BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.

The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been systematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et 2 O and THF for the preparation of most Grignard reagents and their subsequent reactions. † Electronic supplementary information (ESI) available. See

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Convertible Fluorous Linker Assisted Synthesis of Tetrasubstituted Furans. -The approach to furans (III) is achieved through Michael-type [3 + 2] cycloaddition of α,β-unsaturated ketone (I) with β-keto compound (II). The Pfs-substituent is an alternative for triflate and used to introduce aryl-or arylamino groups. -(KADAM, A.; BUCKLEY, S. B.; DINH, T.; FITZGERALD, R.; ZHANG*, W.; Synlett 2011, 11, 1608-1612, http://dx.

Tetrasubstituted furans are prepared by a three-step synthesis including condensation of a fluorous benzaldehyde with an acetophenone followed by Michael-type [3+2] cycloaddition with an 1,3-diketone and Pd-catalyzed coupling reaction for fluorous linker cleavage. The reactions are performed under microwave irradiation and the intermediate purifications are facilitated by fluorous solid-phase extraction (F-SPE).

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Analogues. ‐ Die Darstellung von 2‐aryl‐4‐aroylsubst.