Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC50 of 4.78 ± 0.08 µM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 µM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Genome-wide identification and expression analyses of the pectate lyase (PL) gene family in Fragaria vesca.

BACKGROUND: Pectate lyase (PL, EC 4.2.2.2), as an endo-acting depolymerizing enzyme, cleaves α-1,4-glycosidic linkages in esterified pectin and involves a broad range of cell wall modifications. However, the knowledge concerning the genome-wide analysis of the PL gene family in Fragaria vesca has not been thoroughly elucidated. RESULTS: In this study, sixteen PLs members in F. vesca were identified based on a genome-wide investigation. Substantial divergences existed among FvePLs in gene duplication, cis-acting elements, and tissue expression patterns. Four clusters were classified according to phylogenetic analysis. FvePL6, 8 and 13 in cluster II significantly contributed to the significant expansions during evolution by comparing orthologous PL genes from Malus domestica, Solanum lycopersicum, Arabidopsis thaliana, and Fragaria×ananassa. The cis-acting elements implicated in the abscisic acid signaling pathway were abundant in the regions of FvePLs promoters. The RNA-seq data and in situ hybridization revealed that FvePL1, 4, and 7 exhibited maximum expression in fruits at twenty days after pollination, whereas FvePL8 and FvePL13 were preferentially and prominently expressed in mature anthers and pollens. Additionally, the co-expression networks displayed that FvePLs had tight correlations with transcription factors and genes implicated in plant development, abiotic/biotic stresses, ions/Ca2+, and hormones, suggesting the potential roles of FvePLs during strawberry development. Besides, histological observations suggested that FvePL1, 4 and 7 enhanced cell division and expansion of the cortex, thus negatively influencing fruit firmness. Finally, FvePL1-RNAi reduced leaf size, altered petal architectures, disrupted normal pollen development, and rendered partial male sterility. CONCLUSION: These results provide valuable information for characterizing the evolution, expansion, expression patterns and functional analysis, which help to understand the molecular mechanisms of the FvePLs in the development of strawberries.

Structure Revisions of Phenolic Bisabolane Sesquiterpenes and a Ferroptosis Inhibitor from the Marine-Derived Fungus Aspergillus versicolor YPH93.

Seven new phenolic bisabolane sesquiterpenoids (1-7), along with 10 biogenetically related analogues (8-17), were obtained from the deep-sea-derived fungus Aspergillus versicolor YPH93. The structures were elucidated based on extensive analyses of the spectroscopic data. Compounds 1-3 are the first examples of phenolic bisabolanes that contain two hydroxy groups attached to the pyran ring. The structures of sydowic acid derivatives (1-6 and 8-10) were carefully studied, leading to the structure revisions of six known analogues, including a revision of the absolute configuration for sydowic acid (10). All metabolites were evaluated for their effects on ferroptosis. Compound 7 exerted inhibition on erastin/RSL3-induced ferroptosis with EC50 values ranging from 2 to 4 µM, while it exhibited no effects on TNFα-induced necroptosis or H2O2-induced cell necrosis.

Identification and co-expression network analysis of plumule-preferentially expressed genes in Oryza sativa.

BACKGROUND: The seedling establishment is controlled by the programmed expression of sets of genes at the specific tissues of seed, abundance and environment. Plumule is an important part of the seed embryo and expresses the suits of genes to exert distinct functions during seed germination. Although rice genomic resources are available and developed rapidly, thousands of transcripts have not previously been located in the plumule of rice. OBJECTIVE: This study was performed to identify plumule-preferentially expressed (OsPluP) genes in rice and determine the expression profiles and functions of OsPluP genes. METHODS: We identified the OsPluP genes through Affymetrix microarray data. Meanwhile, qRT-PCR was performed to validate the expression pattern, also found that OsPluP genes were regulated by dark/light treatment. The cis-acting regulatory elements were analyzed in the promoters' regions of OsPluP genes. The T-DNA mutant of the OsPluP seed was used to reveal the function in seed germination. RESULTS: In this study, a genomic survey of OsPluP genes was performed, and we identified 88 OsPluP genes based on Affymetrix microarray data. The expression profiles of 88 OsPluP members in 24 representative tissues covering rice whole life cycle can be roughly classified into three major groups, suggesting functional divergence of OsPluP genes in seed germination. The microarray data, qRT-PCR, and promoter analysis results demonstrated that transcripts of more than half OsPluPs (54 genes) could be enhanced in the darkness and respond to phytohormone. Gene Ontology (GO)and Kyoto encyclopedia of genes and genomes (KEGG) analysis demonstrated that OsPluP and their co-expressed genes were highly enriched in fatty acid metabolism. Moreover, OsPluP82 T-DNA mutant seeds displayed short plumule length and storage lipid accumulation. CONCLUSION: This study would enable the functions of OsPluP genes during seed germination and contribute to the goal of molecular regulatory networks that lay the foundation for further studies of seedling growth.

Phylogenetic relationships and characterization of the complete chloroplast genome of Rosa sterilis.

Rosa sterilis is an economically and important fruit that is extensively grown in Southwestern China. In this study, we determined the complete chloroplast genome of R. sterilis using high-throughput Illumina sequencing. The chloroplast genome of R. sterilis is 156,561 bp in size, containing a large single-copy region (LSC)(85,701 bp), a small single-copy region (SSC) (18,746 bp), and a pair of inverted repeat (IR) regions (each one of 26,057 bp). The overall GC content of the chloroplast genome is 37.23%, while the corresponding values of GC contents of the LSC, SSC, and IR regions are 35.20%, 31.37%, and 42.70%, respectively. The chloroplast genome of R. sterilis contains 130 genes, including 84 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenetic maximum-likelihood tree revealed that Rosa chinensis or Rosa chinensis var. spontanea is the closest related to R. sterilis in the phylogenetic relationship. This complete chloroplast genome can be further used for genomic studies, evolutionary analyses, and genetic engineering studies of the family Rosaceae.