Selective protecting group manipulations on the 1-deoxynojirimycin scaffold

Zhao

et al. 2018

PeerJ

Mulberry (Morus alba L.) represents one of the most commonly utilized plants in traditional medicine and as a nutritional plant used worldwide. The polyhydroxylated alkaloid 1-deoxynojirimycin (DNJ) is the major bioactive compounds of mulberry in treating diabetes. However, the DNJ content in mulberry is very low. Therefore, identification of key genes involved in DNJ alkaloid biosynthesis will provide a basis for the further analysis of its biosynthetic pathway and ultimately for the realization of synthetic biological production. Here, two cDNA libraries of mulberry leaf samples with different DNJ contents were constructed. Approximately 16 Gb raw RNA-Seq data was generated and de novo assembled into 112,481 transcripts, with an average length of 766 bp and an N50 value of 1,392. Subsequently, all unigenes were annotated based on nine public databases; 11,318 transcripts were found to be significantly differentially regulated. A total of 38 unique candidate genes were identified as being involved in DNJ alkaloid biosynthesis in mulberry, and nine unique genes had significantly different expression. Three key transcripts of DNJ biosynthesis were identified and further characterized using RT-PCR; they were assigned to lysine decarboxylase and primary-amine oxidase genes. Five CYP450 transcripts and two methyltransferase transcripts were significantly associated with DNJ content. Overall, the biosynthetic pathway of DNJ alkaloid was preliminarily speculated.

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis and identification of key genes involved in 1-deoxynojirimycin biosynthesis of mulberry (Morus albaL.)

Zhao

et al. 2018

PeerJ

“…The results could help in the design of selective inhibitors of both SSTR subtypes based on iminosugar scaffolds. The recent synthesis of differentially protected DNJ intermediates will aid in the regioselective introduction of pharmacophoric groups to the 2,3 and 4-OH groups of DNJ [24] with a view to optimising binding interactions of iminosugarbased peptidomimetics to SSTRs.…”

Section: Discussionmentioning

confidence: 99%

“…(8). Compound 7 [20,24] (550 mg, 1.85 mmol) was dissolved in anhyd pyridine (4 mL) and DMAP (226 mg) was added. The mixture was cooled to 0 8C and MMTrCl (687 mg, 2.22 mmol) in anhyd pyridine (4 mL) was added dropwise.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Somatostatin Mimetics Based on 1‐Deoxynojirimycin

2008

Self Cite

The synthesis of novel somatostatin mimetics from 1-deoxynojirimycin (DNJ) is described. The dipeptide mimetic, which respectively displayed the side chains of tryptophan and lysine at the nitrogen and O6 atoms of the iminosugar scaffold is a ligand (K(i)=3.2 microM) for the human somatostatin receptor subtype 4 (hSSTR4) but has lower affinity (K(i)>100 microM) for hSSTR5. A benzylated analogue of the Trp-Lys mimetic displays higher affinity for hSSTR5 (K(i)=5 microM).

“…It is well established that actin polymerization, which leads to stress fiber assembly and depolymerization, plays a crucial function in cell motility (21)(22)(23). Hybrid 2 had inhibited stress fiber assembly previously.…”

Section: Effect Of 5 On Expression Of Cyclin D1 P27mentioning

confidence: 99%

“…Effect of 5 on BAEC migration, and on stress fiber assembly and filopodia formation in BAECs Alkyne 5 inhibited BAEC tube formation, and it was thus of interest to establish the effect of 5 on cell migration and on actin polymerization. It is well established that actin polymerization, which leads to stress fiber assembly and depolymerization, plays a crucial function in cell motility (21)(22)(23). Hybrid 2 had inhibited stress fiber assembly previously.…”

Section: Effect Of 5 On Expression Of Cyclin D1 P27 Kip1 and The Phomentioning

confidence: 99%

Biological study of the Angiogenesis Inhibitor N‐(8‐(3‐ethynylphenoxy)octyl‐1‐deoxynojirimycin

2010

Self Cite

The a-glucosidase inhibitors N-methyl-1-deoxynojirimycin (MDNJ) and castanospermine have been shown to inhibit angiogenesis. A hybrid of 1-deoxynojirimycin (DNJ) and an aryl-1,2,3-triazole, which inhibits both an a-glucosidase and methionine aminopeptidase-2 (MetAP2), displayed properties associated with inhibition of angiogenesis (Bioorg. Med. Chem., 16, 2008, 6333-7). The biological evaluation of a structural analogue N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin is described herein. Although this alkyne derivative did not inhibit MetAP2, it inhibited a bacterial a-glucosidase, altered bovine aortic endothelial cell (BAEC) surface oligosaccharide expression and inhibited BAEC proliferation by inducing G1 phase cell cycle arrest. Experiments showed G1 arrest was attributable to the a-glucosidase inhibitor inducing an increase in p27Kip1 expression and high phosphorylation of ERK1 ⁄ 2 without a reduction in cyclin D1. The DNJ derivative (0.1 mM) prevented capillary tube formation from bovine aortic endothelial cells, whereas DNJ or other analogues were unable to inhibit tube formation at the same concentration. Stress fiber assembly in bovine aortic endothelial cells was abolished, and BAEC migration was inhibited indicating the inhibition of tube formation by this derivative is partially a result of a reduction in cell motility. The agent also caused a reduction in secretion of MMP-2 from bovine aortic endothelial cells. Therefore, the new a-glucosidase inhibitor has a different mechanism by which it inhibits angiogenesis in vitro when compared with deoxynojirimycin, the deoxynojirimycin -triazole hybrid, N-methyl-1-deoxynojirimycin and castanospermine.