Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones

6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.     

Behavioural mimicry of honeybees (Apis mellifera) by droneflies (Diptera: Syrphidae: Eristalis spp.)

Droneflies (Syrphidae: Eristalis spp. resemble honeybees (Apis mellifera) in appearance and have often been considered to be Batesian mimics. This study used a focal watch technique in order to compare the foraging behaviour of droneflies Eristalis tenax, Eristalis pertinax, Eristalis arbustorum and Eristalis nemorum) whilst they were feeding on patches of flowers with the behaviour of honeybees and other hymenopterans and dipterans. It was found that, on a range of plant species, the time droneflies spent on individual flowers and the time spent flying between them was more similar to that of honeybees than to the times of other hymenopterans and dipterans. These results suggest that dronefly behaviour has evolved to become more similar to that of honeybees and they support the hypothesis that droneflies are Batesian mimics.     

Effect of genetic background on glycosylation heterogeneity in human antithrombin produced in the mammary gland of transgenic goats

Glycosylation is involved in the correct folding, targeting, bioactivity and clearance of therapeutic glycoproteins. With the development of transgenic animals as expression systems it is important to understand the impact of different genetic backgrounds and lactations on glycosylation. We have evaluated the glycosylation of recombinant antithrombin produced in several transgenic goat lines, from cloned animals and from different types of lactation including induced lactations. Our results show glycosylation patterns from the protein expressed in animals, derived from the same founder goat, are mostly comparable. Furthermore, the protein expressed in two cloned goats had highly consistent oligosaccharide profiles and similar carbohydrate composition. However, there were significantly different oligosaccharide profiles from the proteins derived from different founder goats. Artificial induction of lactation did not have significant effects on overall carbohydrate structures when compared to natural lactation. The only major difference was that recombinant antithrombin from induced lactations contained a slightly higher ratio of N-acetylneuraminic acid to N-glycolylneuraminic acid and less amount of oligosaccharides containing N-glycolylneuraminic acid. The oligosaccharides from all animals were a mixture of high mannose-, hybrid- and complex-type oligosaccharides. Sialic acid was present as alpha-2,6-linkage and no alpha-1,3-linked galactose was observed. These results indicate that transgenic animals with closely related genetic backgrounds express recombinant protein with comparable glycosylation.     

Discovery of novel non-peptidic ketopiperazine-based renin inhibitors

Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).     

The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex

The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.     

Equipotent activity in both enantiomers of a series of ketopiperazine-based renin inhibitors

We have found that both enantiomeric configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns. This enantiomeric flexibility is in contrast to a previously reported 3-alkoxymethyl-4-arylpiperidine scaffold.     

Hepatitis-B virus endemicity: heterogeneity, catastrophic dynamics and control

Hepatitis-B virus infection is globally ubiquitous, but its distribution is very heterogeneous, with prevalence of serological markers in various nations ranging from less than 1% to more than 90%. We propose an explanation for this diversity using a mathematical model of hepatitis-B virus transmission dynamics that shows, for the first time, 'catastrophic' behavior using realistic epidemiological processes and parameters. Our major conclusion is that the prevalence of infection is largely determined by a feedback mechanism that relates the rate of transmission, average age at infection and age-related probability of developing carriage following infection. Using the model we identify possible, highly non-linear, consequences of chemotherapy and immunization interventions, for which the starting prevalence of carriers is the most influential, predictive quantity. Taken together, our results demand a re-evaluation of public health policy towards hepatitis-B.     

Framework of barrier reefs threatened by ocean acidification

To date, studies of ocean acidification (OA) on coral reefs have focused on organisms rather than communities, and the few community effects that have been addressed have focused on shallow back reef habitats. The effects of OA on outer barrier reefs, which are the most striking of coral reef habitats and are functionally and physically different from back reefs, are unknown. Using 5‐m long outdoor flumes to create treatment conditions, we constructed coral reef communities comprised of calcified algae, corals, and reef pavement that were assembled to match the community structure at 17 m depth on the outer barrier reef of Moorea, French Polynesia. Communities were maintained under ambient and 1200 μatm pCO₂ for 7 weeks, and net calcification rates were measured at different flow speeds. Community net calcification was significantly affected by OA, especially at night when net calcification was depressed ~78% compared to ambient pCO₂. Flow speed (2–14 cm s^?1) enhanced net calcification only at night under elevated pCO₂. Reef pavement also was affected by OA, with dissolution ~86% higher under elevated pCO₂ compared to ambient pCO₂. These results suggest that net accretion of outer barrier reef communities will decline under OA conditions predicted within the next 100 years, largely because of increased dissolution of reef pavement. Such extensive dissolution poses a threat to the carbonate foundation of barrier reef communities.