title: 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.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P.R. China.
authors.forename: Zhe-Rui
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, P.R. China.
authors.forename: Jin-Hang
authors.initials: JH
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P.R. China.
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P.R. China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P.R. China.
authors.forename: Pui-Man
authors.initials: PM
authors.lastname: Hoi
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, P.R. China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Tian
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, P.R. China.
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P.R. China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, P.R. China.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D028321:Plant Preparations / Q000737:chemistry / Q000494:pharmacology; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology
chemical_list: D045784:Abietanes; D028321:Plant Preparations; C021751:tanshinone; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor