Open source drug discovery- A new paradigm of collaborative research in tuberculosis drug development

It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. (C) 2011 Elsevier Ltd. All rights reserved.

Catalytic enantioselective construction of quaternary stereocenters by direct vinylogous Michael addition of deconjugated butenolides to nitroolefins

A direct vinylogous Michael reaction of gamma-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20 : 1 dr) and high enantioselectivity (up to 99 : 1 er).

Polymorphs, Salts, and Cocrystals: What's in a Name?

The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable ``API-excipient'' molecular complexes. The Indo U.S. Bilateral Meeting sponsored by the Indo-U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2-4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that are mutually exclusive. This perspective summarizes the discussion in the Indo-U.S. Bilateral Meeting and includes contributions from researchers who were not participants in the meeting.

Catalytic Asymmetric Synthesis of alpha,beta-Disubstituted alpha,gamma-Diaminophosphonic Acid Precursors by Michael Addition of alpha-Substituted Nitrophosphonates to Nitroolefins

Michael additions of alpha-substituted nitrophosphonates to various nitroolefins are shown to proceed with high diastereo- and enantioselectivity when catalyzed by a quinine-derived thiourea-tertiary amine bifunctional catalyst and generate alpha,gamma-diaminophosphonic acid precursors with contiguous quaternary and tertiary stereocenters.

Organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to nitroolefins

The first organocatalytic enantioselective direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactam to nitroolefins is developed using cinchona alkaloids as the catalysts. Both product enantiomers are accessible with moderate to good enantioselectivity.

Organocatalytic asymmetric direct vinylogous Michael addition of alpha,beta-unsaturated gamma-butyrolactam to nitroolefins

The first organocatalytic enantioselective direct vinylogous Michael reaction of alpha,beta-unsaturated gamma-butyrolactam to nitroolefins is developed using cinchona alkaloids as the catalysts. Both product enantiomers are accessible with moderate to good enantioselectivity.

Catalytic Asymmetric Direct Vinylogous Michael Addition of Deconjugated Butenolides to Maleimides for the Construction of Quaternary Stereogenic Centers

Competition under control: A practical and efficient direct asymmetric vinylogous Michael reaction of deconjugated butenolides has been developed (see scheme). The products of this reaction, highly functionalized chiral succinimides, are obtained in excellent yield with high diastereoselectivity (up to d.r.=18:1) and outstanding enantioselectivity (up to e.r.=99.5:0.5).

Catalytic Asymmetric Direct Vinylogous Michael Addition of gamma-Aryl-Substituted Deconjugated Butenolides to Nitroolefins and N-Phenylmaleimide

Direct asymmetric vinylogous Michael reactions of gamma-aryl-substituted deconjugated butenolides with nitroolefins and N-phenylmaleimide are described using bifunctional thiourea derivatives as the catalyst. The resulting butenolide derivatives containing adjacent quaternary and tertiary stereocenters are obtained in good yields (54-90%) and with excellent enantioselectivities (er up to 99:1) and high diastereoselectivities (dr up to > 20:1).

Scale-dependent relationships between tree species richness and ecosystem function in forests

1. The relationship between species richness and ecosystem function, as measured by productivity or biomass, is of long-standing theoretical and practical interest in ecology. This is especially true for forests, which represent a majority of global biomass, productivity and biodiversity. 2. Here, we conduct an analysis of relationships between tree species richness, biomass and productivity in 25 forest plots of area 8-50ha from across the world. The data were collected using standardized protocols, obviating the need to correct for methodological differences that plague many studies on this topic. 3. We found that at very small spatial grains (0.04ha) species richness was generally positively related to productivity and biomass within plots, with a doubling of species richness corresponding to an average 48% increase in productivity and 53% increase in biomass. At larger spatial grains (0.25ha, 1ha), results were mixed, with negative relationships becoming more common. The results were qualitatively similar but much weaker when we controlled for stem density: at the 0.04ha spatial grain, a doubling of species richness corresponded to a 5% increase in productivity and 7% increase in biomass. Productivity and biomass were themselves almost always positively related at all spatial grains. 4. Synthesis. This is the first cross-site study of the effect of tree species richness on forest biomass and productivity that systematically varies spatial grain within a controlled methodology. The scale-dependent results are consistent with theoretical models in which sampling effects and niche complementarity dominate at small scales, while environmental gradients drive patterns at large scales. Our study shows that the relationship of tree species richness with biomass and productivity changes qualitatively when moving from scales typical of forest surveys (0.04ha) to slightly larger scales (0.25 and 1ha). This needs to be recognized in forest conservation policy and management.

A catalytic michael/horner-wadsworth-emmons cascade reaction for enantioselective synthesis of thiochromenes

A catalytic enantioselective sulfa-Michael/Horner-Wadsworth-Emmons reaction cascade has been developed, taking advantage of phosphonate as an electrophilic activator and a traceless binding site. Using a chiral bifunctional urea derivative as the catalyst, a variety of aryl and heteroaryl substituted thiochromenes was obtained in excellent yield with a high level of enantioselectivity.

Catalytic Asymmetric Michael Addition/Cyclization Cascade Reaction of 3-Isothiocyanatooxindoles with Nitro Olefins

The first organocatalytic asymmetric reaction of 3-isothiocyanatooxindoles with nitro olefins has been developed by using a cinchonidine-derived bifunctional catalyst. The resulting products, highly functionalized 3,2-pyrrolidinyl-substituted spirooxindole derivatives, were obtained in high yields with good diastereo- and enantioselectivities (up to dr >20:1 and er = 96:4). This Michael addition/cyclization cascade reaction employs monosubstituted nitro olefins and complements the Zn-II-catalyzed variant, which is only applicable to disubstituted nitro olefins.

CTFS-ForestGEO: a worldwide network monitoring forests in an era of global change

Global change is impacting forests worldwide, threatening biodiversity and ecosystem services including climate regulation. Understanding how forests respond is critical to forest conservation and climate protection. This review describes an international network of 59 long-term forest dynamics research sites (CTFS-ForestGEO) useful for characterizing forest responses to global change. Within very large plots (median size 25ha), all stems 1cm diameter are identified to species, mapped, and regularly recensused according to standardized protocols. CTFS-ForestGEO spans 25 degrees S-61 degrees N latitude, is generally representative of the range of bioclimatic, edaphic, and topographic conditions experienced by forests worldwide, and is the only forest monitoring network that applies a standardized protocol to each of the world's major forest biomes. Supplementary standardized measurements at subsets of the sites provide additional information on plants, animals, and ecosystem and environmental variables. CTFS-ForestGEO sites are experiencing multifaceted anthropogenic global change pressures including warming (average 0.61 degrees C), changes in precipitation (up to +/- 30% change), atmospheric deposition of nitrogen and sulfur compounds (up to 3.8g Nm(-2)yr(-1) and 3.1g Sm(-2)yr(-1)), and forest fragmentation in the surrounding landscape (up to 88% reduced tree cover within 5km). The broad suite of measurements made at CTFS-ForestGEO sites makes it possible to investigate the complex ways in which global change is impacting forest dynamics. Ongoing research across the CTFS-ForestGEO network is yielding insights into how and why the forests are changing, and continued monitoring will provide vital contributions to understanding worldwide forest diversity and dynamics in an era of global change.

Poly(alkylene itaconate)s - an interesting class of polyesters with periodically located exo-chain double bonds susceptible to Michael addition

Itaconic acid is a bio-sourced dicarboxylic acid that carries a double bond; although several reports have dealt with the radical-initiated chain polymerization of dialkyl itaconates, only a few studies have utilized it as a di-acid monomer to prepare polyesters. In this study, we demonstrate that dibutyl itaconate can be melt-condensed with aliphatic diols to generate unsaturated polyesters; importantly, we show that the double bonds remain unaffected during the melt polymerization. A particularly useful attribute of these polyesters is that the exo-chain double bonds are conjugated to the ester carbonyl and, therefore, can serve as excellent Michael acceptors. A variety of organic thiols, such as alkane thiols, MPEG thiol, thioglycerol, derivatized cysteine etc., were shown to quantitatively Michael-add to the exo-chain double bonds and generate interesting functionalized polyesters. Similarly, organic amines, such as N-methyl-benzylamine, diallyl amine and proline, also add across the double bond; thus, these poly(alkylene itaconate)s could serve as potentially bio-benign polyesters that could be quantitatively transformed into a variety of interesting and potentially useful functionalized polymers.

An estimate of the number of tropical tree species

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher's alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between similar to 40,000 and similar to 53,000, i.e., at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of similar to 19,000-25,000 tree species. Continental Africa is relatively depauperate with a minimum of similar to 4,500-6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa.

Phase-field elasticity model based on mechanical jump conditions

Computational models based on the phase-field method typically operate on a mesoscopic length scale and resolve structural changes of the material and furthermore provide valuable information about microstructure and mechanical property relations. An accurate calculation of the stresses and mechanical energy at the transition region is therefore indispensable. We derive a quantitative phase-field elasticity model based on force balance and Hadamard jump conditions at the interface. Comparing the simulated stress profiles calculated with Voigt/Taylor (Annalen der Physik 274(12):573, 1889), Reuss/Sachs (Z Angew Math Mech 9:49, 1929) and the proposed model with the theoretically predicted stress fields in a plate with a round inclusion under hydrostatic tension, we show the quantitative characteristics of the model. In order to validate the elastic contribution to the driving force for phase transition, we demonstrate the absence of excess energy, calculated by Durga et al. (Model Simul Mater Sci Eng 21(5):055018, 2013), in a one-dimensional equilibrium condition of serial and parallel material chains. To validate the driving force for systems with curved transition regions, we relate simulations to the Gibbs-Thompson equilibrium condition