Publications by authors named "Yixiang Sun"

7 Publications

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Design, synthesis, and biological evaluation of 5-aminotetrahydroquinoline-based LSD1 inhibitors acting on Asp375.

Arch Pharm (Weinheim) 2021 May 13:e2100102. Epub 2021 May 13.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC  = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
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http://dx.doi.org/10.1002/ardp.202100102DOI Listing
May 2021

Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Eur J Med Chem 2021 Aug 24;220:113501. Epub 2021 Apr 24.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
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http://dx.doi.org/10.1016/j.ejmech.2021.113501DOI Listing
August 2021

Discovery of 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4: Biological evaluation and docking studies.

Arch Pharm (Weinheim) 2020 Oct 6;353(10):e2000097. Epub 2020 Jul 6.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

In this study, novel 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4 (PAK4) were discovered and evaluated for their biological activity against PAK4. Among the derivatives studied, promising compounds A2, B6, and B8 displayed the highest inhibitory activities against PAK4 (IC  = 18.4, 5.9, and 20.4 nM, respectively). From the cellular assay, compound B6 exhibited the highest potency with an IC value of 2.533 μM against A549 cells. Some compounds were selected for computational ADME (absorption, distribution, metabolism, and elimination) properties and molecular docking studies against PAK4. The detailed structure-activity relationship based on the biochemical activities and molecular docking studies were explored. According to the docking studies, compound B6 had the lowest docking score (docking energy: -7.593 kcal/mol). The molecular docking simulation indicated the binding mode between compound B6 and PAK4. All these results suggest compound B6 as a useful candidate for the development of a PAK4 inhibitor.
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http://dx.doi.org/10.1002/ardp.202000097DOI Listing
October 2020

Integrated systematic approach increase greenhouse tomato yield and reduce environmental losses.

J Environ Manage 2020 Jul 16;266:110569. Epub 2020 Apr 16.

College of Resources and Environment, Academy of Agricultural Sciences, Southwest University, Chongqing, 400716, China; Chongqing Key Laboratory of Efficient Utilization of Soil and Fertilizer Resources, Southwest University, Chongqing, 400716, China. Electronic address:

High input - high output greenhouse vegetable systems are responsible for nutrient surpluses and environmental losses. Integrated strategies that improve soil, crop and nutrient management are needed to ensure more sustainable production systems. We conducted a two-year field experiment to evaluate the potential of integrated soil-crop system management (ISSM) practices to improve the productivity and environmental outcomes from an intensive greenhouse tomato production system in the Yangtze River Basin, China. Four treatments were tested: i) farmers' practice (FP); ii) soil remediation (SR), where lime nitrogen with compost addition was the only management strategy; iii) a treatment that combined soil remediation with optimized crop planting density (SRCO), which increased planting density for improving crop yield; and iv) integrated soil-crop system management (ISSM), as a systematic integrated approach, which included the combined optimization of soil remediation, crop optimization, and nutrient management. In the integrated soil-crop system management treatment, nutrient management was optimized through adoption of the most appropriate type (formula) of fertilizer for the crop, rate and application timing of synthetic fertilizer, and by substituting poultry manure with compost. Our results indicated that the fruit yield of the integrated soil-crop system management treatment was 104 t ha, 13.4%-37.3% higher than that of the other three treatments. The mean reactive nitrogen loss (81.1 kg N ha) and the greenhouse gas emissions (6495 kg CO-eq ha) in the farmers' practice treatment were much higher than in the other three treatments (reactive nitrogen loss: 47.9-54.3 kg N ha; and greenhouse gas emissions: 4926-5468 kg CO-eq ha, respectively). The mean nitrogen and carbon footprints of the integrated soil-crop system management treatment were significantly lower than those of other treatments, as a result of both the lower fertilizer nitrogen use and the greater yield. This study indicates that integrated soil-crop system management could produce greater yields and increase net profit with reduced nitrogen inputs, whilst reducing the environmental cost associated with conventional farmers' practice in plastic-greenhouse vegetable production systems.
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http://dx.doi.org/10.1016/j.jenvman.2020.110569DOI Listing
July 2020

Pursuing sustainable productivity with millions of smallholder farmers.

Nature 2018 03 7;555(7696):363-366. Epub 2018 Mar 7.

Institute of Agricultural Resources and Environment, Hebei Academy of Agriculture and Forestry Sciences, Shijiazhuang 050051, China.

Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook.
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http://dx.doi.org/10.1038/nature25785DOI Listing
March 2018

Exploiting Co-Benefits of Increased Rice Production and Reduced Greenhouse Gas Emission through Optimized Crop and Soil Management.

PLoS One 2015 9;10(10):e0140023. Epub 2015 Oct 9.

Rothamsted Research, Harpenden, Herts, United Kingdom.

Meeting the future food security challenge without further sacrificing environmental integrity requires transformative changes in managing the key biophysical determinants of increasing agronomic productivity and reducing the environmental footprint. Here, we focus on Chinese rice production and quantitatively address this concern by conducting 403 on-farm trials across diverse rice farming systems. Inherent soil productivity, management practices and rice farming type resulted in confounded and interactive effects on yield, yield gaps and greenhouse gas (GHG) emissions (N2O, CH4 and CO2-equivalent) with both trade-offs and compensating effects. Advances in nitrogen, water and crop management (Best Management Practices-BMPs) helped closing existing yield gaps and resulted in a substantial reduction in CO2-equivalent emission of rice farming despite a tradeoff of increase N2O emission. However, inherent soil properties limited rice yields to a larger extent than previously known. Cultivating inherently better soil also led to lower GHG intensity (GHG emissions per unit yield). Neither adopting BMPs only nor improving soils with low or moderate productivity alone can adequately address the challenge of substantially increasing rice production while reducing the environmental footprint. A combination of both represents the most efficient strategy to harness the combined-benefits of enhanced production and mitigating climate change. Extrapolating from our farm data, this strategy could increase rice production in China by 18%, which would meet the demand for direct human consumption of rice by 2030. It would also reduce fertilizer nitrogen consumption by 22% and decrease CO2-equivalent emissions during the rice growing period by 7% compared with current farming practice continues. Benefits vary by rice-based cropping systems. Single rice systems have the largest food provision benefits due to its wider yield gap and total cultivated area, whereas double-rice system (especially late rice) contributes primarily to reducing GHG emissions. The study therefore provides farm-based evidence for feasible, practical approaches towards achieving realistic food security and environmental quality targets at a national scale.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140023PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599856PMC
July 2016

Producing more grain with lower environmental costs.

Nature 2014 Oct 3;514(7523):486-9. Epub 2014 Sep 3.

College of Resources &Environmental Sciences, China Agricultural University, Beijing 100193, China.

Agriculture faces great challenges to ensure global food security by increasing yields while reducing environmental costs. Here we address this challenge by conducting a total of 153 site-year field experiments covering the main agro-ecological areas for rice, wheat and maize production in China. A set of integrated soil-crop system management practices based on a modern understanding of crop ecophysiology and soil biogeochemistry increases average yields for rice, wheat and maize from 7.2 million grams per hectare (Mg ha(-1)), 7.2 Mg ha(-1) and 10.5 Mg ha(-1) to 8.5 Mg ha(-1), 8.9 Mg ha(-1) and 14.2 Mg ha(-1), respectively, without any increase in nitrogen fertilizer. Model simulation and life-cycle assessment show that reactive nitrogen losses and greenhouse gas emissions are reduced substantially by integrated soil-crop system management. If farmers in China could achieve average grain yields equivalent to 80% of this treatment by 2030, over the same planting area as in 2012, total production of rice, wheat and maize in China would be more than enough to meet the demand for direct human consumption and a substantially increased demand for animal feed, while decreasing the environmental costs of intensive agriculture.
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http://dx.doi.org/10.1038/nature13609DOI Listing
October 2014