Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.

Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.

Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B.

The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.

Sequential Michael Addition/Electrophilic Alkynylation: Synthesis of α-Alkynyl-ß-Substituted Ketones and Chromanones.

We describe the synthesis of α-alkynyl-ß-substituted cyclic ketones and analogue chromanones via one-pot Michael addition/hypervalent iodine-based α-alkynylation. Cu(I)-catalyzed Michael addition using either alkyl-aluminum or Grignard reagents, followed by diastereoselective electrophilic alkynylation of the resulting enolate by 1-ethynyl-1λ3,2-benziodoxol-3(1H)-one (EBX) resulted in the α-alkynyl-ß-substituted cyclic ketones or chromanones within 34-89% yield (16 examples). The reaction was successfully upscaled to the 5 mmol scale, and further functionalization of a model alkynylated ketone was demonstrated.

Metal-Free Synthesis of Homopropargylic Alcohols from Aldehydes.

The synthesis of homopropargylic alcohols under metal-free and mild condition is described. This transformation is based on a one-pot procedure involving sequential α-alkynylation of acyclic aldehydes using hypervalent iodine reagents and borohydride reduction. The chemistry exhibits broad substrate scope and good scalability, providing a convenient route for the α-alkynylation of aldehydes along with the formation of a quaternary carbon center. The applicability of the method is demonstrated by the gram-scale synthesis of the key synthetic precursor of botulinum toxin inhibitors.

Selective hydrogenation of indolizines: an expeditious approach to derive tetrahydroindolizines and indolizidines from morita-baylis-hillman adducts.

In this study, we describe the hydrogenation of indolizines derived from Morita-Baylis-Hillman adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared selectively, at low pressure, by simply adjusting the acidity of the medium. Using this simple and straightforward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively in high yield.