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Abstract Background Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer. Methods We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo. Results NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine. Conclusions Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.

The palladium(II) complex (Rp,S)-COP-Cl2and its enantiomer catalyze the rearrangement of linear prochiral O-allyl carbamothioates under mild conditions to provide branched S-allyl carbamothioates in high yield and high enantiomeric purity. [ABSTRACT FROM AUTHOR]

The reaction of trichloroacetimidate derivatives of (Z)-2-alken-1-ols with phenol nucleophiles in the presence of the palladium(II) catalyst COP-OAc2provides 3-aryloxy-1-alkenes in high yields and high enantiomeric purity (typically 63−90% yield and 90−97% ee). The reaction is exemplified by 20 examples. The method employs 1 mol % of the commercially available catalysts (S)- or (R)-COPOAc2, produces the branched isomer with unprecedented regioselectivity, and is compatible with the presence of base-labile functionality in either reactant. [ABSTRACT FROM AUTHOR]

The first total synthesis of gliocladin C, a fungal-derived marine alkaloid containing a rare trioxopiperazine fragment, is reported. This asymmetric synthesis establishes the absolute configuration of this structurally novel natural product. [ABSTRACT FROM AUTHOR]