Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-KrasG12D mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP–protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.
Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.
The
stereospecific ring-opening of O-heterocycles to provide acyclic
alcohols and carboxylic acids with controlled formation of a new C–C
bond is reported. These reactions provide new methods for synthesis
of acyclic polyketide analogs with complex stereochemical arrays.
Stereoselective synthesis of the cyclic template is utilized to control
relative configuration; subsequent stereospecific nickel-catalyzed
ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans
and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling
with a range of Grignard reagents to furnish acyclic alcohols with
high diastereoselectivity. Enantioenriched lactones undergo Negishi-type
cross-coupling with dimethylzinc to afford enantioenriched carboxylic
acids. Application in a two-step enantioselective synthesis of an
anti-dyslipidemia agent is demonstrated.
A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross‐coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni0–NiII catalytic cycle for a stereospecific alkyl–alkyl cross‐coupling reaction, including spectroscopic analysis of the catalyst resting state.
In
this manuscript we highlight the potential of stereospecific
nickel-catalyzed cross-coupling reactions for applications in the
pharmaceutical industry. Using an inexpensive and sustainable nickel
catalyst, we report a gram-scale Kumada cross-coupling reaction. Reactions
are highly stereospecific and proceed with inversion at the benzylic
position. We also expand the scope of our reaction to incorporate
isotopically labeled substituents.
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