Interactive effect of 24-epibrassinolide and silicon on the alleviation of cadmium toxicity in rice (Oryza sativa L.) plants.

Cadmium (Cd) pollution is a serious threat to food safety and human health. Minimization of Cd uptake and enhancing Cd tolerance in plants are vital to improve crop yield and reduce hazardous effects to humans. In this study, we investigate the effect of a synergistic system with phytohormone (24-Epibrassinolide, EBL) and silicon (Si) on Cd toxicity and accumulation of rice plants. The results revealed that Si, EBL and their combination rescued Cd-induced growth inhibition, as evidenced by the increased dry weight of root and shoot. The chlorophyll content and photosynthetic performance were improved. The activity of antioxidant enzymes (SOD, POD and CAT) was increased and oxidative stress was alleviated. More importantly, Cd content in root was decreased by 20.25%, 17.72% and 27.84%, while Cd content in shoot decreased by 21.17%, 16.47% and 25.88%, respectively. Moreover, Si, EBL and Si + EBL treatment enriched cell wall-bound Cd and reduced Cd toxicity to functional organelles. Meanwhile, the residual form of Cd was enriched and the highly toxic forms of Cd (inorganic and water-soluble Cd) were decreased. The joint application showed better effects than applying Si and EBL alone. Collectively, this study provides an effective way for Cd toxicity mitigation in rice plants.

The genetic architecture of trait covariation in Populus euphratica, a desert tree.

Introduction: The cooperative strategy of phenotypic traits during the growth of plants reflects how plants allocate photosynthesis products, which is the most favorable decision for them to optimize growth, survival, and reproduction response to changing environment. Up to now, we still know little about why plants make such decision from the perspective of biological genetic mechanisms. Methods: In this study, we construct an analytical mapping framework to explore the genetic mechanism regulating the interaction of two complex traits. The framework describes the dynamic growth of two traits and their interaction as Differential Interaction Regulatory Equations (DIRE), then DIRE is embedded into QTL mapping model to identify the key quantitative trait loci (QTLs) that regulate this interaction and clarify the genetic effect, genetic contribution and genetic network structure of these key QTLs. Computer simulation experiment proves the reliability and practicability of our framework. Results: In order to verify that our framework is universal and flexible, we applied it to two sets of data from Populus euphratica, namely, aboveground stem length - underground taproot length, underground root number - underground root length, which represent relationships of phenotypic traits in two spatial dimensions of plant architecture. The analytical result shows that our model is well applicable to datasets of two dimensions. Discussion: Our model helps to better illustrate the cooperation-competition patterns between phenotypic traits, and understand the decisions that plants make in a specific environment that are most conducive to their growth from the genetic perspective.

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV-1 RNase H inhibitors.

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV-1 RNase H inhibitory activity. Most of them showed IC50 s at sub- to low-micromolar concentrations in enzymatic assays. The most potent compound was II-25 that showed an IC50 of 0.72 ± 0.07 µM in RNase H inhibition assays carried out with the HIV-1BH10 RT. II-25 was 2.8 times more potent than ß-thujaplicinol in these assays. Interestingly, II-25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure-activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.

5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase.

We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC50RNase H = 1.77 µM, IC50IN = 1.18 µM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles.

Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013-2016): Opportunities and Challenges.

Combinations of antiretroviral drugs are successfully used to treat HIV-infected patients. However, drug resistance is a major problem that makes discovery of new antiretroviral drugs an ongoing priority. The ribonuclease H (RNase H) activity of the HIV-1 reverse transcriptase catalyzes the selective hydrolysis of the RNA strand of RNA:DNA heteroduplex replication intermediates, and represents an attractive unexploited target for drug development. This review reports on recent progress in the characterization of HIV-1 RNase H inhibitors from 2013 to 2016, describing their chemical structures, structureactivity relationship and binding modes. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of RNase H inhibitors.

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48µM and 1.61µM, respectively. They were much potent than the reference drug ddI (EC50=76.0µM) and comparable to 3TC (EC50=2.54µM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

Medicinal Chemistry Insights into Novel HDAC Inhibitors: An Updated Patent Review (2012-2016).

BACKGROUND: Many laboratories have made intensive efforts to develop potent, selective, and orally bioavailable HDAC inhibitors (HDACIs). Novel HDACIs are being developed with the objective of improving potency and selectivity against specific types of cancers or non-cancer diseases. OBJECTIVE: This updated patent review is an attempt to compile the work of various researchers of HDACIs from 2012 to mid 2016, and to enlighten and surprise both newcomers in this field and devoted medicinal chemists. METHOD: According to the literature research and the writers' own research experience in the discovery of HDAC inhibitors. RESULTS: The inhibitors possessing new chemical scaffolds have attracted immense interest because they have the ability to improve HDAC isoform specificity and pharmaceutical properties. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of HDAC inhibitors. CONCLUSION: The development of effective HDACIs is shifting from trial-and-error approaches to sophisticated strategies. Effective profiling technologies will continue to have important utility.

Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries.

The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chemistry is a highly robust and efficient strategy for establishing SAR and for discovering bioactive molecules. This review outlines the current status of this methodology in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.

Medicinal chemistry insights in the discovery of novel LSD1 inhibitors.

LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a broad spectrum of key cellular processes, and its activity is often altered under pathological conditions. LSD1 inhibitors are considered to be candidates for therapy of cancer, viral diseases and neurodegeneration. Many LSD1 inhibitors with various scaffolds have been disclosed, and a few potent molecules are in different stages of clinical development. In this review, we summarize recent biological findings on the roles of LSD1 and the current understanding of the clinical significance of LSD1, and focus on the medicinal chemistry strategies used in the design and development of LSD1 inhibitors as drug-like epigenetic modulators since 2012, including a brief consideration of structure-activity relationships.

[Study on denoising near infrared spectra of wood based on wavelet transform].

Near infrared (NIR) spectra of wood samples are often confused by a series of noise, which greatly influences accurate analytical result. In order to improve analytical precision, the authors need to pretreat the spectrum data. Derivative can correct baseline and background effects, increasing the resolution ratio of the spectra. However, it also increases the noise at the same time. The present paper aims at using wavelet transform to eliminate the noise of the near infrared first derivative spectrum of wood with the methods of 9 point smoothing spectrum, 25 point smoothing spectrum, the nonlinear wavelet hard-threshold spectrum, the nonlinear wavelet soft-threshold spectrum, 9 point smoothing+wavelet transform and 25 point smoothing spectrum+ wavelet transform. The results show that the wavelet transform has particular advantage on noise elimination of the near infrared spectra while reserving the useful information of spectrum. It can also improve the signal to noise ratio of spectrum, promising the prospect of a wide application in the wood near infrared spectroscopic analysis.