The Alkaline Hydrolysis of Sulfonate Esters: Challenges in Interpreting Experimental and Theoretical Data

Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem. 10, 2012, 8095) presented a nonlinear Brønsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Brønsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data

Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

Background: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax–rituximab group (32 events of progression or death in 194 patients) than in the bendamustine–rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax–rituximab group versus 27.8% in the bendamustine–rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax–rituximab group than in the bendamustine–rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax–rituximab group was 3.1% (6 of 194 patients). Conclusions: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471.

Floral Assemblages and Patterns of Insect Herbivory during the Permian to Triassic of Northeastern Italy

To discern the effect of the end-Permian (P-Tr) ecological crisis on land, interactions between plants and their insect herbivores were examined for four time intervals containing ten major floras from the Dolomites of northeastern Italy during a Permian-Triassic interval. These floras are: (i) the Kungurian Tregiovo Flora;(ii) the Wuchiapingian Bletterbach Flora;(iii) three Anisian floras;and (iv) five Ladinian floras. Derived plant-insect interactional data is based on 4242 plant specimens (1995 Permian, 2247 Triassic) allocated to 86 fossil taxa (32 Permian, 56 Triassic), representing lycophytes, sphenophytes, pteridophytes, pterido-sperms, ginkgophytes, cycadophytes and coniferophytes from 37 million-year interval (23 m. yr. Permian, 14 m. yr. Triassic). Major Kungurian herbivorized plants were unaffiliated taxa and pteridosperms;later during the Wuchiapingian cycadophytes were predominantly consumed. For the Anisian, pteridosperms and cycadophytes were preferentially consumed, and subordinately pteridophytes, lycophytes and conifers. Ladinian herbivores overwhelming targeted pteridosperms and subordinately cycadophytes and conifers. Throughout the interval the percentage of insect-damaged leaves in bulk floras, as a proportion of total leaves examined, varied from 3.6% for the Kungurian (N = 464 leaves), 1.95% for the Wuchiapingian (N = 1531), 11.65% for the pooled Anisian (N = 1324), to 10.72% for the pooled Ladinian (N = 923), documenting an overall herbivory rise. The percentage of generalized consumption, equivalent to external foliage feeding, consistently exceeded the level of specialized consumption from internal feeding. Generalized damage ranged from 73.6% (Kungurian) of all feeding damage, to 79% (Wuchiapingian), 65.5% (pooled Anisian) and 73.2% (pooled Ladinian). Generalized-to-specialized ratios show minimal change through the interval, although herbivore component community structure (herbivore species feeding on a single plant-host species) increasingly was partitioned from Wuchiapingian to Ladinian. The Paleozoic plant with the richest herbivore component community, the coniferophyte Pseudovoltzia liebeana, harbored four damage types (DTs), whereas its Triassic parallel, the pteridosperm Scytophyllum bergeri housed 11 DTs, almost four times that of P. liebeana. Although generalized DTs of P. liebeana were similar to S. bergeri, there was expansion of Triassic specialized feeding types, including leaf mining. Permian-Triassic generalized herbivory remained relatively constant, but specialized herbivores more finely partitioned plant- host tissues via new feeding modes, especially in the Anisian. Insect-damaged leaf percentages for Dolomites Kungurian and Wuchiapingian floras were similar to those of lower Permian, north-central Texas, but only one-third that of southeastern Brazil. Global herbivore patterns for Early Triassic plant-insect interactions remain unknown

Monomeric Fullerenes in Lipid Membranes: Effects of Molecular Shape and Polarity

We report a combined theoretical and experimental study on the single-molecule interaction of fullerenes with phospholipid membranes. We studied pristine C(60) (1) and two N-substituted fulleropyrrolidines (2 and 3), one of which (3) bore a paramagnetic nitroxide group. Theoretical predictions of fullerene distribution and permeability across lipid bilayers were combined with electron paramagnetic resonance (EPR) experiments in aligned DMPC/DHPC bicelles containing the paramagnetic fulleropyrrolidine 3 or either one of the diamagnetic fullerenes together with spin-labeled lipids. We found that, at low concentrations, fullerenes are present in the bilayer as single molecules. Their preferred location in the membrane is only slightly influenced by the derivatization: all derivatives were confined just below the hydrophilic/hydrophobic interface, because of the key role played by dispersion interactions between the highly polarizable fullerene cage and the hydrocarbon chains, which are especially tight within this region. However, the deviation from spherical shape is sufficient to induce a preferential orientation of 2 and 3 in the membrane. We predict that monomeric fullerenes spontaneously penetrate the bilayer, in agreement with the results of molecular dynamics simulations, but we point out the limits of the currently used permeability model when applied to hydrophobic solutes