Stereocontrolled Synthesis of the Tricyclic ABC Ring System of Daphnicyclidin A

An enantiocontrolled synthesis pathway has been developed to provide formation of tricyclic amine <b>7</b>, representing the ABC ring system of the complex alkaloid daphnicyclidin A (<b>1</b>). Our efforts describe preparation of the <i>Z</i>-hexahydro-(1<i>H</i>)-azocine <b>29</b> and cyclization to construct the novel 4-azabicyclo[5.3.2]­dodecane <b>31</b>. Transannular reductive amination following the deprotection of <b>31</b> gave the desired tertiary amine <b>7</b>

Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies

Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was <b>29</b> (BRD-6851), with an IC₅₀ of 0.4 μM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by <i>Gli1</i> transcription and alkaline phosphatase induction. Studies with Patched knockout (<i>Ptch</i>^–/–) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists

Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects

The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3’s inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in <i>in vitro</i> systems or <i>in vivo</i> models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydro­quinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, <b>BRD1652</b> and <b>BRD0209</b>, which demonstrated <i>in vivo</i> efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders