Structure-activity relationships of 1'-acetoxychavicol acetate homologues as new nuclear export signal inhibitors.
Bioassay-guided separation use of the fission yeast expressing NES of Rev, a HIV-1 viral regulatory protein, resulted in isolation of 1'-acetoxychavicol acetate (ACA) from Alpinia galanga as a new Rev-transport inhibitor from the nucleus to cytoplasm. Rational design and synthesis of eleven ACA derivatives containing systematic chemical variations were made, biological evaluation of inhibitory activities of these analogues provides the basis to formulate the structure-activity relationship (SAR). The key elements observed were: (1) The para substitution of the acetoxyl and 1'-acetoxypropenyl groups at the benzene ring was essential, (2) linear ethyl and propyl chain carbonates were more active than branching chain carbonates, (3) the substitution of acetoxyl groups with alkyl carbamate groups lost or reduced the activities. This study revealed a new salient pharmacophore features as potential drug leads against the HIV virus.
Liu
Y
Y
Key Laboratory of Marine Bio-resources Sustainable Utilization, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China. yonghongliu@scsio.ac.cn
Murakami
N
N
Zhang
S
S
Xu
T
T
D032429:Alpinia / Q000737:chemistry; D001592:Benzyl Alcohols; D002467:Cell Nucleus / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005982:Glutathione Transferase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D049790:Nuclear Export Signals / Q000187:drug effects*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D001592:Benzyl Alcohols; D049790:Nuclear Export Signals; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes; D005982:Glutathione Transferase; C047948:1'-acetoxychavicol acetate