Total synthesis and biological evaluation of largazole and derivatives with promising selectivity for cancers cells.
The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazole's analogues with trans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.
Zeng
Xin
X
Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou 510663, PR China.
Yin
Biaolin
B
Hu
Zheng
Z
Liao
Chenzhong
C
Liu
Jinglei
J
Li
Shang
S
Li
Zheng
Z
Nicklaus
Marc C
MC
Zhou
Guangbiao
G
Jiang
Sheng
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047630:Depsipeptides; D013844:Thiazoles; C527895:largazole