Journal
CHEMICAL BIOLOGY & DRUG DESIGN
Volume 85, Issue 2, Pages 181-188Publisher
WILEY
DOI: 10.1111/cbdd.12371
Keywords
antitumor activities; geldanamycin; hepatotoxicity; Hsp90; synthesis
Funding
- 973 Program [2010CB833802]
- NSFC [81273384, 81302214, 90913024]
- Independent Innovation Foundation of Shandong University [2010 TB016]
- Post-graduate Independent Innovation Fund of Shandong University [YZC12095]
- Shanghai Nature Science Foundation of Shanghai Science and Technology Committee, China [13ZR1432700]
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Twenty-six 17-phenylethylamine-modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA-MB-231. Five derivatives (2j, 2q, 2v, 2x, and 2y) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC50 values of 0.27 +/- 0.11 and 0.86 +/- 0.23m for LNCaP and MDA-MB-231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17-phenylethylaminegeldanamycins binding to Hsp90.
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