Discovery of Novel 17‐Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors. (26th June 2014)

• Record Type: Journal Article
• Authors: Li, Zhenyu; Jia, Lejiao; Wang, Jifeng; Wu, Xingkang; Shi, Guowei; Lu, Chunhua; Shen, Yuemao
• Is Part Of: Chemical biology & drug design. Volume 85:Number 2(2015:Feb.)
• Page Start: 181
• Page End: 188
• Publication Date: 2014-06-26
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12371
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12371-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<bold>2j</bold>, <bold> 2q</bold>, <bold> 2v</bold>, <bold> 2x</bold>, and <bold>2y</bold>) showed excellent <italic>in vitro</italic> antitumor activities. Among them, compound <bold>2y</bold> was the most potent lead, with IC₅₀ values of 0.27 ± 0.11 and 0.86 ± 0.23 <italic>μ</italic><sc>m</sc> for LNCaP and MDA‐MB‐231, respectively. In particular, compound <bold>2y</bold> was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that <bold>2y</bold> group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that <bold>2y</bold> 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.</p> </abstract>