6-O-alkylated 7-deazainosine nucleoside analogues : discovery of potent and selective anti-sleeping sickness agents

African trypanosomiasis, a deadly infectious disease caused by the protozoan Trypanosoma brucei spp., is spread to new hosts by bites of infected tsetse flies. Currently approved therapies all have their specific drawbacks, prompting a search for novel therapeutic agents. T. brucei lacks the enzymes necessary to forge the purine ring from amino acid precursors, rendering them dependent on the uptake and interconversion of host purines. This dependency renders analogues of purines and corresponding nucleosides an interesting source of potential anti-T. brucei agents. In this study, we synthesized and evaluated a series of 7-substituted 7-deazainosine derivatives and found that 6-O-alkylated analogues in particular showed highly promising in vitro activity with EC50 values in the mid-nanomolar range. SAR investigation of the O-alkyl chain showed that antitrypanosomal activity increased, and also cytotoxicity, with alkyl chain length, at least in the linear alkyl chain series. However, this could be attenuated by introducing a terminal branch point, resulting in the highly potent and selective analogues, 36, 37 and 38. No resistance related to transporter-mediated uptake could be identified, earmarking several of these analogues for further in vivo follow-up studies

Neutrophils enhance early Trypanosoma brucei infection onset.

In this study, Trypanosoma brucei was naturally transmitted to mice through the bites of infected Glossina morsitans tsetse flies. Neutrophils were recruited rapidly to the bite site, whereas monocytes were attracted more gradually. Expression of inflammatory cytokines (il1b, il6), il10 and neutrophil chemokines (cxcl1, cxcl5) was transiently up-regulated at the site of parasite inoculation. Then, a second influx of neutrophils occurred that coincided with the previously described parasite retention and expansion in the ear dermis. Congenital and experimental neutropenia models, combined with bioluminescent imaging, indicate that neutrophils do not significantly contribute to dermal parasite control and elicit higher systemic parasitemia levels during the infection onset. Engulfment of parasites by neutrophils in the skin was rarely observed and was restricted to parasites with reduced motility/viability, whereas live parasites escaped phagocytosis. To our knowledge, this study represents the first description of a trypanosome infection promoting role of early innate immunological reactions following an infective tsetse fly bite. Our data indicate that the trypanosome is not hindered in its early development and benefits from the host innate responses with the neutrophils being important regulators of the early infection, as already demonstrated for the sand fly transmitted Leishmania parasite

Structure-activity relationship exploration of 3’-deoxy-7-deazapurine nucleoside analogues as anti-Trypanosoma brucei agents

Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3'-deoxytubercidin (5), a lead compound with activity against central-nervous-stage human African trypanosomiasis, we investigate the structure-activity relationships of the purine and ribofuranose rings. The purine ring tolerated only modifications at C7, while from the many alterations of the 3'-deoxyribofuranosyl moiety only the arabino analogue 48 showed pronounced antitrypanosomal activity. Profiling of the most potent analogues against resistant T. brucei strains (resistant to pentamidine, diminazene, and isometamidium) showed reduced dependence on uptake mediated by the P2 aminopurine transporter relative to 5. The introduction of a 7-substituent confers up to 10-fold increased affinity for the P1 nucleoside transporter while generally retaining high affinity for P2. Four of the most promising analogues were found to be metabolically stable, earmarking them as suitable backup analogues for lead 5

Nucleoside analogues for the treatment of animal trypanosomiasis

Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species. Compound 7, an inosine analogue, and our previously described lead compound, 3′-deoxytubercidin (8), showed broad spectrum anti-AT activity, metabolic stability in the target host species and absence of toxicity, but with variable efficacy ranging from limited activity to full cure in mouse models of Trypanosoma congolense and T. vivax infection. Several compounds show promise against T. evansi (surra) and T. equiperdum (dourine). Given the preferred target product profile for a broad-spectrum compound against AT, this study emphasizes the need to include T. vivax in the screening cascade given its divergent susceptibility profile and provides a basis for lead optimization toward such broad spectrum anti-AT compound

The 1958–2009 Greenland ice sheet surface melt and the mid-tropospheric atmospheric circulation

peer reviewedaudience: researcherIn order to assess the impact of the mid-tropospheric circulation over the Greenland ice sheet (GrIS) on surface melt, as simulated by the regional climate model MAR, an automatic Circulation type classification (CTC) based on 500 hPa geopotential height from reanalyses is developed. General circulation correlates significantly with the surface melt anomalies for the summers in the period 1958–2009. The record surface melt events observed during the summers of 2007–2009 are linked to the exceptional persistence of atmospheric circulations favouring warm air advection. The CTC emphasizes that summer 500 hPa circulation patterns have changed since the beginning of the 2000s; this process is partly responsible for the recent warming observed over the GrIS

Загальні відомості про рельєф та відклади Бердянської і Білосарайської кіс Азовського моря

Бердянська і Білосарайська коси мають форму майже рівностороннього трикутника з причленованими до звернених до моря вершин вузьких смуг суші, які ще далі вдаються в море

Descriptions de L\ue9pidopt\ue8res nouveaux de la famille des Hesp\ue9rides

Volume: 2Start Page: 237End Page: 23

Essai de revision de la famille des Hesp\ue9rides. 2. Subfamily Hesperiinae

Volume: 16Start Page: 1End Page: 15