed C−N bond-forming processes due to their increased stability under the reaction conditions.
A novel route to enantiopure densely functionalized epoxy sulfinyl tetrahydrofurans, based on the unexpected and highly stereoselective remote nucleophilic epoxidation of hydroxy 1-sulfinyl ...butadienes with t-BuOOK, followed by ring closure and subsequent epoxidation of the resulting sulfinyl dihydrofurans, is described. Alternatively, the treatment of these dienes with m-CPBA followed by acid-catalyzed cyclization gives rise to related sulfonyl dihydrofurans in high yields but with low selectivity. The stereochemical outcome of the nucleophilic epoxidation of these substrates has also been studied.
The nucleophilic epoxidation of simple (γ-silyloxy)vinyl sulfoxides takes place with complete stereocontrol and high yields. For substrates bearing an additional substituent at the γ position, a ...reinforcing/nonreinforcing scenario is operative. While E and Z silylated substrates undergo a primarily sulfur directed epoxidation with good to excellent diastereocontrol, the related (E)-(2-methoxyethoxy)methyl ethers display diminished selectivity for the diastereomer derived from the nonreinforcing scenario.
