Generation of highly potent DYRK1A-dependent inducers of human ß-Cell replication via Multi-Dimensional compound optimization.

Small molecule stimulation of ß-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance ß-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human ß-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human ß-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human ß-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

Vicinal bisheterocyclizations of alkynes via nucleophilic interception of a catalytic platinum carbene.

A novel platinum-catalyzed double heterocyclization of propargylic ethers is described. The transformation exploits the intermediacy of a key α,ß-unsaturated carbene. The reactivity of this carbene is such that systems can be developed which avoid a complicating 1,2-hydrogen migration, allowing remarkable versatility in the selective syntheses of oxygen- and nitrogen-containing vicinal bis-heterocyclic compounds.

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic ß Cells.

Diabetes is a hyperglycemic condition characterized by pancreatic ß-cell dysfunction and depletion. Whereas methods for monitoring ß-cell function in vivo exist, methods to deliver therapeutics to ß cells are lacking. We leveraged the rare ability of ß cells to concentrate zinc to preferentially trap zinc-binding molecules within ß cells, resulting in ß-cell-targeted compound delivery. We determined that zinc-rich ß cells and islets preferentially accumulated TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline) in a zinc-dependent manner compared with exocrine pancreas. Next, we asked whether appending a zinc-chelating moiety onto a ß-cell replication-inducing compound was sufficient to confer preferential ß-cell accumulation and activity. Indeed, the hybrid compound preferentially accumulated within rodent and human islets in a zinc-dependent manner and increased the selectivity of replication-promoting activity toward ß cells. These data resolve the fundamental question of whether intracellular accumulation of zinc-chelating compounds is influenced by zinc content. Furthermore, application of this principle yielded a proof-of-concept method for ß-cell-targeted drug delivery and bioactivity.

Postpartum intracranial hemorrhage disguised as preeclampsia.

A 35-year-old woman, gravida 5 para 3, presented to the emergency department 9 days after a cesarean delivery with a new-onset headache, hypertension, and hyperreflexia. Formal urinalysis did not demonstrate proteinuria. Computed tomography of the brain demonstrated bilateral parietal subarachnoid hemorrhages. The patient was subsequently transferred to a tertiary care hospital where she underwent magnetic resonance imaging and computed tomographic angiography that were not suggestive of intracerebral aneurysm, arteriovenous malformation, sinus thrombosis, or angiopathy. The patient was treated with nimodipine and was successfully discharged without any neurologic sequelae or continued hypertension. This case illustrates the potential for presumed postpartum preeclampsia to mask other serious entities, such as intracranial hemorrhage.

CC-401 Promotes ß-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition.

Pharmacologic expansion of endogenous ß cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control ß-cell growth we screened ∼2400 bioactive compounds for rat ß-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat ß-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) ß-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat ß cells, which were broadly growth responsive to compound treatment, human ß-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3ß (GSK-3ß) or activin A receptor type II-like kinase/transforming growth factor-ß (ALK5/TGF-ß) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human ß-cell-replication induction. However, inhibition of NFAT activity had limited effect on CC-401-induced ß-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the ß-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control ß-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control ß-cell growth.

Platinum-Catalyzed α,ß-Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal.

Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed α,ß-unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic α,ß-unsaturated carbene reaction manifold.

Lewis Acid Mediated Vinylogous Additions of Enol Nucleophiles into an α,ß-Unsaturated Platinum Carbene.

A variety of substituted indoles and benzofurans are accessed via a platinum catalyzed annulation and vinylogous addition of enol nucleophiles. Several ß-dicarbonyl compounds participate in the reaction, as do α-nitro and α-cyano carbonyl species. Subjecting the indole products to acidic conditions results in the formation of fused heterocycles.

Community Perspectives: Combining Serology, Genetics, and Inflammation Markers for the Diagnosis of IBD and Differentiation Between CD and UC.

Diagnosis of inflammatory bowel disease (IBD) is complicated and is based on a combination of patient history and physical examination in association with laboratory, endoscopic, histologic, and radiographic investigations. Determination of the correct diagnosis is important for its implications in selecting treatment and in the timing and type of surgery that may be required. Information from testing incorporating serologic, genetic, and inflammatory markers can help to clarify the clinical picture. Measurement of biomarkers not only helps to differentiate a diagnosis of IBD versus non-IBD, it can also help to distinguish between ulcerative colitis and Crohn's disease in difficult cases. In this monograph, 5 cases illustrate how specialized testing can provide important information that can aid in diagnosis.

Generation of α,ß-unsaturated platinum carbenes from homopropargylic alcohols: rearrangements to polysubstituted furans.

A number of diversely substituted furans are synthesized via a cycloisomerization process that goes through a unique metal carbene species. Both ligand structure and the nature of the leaving group are evaluated. The characteristics of the carbene intermediate can be modulated, resulting in highly selective hydrogen or silicon group migrations.