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Knowledge of aquatic food resources entering terrestrial systems is important for food web studies and conservation planning. Bats, among other terrestrial consumers, often profit from aquatic insect emergence and their activity might be closely related to such events. However, there is a lack of studies which monitor bat activity simultaneously with aquatic insect emergence, especially from lakes. Thus, our aim was to understand the relationship between insect emergence and bat activity, and investigate whether there is a general spatial or seasonal pattern at lakeshores. We assessed whole-night bat activity using acoustic monitoring and caught emerging and aerial flying insects at three different lakes through three seasons. We predicted that insect availability and seasonality explain the variation in bat activity, independent of the lake size and characteristics. Spatial (between lakes) differences of bat activity were stronger than temporal (seasonal) differences. Bat activity did not always correlate to insect emergence, probably because other factors, such as habitat characteristics, or bats' energy requirements, play an important role as well. Aerial flying insects explained bat activity better than the emerged aquatic insects in the lake with lowest insect emergence. Bats were active throughout the night with some activity peaks, and the pattern of their activity also differed among lakes and seasons. Lakes are important habitats for bats, as they support diverse bat communities and activity throughout the night and the year when bats are active. Our study highlights that there are spatial and temporal differences in bat activity and its hourly nocturnal pattern, that should be considered when investigating aquatic-terrestrial interactions or designing conservation and monitoring plans.

Monoclonal antibodies (MoAb) and tyrosine kinase inhibitors (TKI) targeting the EGFR (Epidermal Growth Factor Receptor) pathways are currently used in colorectal cancer treatment. Despite the improvement of median overall survival, resistance is observed notably due to KRAS and BRAF gene mutations. We synthesized four series of thienopyrimidines whose scaffold is structurally close to TKI used in clinical practice. We evaluated apoptosis induced by these compounds using flow cytometry on KRAS and BRAF mutated cell lines. Our results confirm that the mutated cell lines (HCT116 and HT29) are more resistant to apoptosis than the non-mutated cell line (Hela). Interestingly, among the 13 compounds tested, three of them (5b, 6b and 6d) and gefitinib exhibited a noteworthy pro-apoptotic effect, especially on mutated cell lines with an IC(50) value between 70 and 110μM. These three compounds seem particularly attractive for the development of novel treatments for colorectal cancer patients harboring EGFR pathway mutations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The receptor tyrosine kinases (for example EGFR, PDGFR, VEGFR) are a transmembrane protein family which plays a crucial role in tumor growth, survival, metastasis dissemination and angiogenesis. During the past 10 years, many tyrosine kinase inhibitors (TKIs) have been approved for cancer treatment (imatinib, gefitinib, erlotinib, sunitinib, sorafenib). These compounds generally possess a pyrrolo- or pyrimido- pyrimidine scaffold or approaching molecular structure. We synthesized 10 thienopyrimidine compounds (including 5 newly synthesized) whose scaffold is very similar to the agents cited above. The cytotoxicity of these agents was evaluated using a MTT assay and a flow cytometry technique on glioblastoma cell lines. Two compounds showed a similar cytotoxicity to the standard anti-EGFR gefitinib (IC50: gefitinib=51.9 microM, 6b=61.8 microM, 6c=41.2 microM), suggesting a blockade of the EGFR pathway by binding to the TK receptor., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

It has been observed that ticlopidine and clopidogrel show, apart from their delayed antiplatelet properties, an immediate and transient thrombolytic action related to the ability of these thienopyridines to stimulate the secretory function of vascular endothelium. With the objective to construct new molecules with identical thrombolytic potency but at a higher level, we carried out different structural modifications in the thienopyridine chemical molecule to conclude that the presence of a second N atom in the pyridine cycle (yielding pyrimidine moiety) and the presence of an additional cycle fused to the thienyl ring would lead to enhanced thrombolytic effects. Here we report the six-step synthesis of a series of new benzothienopyrimidinone derivatives characterized by this searched for potent thrombolytic activity. The pharmacological assay used anaesthetised Wistar rats with extracorporal circulation in which arterial blood superfused thrombi adhering to a strip of collagen. Weight of thrombi was continuously monitored. Six compounds of the series were much more potent thrombolytic agents than their thienopyridine references: the effective thrombolytic dose that produced 30% of maximum thrombolysis (ED30) was at a range of 8 to 170 microg kg(-1) as compared with ED30 values of 16000 to 20000 microg kg(-1) for clopidogrel and ticlopidine respectively. Especially with the most active compound, this difference in the threshold thrombolytic dose, giving an intensity of action higher by three orders of magnitude, was accompanied by a lengthening of the response. Apart from that these compounds have shown to be synthetic thrombolytics, they certainly deserve further studying.

We propose that anti-platelet thienopyridines, such as ticlopidine or clopidogrel, are thrombolytic owing to endothelial release of prostacyclin (PGI2) and tissue plasminogen activator (t-PA). In this study we used anaesthetised Wistar rats with extracorporal circulation in which arterial blood superfused thrombi which adhered to a strip of collagen. Weight of thrombi was continuously monitored. When administered intravenously, clopidogrel or its R enantiomer deprived of anti-platelet action, both at doses of 3 mg x kg(-1), produced lost in weight of thrombi by 14.1 +/- 1.3% or 16.0 +/- 1.4% (n = 9), and at doses 10 mg x kg(-1) by 28.3 +/- 2.3% or 30.4 +/- 1.9% (n = 8), respectively. Maximum of thrombolysis occurred 30-45 min following the drug administration. Ticlopidine at a dose of 30 mg x kg(-1) reduced weight of thrombi by 33.7 +/- 1.7% (n = 32). Thrombolytic action of ticlopidine was accompanied by a rise in 6!keto-PGF1alpha blood levels from 0.42 +/- 0.10 to 1.58 +/- 0.29 ng x ml(-1) and t-PA antigen plasma levels from 4.70 +/- 1.00 to 12.90 +/- 1.15 ng x ml(-1) (n = 7). Five out of eleven tested thienopyridine congeners with pyrimidine or pyrimidinone instead of pyridine rings had thrombolytic potencies similar to that of clopidogrel (ED30s at a range of 6.2-11.4 mg x kg(-1)). A substantial increase in thrombolytic potency (ED30s at a range of 0.3-2.1 mg x kg(-1)) was observed for congeners in which thienyl ring was condensed with an additional cyclopentyl, cyclohexyl or cycloheptyl structures or in which thienopyridine complex was replaced for a pyridopyrimidine one. We claim that thienopyridines, independently of their delayed anti-platelet action, do produce immediate thrombolysis in vivo. This new activity emulates capacity of their native, non-metabolised molecules to release prostacyclin and tissue plasminogen activator. We have also shown that structural changes in molecules of thienopyridines may intensify their thrombolytic potency.

Some new derivatives of pyrido[2,3-d]pyrimidin-4(3H)-one A and 1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidines B were prepared. The study of their in vitro antiaggregating activity showed that the compounds A possessed an inhibitory potency when aggregation was induced with ADP. Their reduction to derivatives of 1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine B led to a new series of molecules possessing a greater antiaggregating power. When compared to that of acetylsalicylic acid under the same conditions, this activity was weaker with collagen, the same with arachidonic acid-induced aggregation, but greater when aggregation was induced by ADP. However, they inhibited serotonin release only slightly. Compared to ginkgolide they remained weaker with PAF-induced aggregation.

Some derivatives of thieno[2,3-d]pyrimidin-4(3 H)-one A and their 1,2-dihydrogenated homologues B were synthesized. The study of their in vitro antiaggregating activity showed that the first compounds exhibited significant inhibiting power when aggregation was induced with ADP. Their reduction to derivatives of 1,2-dihydrothieno[2,3-d]pyrimidin-4(3 H)-one led to a new series of molecules possessing a large antiaggregant activity. When compared to that of acetylsalicylic acid under the same conditions, this activity was the same with collagen or arachidonic acid-induced aggregation, but greater when aggregation was induced by ADP. Serotonin release was also inhibited.

Some new 4-quinazolinones were prepared. Their antiplatelet activity was evaluated in vitro with respect to aggregation induced by ADP, collagen, arachidonic acid and the platelet serotonin release reaction. Most molecules showed an inhibiting power similar to that of acetylsalicylic acid under the same conditions, and even greater when aggregation was induced by ADP. Reduction of the 4-quinazolinone derivatives to their 1,2,3,4-tetrahydroquinazoline homologues produced an increase in platelet inhibitory action except when ADP is the inductor.

A dozen acetoxy benzene derivatives (mono- or diacetylated diphenols) were tested for inhibitory activity on platelet aggregation in human platelet rich plasma induced with collagen, ADP and arachidonic acid. All the compounds tested showed an activity, and the results emphasize the antiaggregant properties of diacetylated derivatives which are more potent than aspirin. Unlike aspirin, their action is not prevented by salicylate. However, the large inhibition of serotonin release and thromboxane synthesis localizes their activity in arachidonic acid metabolism.

Thirteen aspirin-related compounds were tested for inhibitory activity on platelet aggregation in human platelet rich plasma (PRP) induced with ADP, collagen and arachidonic acid. The following structure-activity relationships were found: none of the functional groups used to replace the acetyl group retained the significant antiaggregant activity of aspirin; anti-aggregant activity was enhanced when the carboxylic group was replaced with a hydroxyl or an acetylated hydroxyl group. The activity of these mono and diacetylated pyrocatechol derivatives was unaffected by incubation of PRP with sodium salicylate.