The function of DNA during oxidative stress and its suitability as a potential building block for molecular devices depend on long-distance transfer of electrons and holes through the molecule, yet many conflicting measurements of the efficiency of this process have been reported. It is accepted that charges are transported over long distances through a multistep hopping reaction; this 'G-hopping' involves positive charges moving between guanines (Gs), the DNA bases with the lowest ionization potential. But the mechanism fails to explain the persistence of efficient charge transfer when the guanine sites are distant, where transfer rates do not, as expected, decrease rapidly with transfer distance. Here we show experimentally that the rate of charge transfer between two guanine bases decreases with increasing separation only if the guanines are separated by no more than three base pairs; if more bridging base pairs are present, the transfer rates exhibit only a weak distance dependence. We attribute this distinct change in the distance dependence of the rate of charge transfer through DNA to a shift from coherent superexchange charge transfer (tunnelling) at short distances to a process mediated by thermally induced hopping of charges between adenine bases (A-hopping) at long distances. Our results confirm theoretical predictions of this behaviour, emphasizing that seemingly contradictory observations of a strong as well as a weak influence of distance on DNA charge transfer are readily explained by a change in the transfer mechanism.

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.

The thermal reaction of sulfenates (RS-OR), yielding their corresponding sulfoxides (RS(dO)R), was studied experimentally. The first step of the reaction was found to be the formation a radical pair by homolytic cleavage of the carbon-oxygen bond of the sulfenate. The two transient radicals formed then recombine to form the carbon-sulfur bond of the sulfoxide. The thermolysis of cinnamyl-4-nitrobenzenesulfenate has a positive entropy of activation (∆S q ) 6.4 ( 2.0 eu in toluene), characteristic of a dissociative pathway. A normal secondary kinetic isotope effect (k H /k D ) 1.19 ( 0.04) was also measured with this substrate. Finally, a trapping experiment allowed the isolation and characterization of a product coming from the coupling of the cinnamyl radical and TEMPO. These studies confirm a mechanism that was proposed earlier based on computational studies. The experimentally determined bond dissociation energy of the carbon-oxygen bond of ∼28 kcal‚mol -1 is in good agreement with the computed value of ∼26 kcal‚mol -1 . These studies confirm a unique structural feature of the sulfenate moiety, where the weakest bond of the molecule in the ground state is not the heteroatom-heteroatom bond intuitively considered to be the weakest based on the analogy to peroxides or disulfides. Radical stabilizing substituents are expected to have a large effect on the thermal reactivity of sulfenates. Evidence for a competing acid-catalyzed mechanism has also been observed.

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The radical cation of 1,3,6,8-tetraazatricyclo [4.4.1.1(3,8)]dodecane (TTD) has been studied using magnetic resonance and optical spectroscopic methods and computational techniques. With the help of deuterated isotopomers, assignments of EPR and resonance Raman spectra could be unequivocally established. The results demonstrate that the radical cation has D(2d) symmetry, and instantaneous electron delocalization over the four equivalent nitrogen atoms occurs. This extensive delocalization in a completely saturated system is a unique feature of the TTD radical cation. The spectroscopy of TTD, in contrast to that of simpler diamines such as 1,4-diaza[2.2.2]bicyclooctane, simultaneously reveals the consequences of orbital interactions through space and through bonds. The relationship between nitrogen pyramidalization and hyperfine coupling constants in nitrogen-centered radical cations with a number of different bonding arrangements is reviewed.