Publications by authors named "Daniel Delorme"

36 Publications

Prevalence and intensity of Alaria alata (Goeze, 1792) in water frogs and brown frogs in natural conditions.

Parasitol Res 2015 Dec 29;114(12):4405-12. Epub 2015 Aug 29.

EA 4688 - USC Anses « VECPAR », UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096, Reims, France.

In the last 15 years, the mesocercariae of Alaria alata have frequently been reported in the wild boar during routine Trichinella inspections made compulsory for the trade of venison meat in Europe. If these studies have focused primarily on mesocercariae isolated from meat, few works have been done so far to understand the circulation of the parasite in natural conditions especially in the intermediate hosts. This study focuses on the second intermediate hosts of this parasite assessing the suitability of two amphibian groups-brown frogs and water frogs sensu lato-for mesocercarial infection on an area where A. alata has already been identified in water snails and wild boars. During this study, both groups showed to be suitable for mesocercarial infection, with high prevalence and parasite burdens. Prevalence was higher in the brown frog group (56.9 versus 11.54 % for water frogs) which would indicate that it is a preferential group for infection on the study area, though reasons for this remain to be investigated. No significant difference among prevalences was observed between tadpoles and frogs. This study, the first focusing on A. alata in these amphibians in Europe, provides further information on circulation of this parasite in natura.
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http://dx.doi.org/10.1007/s00436-015-4680-zDOI Listing
December 2015

Quantifying the influence of measured and unmeasured individual differences on demography.

J Anim Ecol 2015 Sep 3;84(5):1434-45. Epub 2015 Jul 3.

Université de Lyon, F-69000, Lyon, France.

1. Demographic rates can vary not only with measured individual characters like age, sex and mass but also with unmeasured individual variables like behaviour, genes and health. 2. Predictions from population models that include measured individual characteristics often differ from models that exclude them. Similarly, unmeasured individual differences have the potential to impact predictions from population models. However, unmeasured individual differences are rarely included in population models. 3. We construct stage- and age-structured models (where stage is mass) of a roe deer population, which are parameterized from statistical functions that either include, or ignore, unmeasured individual differences. 4. We found that mass and age structures substantially impacted model parameters describing population dynamics, as did temporal environmental variation, while unmeasured individual differences impacted parameters describing population dynamics to a much smaller extent once individual heterogeneity related to mass and age has been included in the model. We discuss how our assumptions (unmeasured individual differences only in mean trait values) could have influenced our findings and under what circumstances unmeasured individual differences could have had a larger impact on population dynamics. 5. There are two reasons explaining the relative small influence of unmeasured individual differences on population dynamics in roe deer. First, individual body mass and age both capture a large amount of individual differences in roe deer. Second, in large populations of long-lived animals, the average quality of individuals (independent of age and mass) within the population is unlikely to show substantial variation over time, unless rapid evolution is occurring. So even though a population consisting of high-quality individuals would have much higher population growth rate than a population consisting of low-quality individuals, the probability of observing a population consisting only of high-quality individuals is small.
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http://dx.doi.org/10.1111/1365-2656.12393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642278PMC
September 2015

Fitness consequences of environmental conditions at different life stages in a long-lived vertebrate.

Proc Biol Sci 2014 Jun 30;281(1785):20140276. Epub 2014 Apr 30.

Université de Lyon, 69 000, Lyon; Université Lyon 1; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, 69 622 Villeurbanne, France, Department of Ecology and Natural Resource Management, Norwegian University of Life Sciences, , PO Box 5003, 1432 Aas, Norway, Office National de la Chasse et de la Faune Sauvage, CNERA Cervidés Sangliers, , 1 place Exelmans, 55 000 Bar-le-Duc, France, Centre d'Études Biologiques de Chizé, CNRS Université de la Rochelle UMR 7372, , 79 360 Beauvoir-sur-Niort, France.

The predictive adaptive response (PAR) hypothesis proposes that animals adjust their physiology and developmental trajectory during early life in anticipation of their future environments. Accordingly, when environmental conditions in early life match environmental conditions during adulthood, individual fitness should be greater. Here, we test this hypothesis in a long-lived mammal, the roe deer, using data from two contrasting populations, intensively monitored for more than 35 years. In the highly productive site, the fitness of female roe deer increased with the quality of environment during adulthood and, contrary to predictions of PAR, individuals born in good conditions always outperformed those born under poor conditions. In the resource-limited site, the fitness of female roe deer born in poor years was better than those born in good conditions in poor years when the animals were adult, but not in good years. Although consistent with predictions of PAR, we showed that this pattern is likely to be a consequence of increased viability selection during the juvenile stage for animals born in poor years. While PARs are often advanced in evolutionary medicine, our findings suggest that detailed biological processes should be investigated before drawing conclusions about the existence of this phenomenon.
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http://dx.doi.org/10.1098/rspb.2014.0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024291PMC
June 2014

Mismatch between birth date and vegetation phenology slows the demography of roe deer.

PLoS Biol 2014 Apr 1;12(4):e1001828. Epub 2014 Apr 1.

Laboratoire "Biométrie et Biologie Évolutive," Unité Mixte de Recherche 5558, Université Claude Bernard Lyon 1, Lyon, France.

Marked impacts of climate change on biodiversity have frequently been demonstrated, including temperature-related shifts in phenology and life-history traits. One potential major impact of climate change is the modification of synchronization between the phenology of different trophic levels. High phenotypic plasticity in laying date has allowed many bird species to track the increasingly early springs resulting from recent environmental change, but although changes in the timing of reproduction have been well studied in birds, these questions have only recently been addressed in mammals. To track peak resource availability, large herbivores like roe deer, with a widespread distribution across Europe, should also modify their life-history schedule in response to changes in vegetation phenology over time. In this study, we analysed the influence of climate change on the timing of roe deer births and the consequences for population demography and individual fitness. Our study provides a rare quantification of the demographic costs associated with the failure of a species to modify its phenology in response to a changing world. Given these fitness costs, the lack of response of roe deer birth dates to match the increasingly earlier onset of spring is in stark contrast with the marked phenotypic responses to climate change reported in many other mammals. We suggest that the lack of phenotypic plasticity in birth timing in roe deer is linked to its inability to track environmental cues of variation in resource availability for the timing of parturition.
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http://dx.doi.org/10.1371/journal.pbio.1001828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972086PMC
April 2014

Variation in adult body mass of roe deer: early environmental conditions influence early and late body growth of females.

Ecology 2013 Aug;94(8):1805-14

Université de Lyon, F-69000, Lyon, France.

There is increasing evidence that environmental conditions experienced early in life can markedly affect an organism's life history, but the pathways by which early environment influences adult phenotype are poorly known. We used long-term data from two roe deer (Capreolus capreolus) populations (Chizé and Trois-Fontaines, France) to investigate the direct and indirect (operating through fawn body mass) effects of environmental conditions during early life on adult body mass. We found that environmental conditions (population size and spring temperatures) around birth influenced body mass of adult females through both direct and indirect effects in both populations. The occurrence of direct effects means that, for a given fawn body mass, adult female mass decreases with adverse conditions in early life. In contrast, we found no evidence for direct effects of early-life conditions on adult body mass of males, suggesting the existence of sex-specific long-term responses of body mass to stressful early conditions. Our results provide evidence that early environmental conditions influence the adult phenotype through persistent effects over the body development in wild mammal populations.
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http://dx.doi.org/10.1890/13-0034.1DOI Listing
August 2013

Parturition date for a given female is highly repeatable within five roe deer populations.

Biol Lett 2013 Feb 12;9(1):20120841. Epub 2012 Dec 12.

Laboratoire de Biométrie et Biologie Évolutive, Université de Lyon, 69000, Lyon, France.

Births are highly synchronized among females in many mammal populations in temperate areas. Although laying date for a given female is also repeatable within populations of birds, limited evidence suggests low repeatability of parturition date for individual females in mammals, and between-population variability in repeatability has never, to our knowledge, been assessed. We quantified the repeatability of parturition date for individual females in five populations of roe deer, which we found to vary between 0.54 and 0.93. Each year, some females gave birth consistently earlier in the year, whereas others gave birth consistently later. In addition, all females followed the same lifetime trajectory for parturition date, giving birth progressively earlier as they aged. Giving birth early should allow mothers to increase offspring survival, although few females managed to do so. The marked repeatability of parturition date in roe deer females is the highest ever reported for a mammal, suggesting low phenotypic plasticity in this trait.
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http://dx.doi.org/10.1098/rsbl.2012.0841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565495PMC
February 2013

Patterns of body mass senescence and selective disappearance differ among three species of free-living ungulates.

Ecology 2011 Oct;92(10):1936-47

Institute of Evolutionary Biology, University of Edinburgh, The Kings' Buildings, West Mains Road, Edinburgh EH9 3JT, United Kingdom.

Declines in survival and reproduction with age are prevalent in wild vertebrates, but we know little about longitudinal changes in behavioral, morphological, or physiological variables that may explain these demographic declines. We compared age-related variation in body mass of adult females in three free-living ungulate populations that have been the focus of long-term, individual-based research: bighorn sheep (Ovis canadensis) at Ram Mountain, Canada; roe deer (Capreolus capreolus) at Trois Fontaines, France; and Soay sheep (Ovis aries) on St. Kilda, Scotland. We use two recently proposed approaches to separate contributions to age-dependent variation at the population level from within-individual changes and between-individual selective disappearance. Selective disappearance of light individuals in all three populations was most evident at the youngest and oldest ages. In later adulthood, bighorn sheep and roe deer showed a continuous decline in body mass that accelerated with age while Soay sheep showed a precipitous decrease in mass in the two years preceding death. Our results highlight the importance of mass loss in explaining within-individual demographic declines in later adulthood in natural populations. They also reveal that the pattern of senescence, and potentially also the processes underlying demographic declines in late life, can differ markedly across related species with similar life histories.
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http://dx.doi.org/10.1890/11-0308.1DOI Listing
October 2011

Population density and phenotypic attributes influence the level of nematode parasitism in roe deer.

Oecologia 2011 Nov 24;167(3):635-46. Epub 2011 May 24.

Université de Lyon, Université Lyon 1, UMR5558 Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.

The impact of parasites on population dynamics is well documented, but less is known on how host population density affects parasite spread. This relationship is difficult to assess because of confounding effects of social structure, population density, and environmental conditions that lead to biased among-population comparisons. Here, we analyzed the infestation by two groups of nematodes (gastro-intestinal (GI) strongyles and Trichuris) in the roe deer (Capreolus capreolus) population of Trois Fontaines (France) between 1997 and 2007. During this period, we experimentally manipulated population density through changes in removals. Using measures collected on 297 individuals, we quantified the impact of density on parasite spread after taking into account possible influences of date, age, sex, body mass, and weather conditions. The prevalence and abundance of eggs of both parasites in females were positively related to roe deer density, except Trichuris in adult females. We also found a negative relationship between parasitism and body mass, and strong age and sex-dependent patterns of parasitism. Prime-age adults were less often parasitized and had lower fecal egg counts than fawns or old individuals, and males were more heavily and more often infected than females. Trichuris parasites were not affected by weather, whereas GI strongyles were less present after dry and hot summers. In the range of observed densities, the observed effect of density likely involves a variation of the exposure rate, as opposed to variation in host susceptibility.
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http://dx.doi.org/10.1007/s00442-011-2018-9DOI Listing
November 2011

No difference between the sexes in fine-scale spatial genetic structure of roe deer.

PLoS One 2010 Dec 28;5(12):e14436. Epub 2010 Dec 28.

Laboratoire Comportement et Ecologie de la Faune Sauvage, Institut National de la Recherche Agronomique, Castanet-Tolosan, France.

Background: Data on spatial genetic patterns may provide information about the ecological and behavioural mechanisms underlying population structure. Indeed, social organization and dispersal patterns of species may be reflected by the pattern of genetic structure within a population.

Methodology/principal Findings: We investigated the fine-scale spatial genetic structure of a roe deer (Capreolus capreolus) population in Trois-Fontaines (France) using 12 microsatellite loci. The roe deer is weakly polygynous and highly sedentary, and can form matrilineal clans. We show that relatedness among individuals was negatively correlated with geographic distance, indicating that spatially proximate individuals are also genetically close. More unusually for a large mammalian herbivore, the link between relatedness and distance did not differ between the sexes, which is consistent with the lack of sex-biased dispersal and the weakly polygynous mating system of roe deer.

Conclusions/significance: Our results contrast with previous reports on highly polygynous species with male-biased dispersal, such as red deer, where local genetic structure was detected in females only. This divergence between species highlights the importance of socio-spatial organization in determining local genetic structure of vertebrate populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014436PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010998PMC
December 2010

N,N-Diethyl-4-[(3-hydroxyphenyl)(piperidin-4-yl)amino] benzamide derivatives: the development of diaryl amino piperidines as potent delta opioid receptor agonists with in vivo anti-nociceptive activity in rodent models.

Bioorg Med Chem Lett 2009 Nov 22;19(21):5994-8. Epub 2009 Sep 22.

Department of Medicinal Chemistry, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9.

We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.
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http://dx.doi.org/10.1016/j.bmcl.2009.09.072DOI Listing
November 2009

A slow life in hell or a fast life in heaven: demographic analyses of contrasting roe deer populations.

J Anim Ecol 2009 May;78(3):585-94

Hedmark University College, Evenstad, Koppang 2480, Norway.

1. Environmental conditions shape population growth through their impact on demographic parameters. While knowledge has accumulated concerning the effects of population density and climatic conditions, a topical question now concerns how predation and harvest influence demographic parameters and population growth (lambda). 2. We performed a comparative demographic analysis based on projection matrix models for female roe deer. Population-specific matrices were parameterized based on longitudinal data from five intensively monitored populations in Norway and France, spanning a large variability in environmental characteristics such as densities of large predators, hunter harvest and seasonality. 3. As expected for a large iteroparous vertebrate, temporal variation was invariably higher in recruitment than in adult survival, and the elasticity of adult survival was consistently higher than that of recruitment. However, the relative difference in elasticity of lambda to recruitment and adult survival varied strongly across populations, and was closely correlated with adult survival. 4. Different traits accounted for most of the variance in lambda in different ecological settings. Adult survival generally contributed more in populations with low mean adult survival and low mean growth rate during the study period. Hunters and predators (Eurasian lynx and red foxes) occurred in two of our study populations and contributed substantially to the variance in lambda, accounting for a total of 35% and 70% in the two populations respectively. 5. Across populations, we did not find any evidence that roe deer increased their reproductive output when faced with harsh conditions, resulting in some populations having negative growth rates. 6. Generation time, a measure of the speed of the life-history cycle, increased from less than 4 years in the most productive population ('roe deer heaven') to more than 6 years in declining populations facing predation from lynx, red fox and hunters ('roe deer hell'), and was tightly and inversely correlated with lambda. Such a deceleration of the life cycle in declining populations might be a general feature in large herbivores. 7. Our results shows that the plethora of environmental conditions faced by populations of large herbivores also induce high intraspecific variation in their ranking along the 'fast-slow' continuum of life-history tactics.
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http://dx.doi.org/10.1111/j.1365-2656.2009.01523.xDOI Listing
May 2009

Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.

Bioorg Med Chem Lett 2009 May 28;19(10):2742-6. Epub 2009 Mar 28.

MethylGene Inc., Department of Medicinal Chemistry, Montreal, Quebec, Canada.

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.
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http://dx.doi.org/10.1016/j.bmcl.2009.03.132DOI Listing
May 2009

SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes.

Bioorg Med Chem Lett 2009 May 28;19(10):2747-51. Epub 2009 Mar 28.

MethylGene Inc., Departments of Medicinal Chemistry, Montreal, Quebec, Canada.

The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.
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http://dx.doi.org/10.1016/j.bmcl.2009.03.113DOI Listing
May 2009

Heterozygosity-fitness correlations revealed by neutral and candidate gene markers in roe deer from a long-term study.

Evolution 2009 Feb 18;63(2):403-17. Epub 2008 Nov 18.

Laboratoire de Biométrie et Biologie Evolutive, Unité Mixte de Recherche du Centre National de Recherche Scientifique No. 5558, Université Claude Bernard Lyon I, 43 Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France.

Heterozygosity-fitness correlations (HFCs) are increasingly reported but the underlying mechanisms causing HFCs are generally poorly understood. Here, we test for HFCs in roe deer (Capreolus capreolus) using 22 neutral microsatellites widely distributed in the genome and four microsatellites in genes that are potentially under selection. Juvenile survival was used as a proxy for individual fitness in a population that has been intensively studied for 30 years in northeastern France. For 222 juveniles, we computed two measures of genetic diversity: individual heterozygosity (H), and mean d(2) (relatedness of parental genomes). We found a relationship between genetic diversity and fitness both for the 22 neutral markers and two candidate genes: IGF1 (Insulin-like Growth Factor I) and NRAMP (natural resistance-associated macrophage protein). Statistical evidence and the size of genetic effects on juvenile survival were comparable to those reported for early development and cohort variation, suggesting a substantial influence of genetic components on fitness in this roe deer population. For the 22 neutral microsatellites, a correlation with fitness was revealed for mean d(2), but not for H, suggesting a possible outbreeding advantage. This heterosis effect could have been favored by introduction of genetically distant (Hungarian) roe deer to the population in recent times and, possibly, by the structuring of the population into distinct clans. The locus-specific correlations with fitness may be driven by growth rate advantages and resistance to diseases known to exist in the studied population. Our analyses of neutral and candidate gene markers both suggest that the observed HFCs are likely mainly due to linkage with dominant or overdominant loci that affect fitness ("local" effect) rather than to a genome-wide relationship with homozygosity due to inbreeding ("general" effect).
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http://dx.doi.org/10.1111/j.1558-5646.2008.00542.xDOI Listing
February 2009

SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).

Bioorg Med Chem Lett 2009 Feb 24;19(3):644-9. Epub 2008 Dec 24.

MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1.

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
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http://dx.doi.org/10.1016/j.bmcl.2008.12.048DOI Listing
February 2009

Maternal and individual effects in selection of bed sites and their consequences for fawn survival at different spatial scales.

Oecologia 2009 Mar 17;159(3):669-78. Epub 2008 Dec 17.

Unité Mixte de Recherche no. 5558, Biométrie et Biologie Evolutive, Bâtiment 711, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France.

We examined the relationship between survival of roe deer (Capreolus capreolus) fawns at Trois Fontaines, Champagne-Ardennes, France, and factors related to bed-site selection (predator avoidance and thermoregulation) and maternal food resources (forage availability in the maternal home range). Previous studies have demonstrated that at small scales, the young of large herbivores select bed sites independently from their mothers, although this selection takes place within the limits of their mother's home range. Fawn survival was influenced largely by the availability of good bed sites within the maternal home range, not by the fawn's selection of bed sites; however, selection for thermal cover when selecting bed sites positively influenced survival of young fawns. Typical features of a good home range included close proximity to habitat edges, which is related to forage accessibility for roe deer. The availability of bed sites changed as fawns aged, probably due to an increased mobility of the fawn or a different use of the home range by the mother; sites offering high concealment and thermal protection became less available in favor of areas with higher forage accessibility. Despite the minor influence of bed-site selection on survival, roe deer fawns strongly selected their bed sites according to several environmental factors linked to predator avoidance and thermoregulation. Fawns selected for sites providing concealment, light penetration, and avoided signs of wild boar (Sus scrofa) activity. Avoidance of sites with high light penetration by young fawns positively affected their survival, confirming a negative effect on thermoregulation due to reduced thermal cover. Selection for light penetration by older fawns was less clear. We discuss these results in the context of cross-generational effects in habitat selection across multiple scales, and the potential influence of the 'ghost of predation past'.
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http://dx.doi.org/10.1007/s00442-008-1245-1DOI Listing
March 2009

Linking bisphosphonates to the free amino groups in fluoroquinolones: preparation of osteotropic prodrugs for the prevention of osteomyelitis.

J Med Chem 2008 Nov 4;51(21):6955-69. Epub 2008 Oct 4.

Targanta Therapeutics Inc, 7170 Avenue Frederick Banting, St. Laurent, Québec, H4S 2A1, Canada.

Osteomyelitis is an infection located in bone and a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered antibiotics. Targeting antibiotics to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. By taking advantage of the affinity of the bisphosphonate group for bone mineral, we have prepared a set of 13 bisphosphonated antibacterial prodrugs based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. While all but one of the prodrugs were shown in vitro to be effective and rapid bone binders (over 90% in 1 h), only eight of them demonstrated the capacity to significantly regenerate the parent drug. In a rat model of the disease, a selected group of agents demonstrated their ability to prevent osteomyelitis when used in circumstances under which the parent drug had already been cleared and is thus inactive.
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http://dx.doi.org/10.1021/jm801007zDOI Listing
November 2008

Bisphosphonated fluoroquinolone esters as osteotropic prodrugs for the prevention of osteomyelitis.

Bioorg Med Chem 2008 Oct 9;16(20):9217-29. Epub 2008 Sep 9.

Targanta Therapeutics Inc., 7170 Avenue Frederick Banting, Saint Laurent, Qué., Canada H4S 2A1.

Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not.
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http://dx.doi.org/10.1016/j.bmc.2008.09.010DOI Listing
October 2008

Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.

J Med Chem 2008 Jul 21;51(14):4072-5. Epub 2008 Jun 21.

MethylGene Inc., 7220 Frederick-Banting, Montréal, Québec H4S 2A1, Canada.

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
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http://dx.doi.org/10.1021/jm800251wDOI Listing
July 2008

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.

Mol Cancer Ther 2008 Apr;7(4):759-68

Department of Molecular Biology, MethylGene, Inc., 7220 Frederick-Banting, Montreal, Quebec H4S 2A1, Canada.

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
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http://dx.doi.org/10.1158/1535-7163.MCT-07-2026DOI Listing
April 2008

4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors.

Bioorg Med Chem Lett 2008 Feb 25;18(4):1502-6. Epub 2007 Dec 25.

MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, QC, Canada.

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.057DOI Listing
February 2008

Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]-N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors.

Bioorg Med Chem Lett 2008 Feb 10;18(3):1067-71. Epub 2007 Dec 10.

MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, QC, Canada.

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.009DOI Listing
February 2008

N-(2-Amino-phenyl)-4-(heteroarylmethyl)-benzamides as new histone deacetylase inhibitors.

Bioorg Med Chem Lett 2007 Dec 18;17(24):6729-33. Epub 2007 Oct 18.

MethylGene Inc., Department of Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada.

A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
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http://dx.doi.org/10.1016/j.bmcl.2007.10.050DOI Listing
December 2007

Bigger teeth for longer life? Longevity and molar height in two roe deer populations.

Biol Lett 2007 Jun;3(3):268-70

Department of Arctic Biology, University Centre in Svalbard, PO Box 156, 9171 Longyearbyen, Norway.

The role of tooth wear as a proximate cause of senescence in ruminants has recently been highlighted. There are two competing hypotheses to explain variation in tooth height and wear; the diet-quality hypothesis predicting increased wear in low-quality habitats, and the life-history hypothesis predicting molar height to be related to expected longevity. We compared tooth height and wear from roe deer of known age from two contrasting populations of roe deer (Capreolus capreolus) in France: Trois Fontaines (TF) with good habitat and shorter animal life expectancy and Chizé (CH) with poor habitat and longer animal life expectancy. There was no population difference in tooth wear, leading to rejection of the diet-quality hypothesis. However, despite their smaller body size, initial molar height for animals from CH was larger than for animals from TF. This provides the first evidence that variation in longevity between populations can lead to differences in molar height within a species.
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http://dx.doi.org/10.1098/rsbl.2006.0610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2464678PMC
June 2007

Antler size provides an honest signal of male phenotypic quality in roe deer.

Am Nat 2007 Apr;169(4):481-93

Laboratoire Comportement et Ecologie de la Faune Sauvage, Institut National de la Recherche Agronomique, BP 52627, F-31326 Castanet-Tolosan Cedex, France.

Identifying factors shaping secondary sexual traits is essential in understanding how their variation may influence male fitness. Little information is available on the allocation of resources to antler growth in territorial ungulates with low sexual size dimorphism. We investigated phenotypic and environmental factors affecting both absolute and relative antler size of male roe deer in three contrasting populations in France and Sweden. In the three populations, we found marked age-specific variation in antler size, with an increase in both absolute and relative antler size between yearling and prime-age stages, followed by a decrease (senescence) for males older than 7 years. Antler size increased allometrically with body mass. This increase was particularly strong for senescent males, suggesting the evolution of two reproductive tactics: heavy old males invested particularly heavily in antler growth (potentially remaining competitive for territories), whereas light old males grew small antlers (potentially abandoning territory defense). Finally, environmental conditions had little effect on antler size: only population density negatively affected absolute antler size in one of the three populations. Antler size may therefore provide an honest signal of male phenotypic quality in roe deer. We discuss the implications of these results in terms of territory tenure and mating competition.
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http://dx.doi.org/10.1086/512046DOI Listing
April 2007

A new class of small molecule RNA polymerase inhibitors with activity against rifampicin-resistant Staphylococcus aureus.

Bioorg Med Chem 2006 Sep 8;14(17):5812-32. Epub 2006 Jun 8.

Targanta Therapeutics Inc, 7170 Frederick Banting, 2nd Floor, St. Laurent, Que., Canada H4S 2A1.

The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
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http://dx.doi.org/10.1016/j.bmc.2006.05.035DOI Listing
September 2006

Substituted N-(2-aminophenyl)-benzamides, (E)-N-(2-aminophenyl)-acrylamides and their analogues: novel classes of histone deacetylase inhibitors.

Bioorg Med Chem Lett 2006 Aug 18;16(15):4048-52. Epub 2006 May 18.

MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, QC, Canada H4S 2A1.

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.
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http://dx.doi.org/10.1016/j.bmcl.2006.05.005DOI Listing
August 2006

Substituted coumarins as potent 5-lipoxygenase inhibitors.

Bioorg Med Chem Lett 2006 May 7;16(9):2528-31. Epub 2006 Feb 7.

Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1.

Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure-activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.
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http://dx.doi.org/10.1016/j.bmcl.2006.01.085DOI Listing
May 2006

Novel non-nucleobase inhibitors of Staphylococcus aureus DNA polymerase IIIC.

Bioorg Med Chem Lett 2006 Feb 17;16(4):891-6. Epub 2005 Nov 17.

Targanta Therapeutics Inc., 7170 Frederick-Banting, 2nd Floor, Montréal, Québec, Canada H4S 2A1.

The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified.
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http://dx.doi.org/10.1016/j.bmcl.2005.11.009DOI Listing
February 2006

(2-amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors.

Bioorg Med Chem Lett 2004 Jan;14(1):283-7

Department of Medicinal Chemistry, MethylGene Inc., 7220 Frederick-Banting, Montreal, Quebec, Canada H4S 2A1.

A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.
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http://dx.doi.org/10.1016/j.bmcl.2003.08.083DOI Listing
January 2004