Apparent Alkyl Transfer and Phenazine Formation via an Aryne Intermediate

Treatment of chlorotriaryl derivatives 3a and 3d or fluorotriaryl derivatives 3b and 3e with potassium diisopropylamide afforded alkyl-shifted phenazine derivatives 5a/5b, rather than the expected 9-membered triazaorthocyclophane 2a. The phenazine derivatives were isolated in 78–98% yield depending on the halogen and alkyl group present. In the absence of the halogen (chloro or fluoro), the apparent alkyl shift proceeds more slowly and cannot proceed via the intermediacy of the aryne intermediate. Mechanistic possibilities include intramolecular nucleophilic attack on an aryne intermediate leading to a zwitterionic intermediate and alkyl transfer via a 5-endo-tet process, or via a Smiles rearrangement

Iron(II) Complexes of Di­methyl­tri­aza­cyclo­phane

Treatment of the ortho-tri­aza­cyclo­phane 1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-triene [(C6H5)3(NH)(NCH3)2, L1] with Fe[N(SiMe3)2]2 yields the dimeric iron(II) complex bis­(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido)bis­[(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido)iron(II)], [Fe(C20H18N3)4] or Fe2(L1)4 (9). Dissolution of 9 in tetra­hydro­furan (THF) results in solvation by two THF ligands and the formation of a simpler monoiron complex, namely bis­(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido-κN7)bis­(tetra­hydro­furan-κO)iron(II), [Fe(C20H18N3)2(C4H8O)2] or (L1)2Fe(THF)2 (10). The reaction is reversible and 10 reverts in vacuo to diiron complex 9. In the structures of both 9 and 10, the monoanionic tri­aza­cyclo­phane ligand L1− is observed in only the less-symmetric saddle conformation. No bowl-shaped crown conformers are observed in the solid state, thus preventing chelating κ3-coordination to the metal as had been proposed earlier based on density functional theory (DFT) calculations. Instead, the L1− ligands are bound in either a η2-chelating fashion through the amide and one amine donor (for one of the four ligands of 9), or solely through their amide N atoms in an even simpler monodentate η1-coordination mode. Density functional calculations on dimer 9 revealed nearly full cationic charges on each Fe atom and no bonding inter­action between the two metal centers, consistent with the relatively long FeFe distance of 2.912 (1) Å observed in the solid state

Apparent Alkyl Transfer and Phenazine Formation via an Aryne Intermediate

Treatment of chlorotriaryl derivatives <b>3a</b> and <b>3d</b> or fluorotriaryl derivatives <b>3b</b> and <b>3e</b> with potassium diisopropylamide afforded alkyl-shifted phenazine derivatives <b>5a</b>/<b>5b</b>, rather than the expected 9-membered triazaorthocyclophane <b>2a</b>. The phenazine derivatives were isolated in 78–98% yield depending on the halogen and alkyl group present. In the absence of the halogen (chloro or fluoro), the apparent alkyl shift proceeds more slowly and cannot proceed via the intermediacy of the aryne intermediate. Mechanistic possibilities include intramolecular nucleophilic attack on an aryne intermediate leading to a zwitterionic intermediate and alkyl transfer via a 5-<i>endo-tet</i> process, or via a Smiles rearrangement

Apparent Alkyl Transfer and Phenazine Formation via an Aryne Intermediate

Treatment of chlorotriaryl derivatives <b>3a</b> and <b>3d</b> or fluorotriaryl derivatives <b>3b</b> and <b>3e</b> with potassium diisopropylamide afforded alkyl-shifted phenazine derivatives <b>5a</b>/<b>5b</b>, rather than the expected 9-membered triazaorthocyclophane <b>2a</b>. The phenazine derivatives were isolated in 78–98% yield depending on the halogen and alkyl group present. In the absence of the halogen (chloro or fluoro), the apparent alkyl shift proceeds more slowly and cannot proceed via the intermediacy of the aryne intermediate. Mechanistic possibilities include intramolecular nucleophilic attack on an aryne intermediate leading to a zwitterionic intermediate and alkyl transfer via a 5-<i>endo-tet</i> process, or via a Smiles rearrangement

Suppression of FVIII Inhibitor Formation in Hemophilic Mice by Delivery of Transgene Modified Apoptotic Fibroblasts

The development of inhibitory antibodies to factor VIII (FVIII) is currently the most significant complication of FVIII replacement therapy in the management of patients with severe hemophilia A. Immune tolerance protocols for the eradication of inhibitors require daily delivery of intravenous FVIII for at least 6 months and are unsuccessful in 20–40% of treated patients. We hypothesize that tolerance can be induced more efficiently and reliably by delivery of FVIII antigen within autologous apoptotic cells (ACs). In this study, we demonstrated suppression of the T cell and inhibitor responses to FVIII by infusion of FVIII expression vector modified apoptotic syngeneic fibroblasts in both naive and preimmunized hemophilia A mice. ACs without FVIII antigen exerted modest generalized immune suppression mediated by anti-inflammatory signals. However, FVIII expressing apoptotic syngeneic fibroblasts produced much stronger antigen-specific immune suppression. Mice treated with these fibroblasts generated CD4+ T cells that suppressed the immune response to FVIII after adoptive transfer into naive recipients and antigen-specific CD4+CD25+ regulatory T cells (Tregs) that inhibited the proliferation of FVIII responsive effector T cells in vitro. These preclinical results demonstrate the potential for using FVIII vector modified autologous ACs to treat high-titer inhibitors in patients with hemophilia A

The Fourth Bioelectronic Medicine Summit "Technology Targeting Molecular Mechanisms" : current progress, challenges, and charting the future

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here