PMID- 31408333
OWN - NLM
STAT- MEDLINE
DCOM- 20200629
LR  - 20200629
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 62
IP  - 17
DP  - 2019 Sep 12
TI  - Germacrane Sesquiterpenoids as a New Type of Anticardiac Fibrosis Agent Targeting 
      Transforming Growth Factor beta Type I Receptor.
PG  - 7961-7975
LID - 10.1021/acs.jmedchem.9b00708 [doi]
AB  - A germacrane sesquiterpenoid library containing 30 compounds (2-31) was 
      constructed by structural modification of a major component aristolactone (1) 
      from the traditional Chinese medicine Aristolochia yunnanensis. Compound 11 was 
      identified as a promising anticardiac fibrosis agent by systematic screening of 
      this library. 11 could inhibit the expression of fibronectin (FN), alpha-smooth 
      muscle actin (alpha-SMA), and collagens in transforming growth factor beta 1 
      (TGFbeta1)-stimulated cardiac fibroblasts at a micromolar level and ameliorate 
      myocardial fibrosis and heart function in abdominal aortic constriction (AAC) 
      rats at 5 mg/kg dose. Mechanistic study revealed that 11 inhibited the TGFbeta/small 
      mother against decapentaplegic (Smad) signaling pathway by targeting TGFbeta type I 
      receptor (IC(50) = 14.9 +/- 1.6 nM). The structure-activity relationships (SARs) 
      study indicated that the unsaturated gamma-lactone ring and oxidation of C-1 were 
      important to the activity. These findings may provide a new type of structural 
      motif for future anticardiac fibrosis drug development.
FAU - Lou, Lan-Lan
AU  - Lou LL
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Ni, Fu-Qiang
AU  - Ni FQ
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Chen, Lin
AU  - Chen L
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Shaker, Sharpkate
AU  - Shaker S
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Li, Wei
AU  - Li W
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Wang, Rong
AU  - Wang R
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Tang, Gui-Hua
AU  - Tang GH
AUID- ORCID: 0000-0002-8831-7154
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
FAU - Yin, Sheng
AU  - Yin S
AUID- ORCID: 0000-0002-5678-6634
AD  - School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , 
      People's Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190826
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Sesquiterpenes, Germacrane)
SB  - IM
MH  - Animals
MH  - Aorta/drug effects/physiopathology
MH  - Constriction
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Fibroblasts/drug effects/metabolism/pathology
MH  - Fibrosis/*drug therapy/metabolism/pathology
MH  - Male
MH  - Molecular Structure
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism
MH  - Sesquiterpenes, Germacrane/chemistry/isolation & purification/*pharmacology
MH  - Structure-Activity Relationship
EDAT- 2019/08/14 06:00
MHDA- 2020/07/01 06:00
CRDT- 2019/08/14 06:00
PHST- 2019/08/14 06:00 [pubmed]
PHST- 2020/07/01 06:00 [medline]
PHST- 2019/08/14 06:00 [entrez]
AID - 10.1021/acs.jmedchem.9b00708 [doi]
PST - ppublish
SO  - J Med Chem. 2019 Sep 12;62(17):7961-7975. doi: 10.1021/acs.jmedchem.9b00708. Epub 
      2019 Aug 26.