Structure-specific fragmentations of 2,2,4-trisubstituted 1,2-dihydroquinazolines

Fragmentations of a series of 2,2,4-trisubstituted 1,2-dihydroquinazolines were studied by electron impact (EI) ionization and positive- and negative-ion fast atom bombardment (FAB) coupled with collision-induced decomposition (CID). The EI mass spectra give information that directly indicates the specific location of each substituent. The FAB–CID spectra provide data regarding the masses of each substituent, but no definitive information regarding location.     

From perception to action: phase-locked gamma oscillations correlate with reaction times in a speeded response task

Background  

Phase-locked gamma oscillations have so far mainly been described in relation to perceptual processes such as sensation, attention or memory matching. Due to its very short latency (≈90 ms) such oscillations are a plausible candidate for very rapid integration of sensory and motor processes.     

In‐house and synchrotron X‐ray diffraction studies of 2‐phenyl‐1,10‐phenanthroline,protonated salts,complexes with gold(III) and copper(II), and an orthometallation product with palladium(II)

Different salts of the 2‐phenyl‐1,10‐phenanthrolin‐1‐ium cation, (pnpH)⁺, are obtained by reacting 2‐phenyl‐1,10‐phenanthroline (pnp), C₁₈H₁₂N₂, (I), with a variety of anions, such as hexafluoridophosphate, C₁₈H₁₃N₂⁺·PF₆⁻, (II), trifluoromethanesulfonate, C₁₈H₁₃N₂⁺·CF₃SO₃⁻, (III), tetrachloridoaurate, (C₁₈H₁₃N₂)[AuCl₄], (IV), and bromide (as the dihydrate), C₁₈H₁₃N₂⁺·Br⁻·2H₂O, (V). Compound (I) crystallizes with Z′ = 2, with both independent molecules adopting a coplanar conformation. In (II)–(IV), a hydrogen bond exists between the cation and anion, while one of the lattice water molecules serves as a hydrogen‐bonded bridge between the cation and anion in (V). Reaction of (I) with HAuCl₄ gives the salt complex (IV); however, reaction with KAuCl₄ produces the monodentate complex trichlorido(2‐phenyl‐1,10‐phenanthroline‐κN¹⁰)gold(III), [AuCl₃(C₁₈H₁₂N₂)], (VI). Dichlorido(2‐phenyl‐1,10‐phenanthroline‐κ²N,N′)copper(II), [CuCl₂(C₁₈H₁₂N₂)], (VII), results from the reaction of CuCl₂·2H₂O and (I), in which the Cu^II center adopts a tetrahedrally distorted square‐planar geometry. The pendent phenyl ring twists to a bisecting position relative to the phenanthroline plane. The square‐planar Pd^II complex, bromido[2‐(phenanthrolin‐2‐yl)phenyl‐κ³C¹,N,N′]palladium(II), [PdBr(C₁₈H₁₁N₂)], (VIII), is obtained from the reaction of (I) with [PdCl₂(cycloocta‐1,5‐diene)], followed by addition of bromine. A coplanar geometry for the pendent ring is adopted as a result of the tridentate bonding motif.     

Isopenicillin N synthase mediates thiolate oxidation to sulfenate in a depsipeptide substrate analogue: implications for oxygen binding and a link to nitrile hydratase?

Isopenicillin N synthase (IPNS) is a nonheme iron oxidase that catalyzes the central step in the biosynthesis of beta-lactam antibiotics: oxidative cyclization of the linear tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). The ACV analogue delta-L-alpha-aminoadipoyl-L-cysteine (1-(S)-carboxy-2-thiomethyl)ethyl ester (ACOmC) has been synthesized as a mechanistic probe of IPNS catalysis and crystallized with the enzyme. The crystal structure of the anaerobic IPNS/Fe(II)/ACOmC complex was determined to 1.80 A resolution, revealing a highly congested active site region. By exposing these anaerobically grown crystals to high-pressure oxygen gas, an unexpected sulfenate product has been observed, complexed to iron within the IPNS active site. A mechanism is proposed for formation of the sulfenate-iron complex, and it appears that ACOmC follows a different reaction pathway at the earliest stages of its reaction with IPNS. Thus it seems that oxygen (the cosubstrate) binds in a different site to that observed in previous studies with IPNS, displacing a water ligand from iron in the process. The iron-mediated conversion of metal-bound thiolate to sulfenate has not previously been observed in crystallographic studies with IPNS. This mode of reactivity is of particular interest when considered in the context of another family of nonheme iron enzymes, the nitrile hydratases, in which post-translational oxidation of two cysteine thiolates to sulfenic and sulfinic acids is essential for enzyme activity.     

Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.