PUBLICATION

In Vivo Angiogenesis Screening and Mechanism of Action of Novel Tanshinone Derivatives Produced by One-Pot Combinatorial Modification of Natural Tanshinone Mixture from Salvia Miltiorrhiza

Authors
Zhang, Z.R., Li, J.H., Li, S., Liu, A.L., Hoi, P.M., Tian, H.Y., Ye, W.C., Lee, S.M., Jiang, R.W.
ID
ZDB-PUB-140706-9
Date
2014
Source
PLoS One   9: e100416 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Cell Proliferation/drug effects
  • Signal Transduction/drug effects
  • Animals
  • MCF-7 Cells
  • Salvia miltiorrhiza/chemistry*
  • Fibroblast Growth Factors/metabolism
  • Abietanes/chemistry
  • Abietanes/isolation & purification
  • Abietanes/pharmacology*
  • Humans
  • Neovascularization, Physiologic/drug effects*
  • Plant Preparations/chemistry
  • Plant Preparations/pharmacology
  • Embryo, Nonmammalian/drug effects
  • Zebrafish/embryology
  • Epidermal Growth Factor/metabolism
  • Models, Biological
(all 17)
PubMed
24992590 Full text @ PLoS One
Abstract
Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.
In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1-10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.
Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.
Genes / Markers
Figures
Figure Gallery (3 images)
Show all Figures
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    y1Tg
    1 - 1 of 1
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available