Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors (IC50 between 0.04 and 0.71 M). Also, these highly active methyl sulfones displayed greater COX-2 activity than the parent carboxylic NSAIDs, thus indicating that the replacement of the acetic or propionic acids by a methyl sulfone group enables some of these structures to possess higher COX-2 inhibitory activity than that of the corresponding alkyl carboxylic analogues. The improved inhibitory activity is attributed to the higher flexibility of the sulfone-receptor interaction that enables more profound exploration of the binding site compared with that of acidic analogues. This observation is underpinned by molecular modeling studies that indicates a change in the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs

New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands.

Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligand

Synthesis and cytotoxic activity of pyridazino[1 ',6 ': 1,2] pyrido[3,4-b]indol-5-inium derivatives as anti-cancer agents

Several new pyridazino[1′,6′:1,2]pyrido[3,4-b]indol-5-inium derivatives were synthesised from β-carboline derivatives and their cytotoxic activity and effect on the cell cycle were evaluated against L1210 cancer cells

Study of Human RIG-I Polymorphisms Identifies Two Variants with an Opposite Impact on the Antiviral Immune Response

International audienceBACKGROUND: RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, very little information is available on RIG-I single-nucleotide polymorphisms (SNPs) presenting a functional impact on the host response. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied all non-synonymous SNPs of RIG-I using biochemical and structural modeling approaches. We identified two important variants: (i) a frameshift mutation (P(229)fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S(183)I), which drastically inhibits antiviral signaling and exerts a down-regulatory effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key downstream adapter protein. CONCLUSIONS/SIGNIFICANCE: Hence, this study characterized P(229)fs and S(183)I SNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility. This work also demonstrated that serine 183 is a residue that critically regulates RIG-I-induced antiviral signaling

Autonomous space exploration using the Turtlebot mobile platform

Cilj diplomske naloge je implementacija avtonomnega raziskovanja prostora na mobilni platformi Turtlebot, ki uporablja razvojno okolje ROS. Implementirali smo raziskovalni algoritem, ki temelji na zaznavi obrobij in njihovi uporabi kot potencialnih raziskovalnih ciljev. Ker pa lahko algoritem pri izbiri raziskovalnih ciljev upošteva različne kombinacije ocen raziskovanja, smo nato preizkušali in primerjali, katera kombinacija ocen omogoča najbolj učinkovito raziskovanje prostora. Različne strategije izbire raziskovalnih ciljev smo ocenjevali in primerjali na podlagi štirih kriterijev ter referenčne strategije, ki naključno izbira raziskovalne cilje. Podatke za primerjavo smo dobili tako, da smo za vsako strategijo opravili deset uspešnih raziskovanj. Te smo nato kot skupine povprečnih vrednosti in odstopanj primerjali med seboj na podlagi referenčne strategije in kriterijev. Implementirali smo modul, ki poleg raziskanosti prostora in časa raziskovanja omogoča tudi beleženje zgodovine premikov in s tem pot raziskovanja, ki jo opravi Turtlebot.The purpose of this undergraduate thesis is to implement the autonomous exploration of space on the Turtlebot mobile platform that uses the ROS development environment. We implemented an exploration algorithm based on the detection and use of frontier regions as potential exploration goals. Since the algorithm is able to choose an exploration goal based on the combination of different assessments, we tested and compared which combination of goal assessments enables the most efficient exploration of a given space. We assessed and compared different strategies of goal setting on the basis of four criteria and a referential strategy which selects its exploration goals randomly. In order to get the data necessary for comparison, we conducted ten successful explorations per strategy and compared them on the basis of the referential strategy and criteria. We implemented our own module, which tracks the amount of space explored and the time spent for exploration, while also documenting the path traveled by the Turtlebot during exploration

New Fluorinated 1,2,4-Benzothiadiazine 1,1-Dioxides: Discovery of an Orally Active Cognitive Enhancer Acting through Potentiation of the 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro- substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability

MASTREE+ : time-series of plant reproductive effort from six continents

Significant gaps remain in understanding the response of plant reproduction to environmental change. This is partly because measuring reproduction in long-lived plants requires direct observation over many years and such datasets have rarely been made publicly available. Here we introduce MASTREE+, a data set that collates reproductive time-series data from across the globe and makes these data freely available to the community. MASTREE+ includes 73,828 georeferenced observations of annual reproduction (e.g. seed and fruit counts) in perennial plant populations worldwide. These observations consist of 5971 population-level time-series from 974 species in 66 countries. The mean and median time-series length is 12.4 and 10 years respectively, and the data set includes 1122 series that extend over at least two decades (≥20 years of observations). For a subset of well-studied species, MASTREE+ includes extensive replication of time-series across geographical and climatic gradients. Here we describe the open-access data set, available as a.csv file, and we introduce an associated web-based app for data exploration. MASTREE+ will provide the basis for improved understanding of the response of long-lived plant reproduction to environmental change. Additionally, MASTREE+ will enable investigation of the ecology and evolution of reproductive strategies in perennial plants, and the role of plant reproduction as a driver of ecosystem dynamics

MASTREE+: Time-series of plant reproductive effort from six continents.

Significant gaps remain in understanding the response of plant reproduction to environmental change. This is partly because measuring reproduction in long-lived plants requires direct observation over many years and such datasets have rarely been made publicly available. Here we introduce MASTREE+, a data set that collates reproductive time-series data from across the globe and makes these data freely available to the community. MASTREE+ includes 73,828 georeferenced observations of annual reproduction (e.g. seed and fruit counts) in perennial plant populations worldwide. These observations consist of 5971 population-level time-series from 974 species in 66 countries. The mean and median time-series length is 12.4 and 10 years respectively, and the data set includes 1122 series that extend over at least two decades (≥20 years of observations). For a subset of well-studied species, MASTREE+ includes extensive replication of time-series across geographical and climatic gradients. Here we describe the open-access data set, available as a.csv file, and we introduce an associated web-based app for data exploration. MASTREE+ will provide the basis for improved understanding of the response of long-lived plant reproduction to environmental change. Additionally, MASTREE+ will enable investigation of the ecology and evolution of reproductive strategies in perennial plants, and the role of plant reproduction as a driver of ecosystem dynamics

Limits to reproduction and seed size-number trade-offs that shape forest dominance and future recovery

International audienceThe relationships that control seed production in trees are fundamental to understanding the evolution of forest species and their capacity to recover from increasing losses to drought, fire, and harvest. A synthesis of fecundity data from 714 species worldwide allowed us to examine hypotheses that are central to quantifying reproduction, a foundation for assessing fitness in forest trees. Four major findings emerged. First, seed production is not constrained by a strict trade-off between seed size and numbers. Instead, seed numbers vary over ten orders of magnitude, with species that invest in large seeds producing more seeds than expected from the 1:1 trade-off. Second, gymnosperms have lower seed production than angiosperms, potentially due to their extra investments in protective woody cones. Third, nutrient-demanding species, indicated by high foliar phosphorus concentrations, have low seed production. Finally, sensitivity of individual species to soil fertility varies widely, limiting the response of community seed production to fertility gradients. In combination, these findings can inform models of forest response that need to incorporate reproductive potential

Limits to reproduction and seed size-number tradeoffs that shape forest dominance and future recovery

The relationships that control seed production in trees are fundamental to understanding the evolution of forest species and their capacity to recover from increasing losses to drought, fire, and harvest. A synthesis of fecundity data from 714 species worldwide allowed us to examine hypotheses that are central to quantifying reproduction, a foundation for assessing fitness in forest trees. Four major findings emerged. First, seed production is not constrained by a strict trade-off between seed size and numbers. Instead, seed numbers vary over ten orders of magnitude, with species that invest in large seeds producing more seeds than expected from the 1:1 trade-off. Second, gymnosperms have lower seed production than angiosperms, potentially due to their extra investments in protective woody cones. Third, nutrient-demanding species, indicated by high foliar phosphorus concentrations, have low seed production. Finally, sensitivity of individual species to soil fertility varies widely, limiting the response of community seed production to fertility gradients. In combination, these findings can inform models of forest response that need to incorporate reproductive potential