Suchergebnisse

Naturally-derived macrocyclic compounds are associated with a diverse range of biological activities, including antibacterial effects, and there are over 100 marketed macrocycle drugs derived from natural products. However, synthetic macrocycles are widely considered to be poorly explored in antibiotic development (indeed, within drug discovery in general). This has been attributed to challenges associated with the generation of such compounds. Whilst there are synthetic methods that can produce large collections of structurally similar macrocycles (i.e., compounds with varying appendages based around similar core macrocyclic ring architectures) there is a relative dearth of strategies for the efficient generation of more structurally diverse macrocycle collections in which there is greater variation in the nature of macrocyclic scaffolds present. Such macrocycle collections should contain compounds with a broad range of biological activities (including antibacterial activities) and the requisite robust synthetic methodology useful for analogue synthesis and lead optimization once an active compound has been identified in a biological screen. Herein, we describe a new and expedient diversity-oriented synthesis (DOS) strategy for the generation of a library of novel structurally diverse macrocyclic compounds with a high level of scaffold diversity. The strategy is concise, proceeds from readily-available starting materials, is modular in nature and features a variety of macrocyclisation techniques. In this proof-of-concept study, the synthesis of several previously unreported macrocyclic compounds was achieved. Each of these macrocycles was based around a distinct molecular scaffold and contained natural product-like structural features (e.g., three-dimensionality and multiple hydrogen bond donors and acceptors) as well as synthetic handles for potential further elaboration. The successful generation of these macrocycles demonstrates the feasibility of the new DOS strategy as a synthetic platform for library generation. ; The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Welcome Trust.

The coal-dominated electricity system poses major challenges for India to tackle air pollution and climate change. Although the government has issued a series of clean air policies and low-carbon energy targets, a key barrier remains enforcement. Here, we quantify the importance of policy implementation in India's electricity sector using an integrated assessment method based on emissions scenarios, air quality simulations, and health impact assessments. We find that limited enforcement of air pollution control policies leads to worse future air quality and health damages (e.g., 14 200 to 59 000 more PM2.5-related deaths in 2040) than when energy policies are not fully enforced (5900 to 8700 more PM2.5-related deaths in 2040), since coal power plants with end-of-pipe controls already emit little air pollution. However, substantially more carbon dioxide will be emitted if low-carbon and clean coal policies are not successfully implemented (e.g., 400 to 800 million tons more CO2 in 2040). Thus, our results underscore the important role of effectively implementing existing air pollution and energy policy to simultaneously achieve air pollution, health, and carbon mitigation goals in India.

The coal-dominated electricity system poses major challenges for India to tackle air pollution and climate change. Although the government has issued a series of clean air policies and low-carbon energy targets, a key barrier remains enforcement. Here, we quantify the importance of policy implementation in India's electricity sector using an integrated assessment method based on emissions scenarios, air quality simulations, and health impact assessments. We find that limited enforcement of air pollution control policies leads to worse future air quality and health damages (e.g., 14 200 to 59 000 more PM2.5-related deaths in 2040) than when energy policies are not fully enforced (5900 to 8700 more PM2.5-related deaths in 2040), since coal power plants with end-of-pipe controls already emit little air pollution. However, substantially more carbon dioxide will be emitted if low-carbon and clean coal policies are not successfully implemented (e.g., 400 to 800 million tons more CO2 in 2040). Thus, our results underscore the important role of effectively implementing existing air pollution and energy policy to simultaneously achieve air pollution, health, and carbon mitigation goals in India.