Developing the Saegusa-Ito cyclisation for the synthesis of difluorinated cyclohexenones

Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile achieved the turnover of the initial palladium(II) salt, while the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry

Atom efficient synthesis of selectively difluorinated carbocycles through a gold(I) catalyzed cyclization

The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Suzuki−Miyaura coupling reactions of iodo(difluoroenol) derivatives, fluorinated building blocks accessible at near-ambient temperatures

A recently developed method for the nearambient generation of difluorovinylzinc reagents has facilitated the preparation of 1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-1 - i o d o e t h e n e and 2 , 2 - d i fl u o r o - 1 - i o d o - 1 - ( 2 ′ - methoxyethoxymethoxy)ethene. The utility of these reagents has been investigated in Suzuki−Miyaura couplings with a range of potassium trifluoroborate coupling partners, with the scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from i-PrOH to t-BuOH suppressed the pathway to these species and improved coupling yields

Suzuki–Miyaura Coupling Reactions of Iodo(difluoroenol) Derivatives, Fluorinated Building Blocks Accessible at Near-Ambient Temperatures

A recently developed method for the near-ambient generation of difluorovinylzinc reagents has facilitated the preparation of 1-(<i>N</i>,<i>N</i>-diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene and 2,2-difluoro-1-iodo-1-(2′-methoxyethoxymethoxy)­ethene. The utility of these reagents has been investigated in Suzuki–Miyaura couplings with a range of potassium trifluoroborate coupling partners, with the scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from <i>i</i>-PrOH to <i>t</i>-BuOH suppressed the pathway to these species and improved coupling yields

Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer.

Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy