The ARGUS Vertex Trigger

A fast second level trigger has been developed for the ARGUS experiment which recognizes tracks originating from the interaction region. The processor compares the hits in the ARGUS Micro Vertex Drift Chamber to 245760 masks stored in random access memories. The masks which are fully defined in three dimensions are able to reject tracks originating in the wall of the narrow beampipe of 10.5\,mm radius.Comment: gzipped Postscript, 27 page

Limits for the central production of Θ+ and Ξ−− pentaquarks in 920-GeV pA collisions

We have searched for Θ+(1540) and Ξ−−(1862) pentaquark candidates in proton-inducedreactions on C, Ti, and W targets at midrapidity and s√=41.6  GeV. In 2×108 inelastic eventswe find no evidence for narrow (σ≈5  MeV) signals in the Θ+→pK0S and Ξ−−→Ξ−π− channels; our 95% C.L. upper limits (UL) forthe inclusive production cross section times branching fraction B dσ/dy $y ≈0 are (4-16) μb/N for a Θ+ mass between 1521 and 1555 MeV,and 2.5μb/N for the Ξ−−. The UL of the yield ratio of Θ+/Λ(1520)<(3-12)% is significantly lower than model predictions.Our UL of B Ξ−−/Ξ(1530)0<4% is at variance with the results that have provided the first evidencefor the Ξ−−

A Search for the Electric Dipole Moment of the Tau-Lepton

Using the ARGUS detector at the e+e- storage ring DORIS II, we have searched for the real and imaginary part of the electric dipole formfactor d_tau of the tau lepton in the production of tau pairs at q^2=100 GeV^2. This is the first direct measurement of this CP violating formfactor. We applied the method of optimised observables which takes into account all available information on the observed tau decay products. No evidence for CP violation was found, and we derive the following results: Re(d_tau)=(1.6+-.9)*10^(-16) ecm and Im(d_tau)=(-0.2+-0.8)*10^(-16) ecm, where statistical and systematic errors have been combined.Comment: 8 pages, 5 figures (10 subfigures

Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6

Histone deacetylase 6 (HDAC6) is an important drug target in oncology and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize a hydroxamic acid as zinc-binding group which limits the therapeutic opportunities due its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i, but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields the deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally results in an essentially irreversible inhibition of HDAC6

Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6

Histone deacetylase 6 (HDAC6) is an important drug target in oncology and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize a hydroxamic acid as zinc-binding group which limits the therapeutic opportunities due its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i, but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields the deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally results in an essentially irreversible inhibition of HDAC6.</jats:p

Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6

Histone deacetylase 6 (HDAC6) is an important drug target in oncology and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize a hydroxamic acid as zinc-binding group which limits the therapeutic opportunities due its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i, but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields the deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally results in an essentially irreversible inhibition of HDAC6.</jats:p

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase <b>6</b>

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6

Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase <b>6</b>

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6