RRC ID 59802
著者 Radwan MO, Ciftci HI, Ali TFS, Ellakwa DE, Koga R, Tateishi H, Nakata A, Ito A, Yoshida M, Okamoto Y, Fujita M, Otsuka M.
タイトル Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement.
ジャーナル Molecules
Abstract S-trityl-l-cysteine (STLC) is a well-recognized lead compound known for its anticancer activity owing to its potent inhibitory effect on human mitotic kinesin Eg5. STLC contains two free terminal amino and carboxyl groups that play pivotal roles in binding to the Eg5 pocket. On the other hand, such a zwitterion structure complicates the clinical development of STLC because of the solubility issues. Masking either of these radicals reduces or abolishes STLC activity against Eg5. We recently identified and characterized a new class of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of sirtuin protein (SIRT2) inhibitors that can be utilized as cytotoxic agents based on an S-trityl-l-histidine scaffold. Herein, we propose new STLC-derived compounds that possess pronounced SIRT2 inhibition effects. These derivatives contain modified amino and carboxyl groups, which conferred STLC with SIRT2 bioactivity, representing an explicit repurposing approach. Compounds STC4 and STC11 exhibited half maximal inhibitory concentration values of 10.8 ± 1.9 and 9.5 ± 1.2 μM, respectively, against SIRT2. Additionally, introduction of the derivatizations in this study addressed the solubility limitations of free STLC, presumably due to interruption of the zwitterion structure. Therefore, we could obtain drug-like STLC derivatives that work by a new mechanism of action. The new derivatives were designed, synthesized, and their structure was confirmed using different spectroscopic approaches. In vitro and cellular bioassays with various cancer cell lines and in silico molecular docking and solubility calculations of the synthesized compounds demonstrated that they warrant attention for further refinement of their bioactivity.
巻・号 24(18)
公開日 2019-1-1
DOI 10.3390/molecules24183295
PII molecules24183295
PMID 31510043
PMC PMC6766826
MeSH Cell Line, Tumor Computer Simulation Cysteine / chemistry Gene Expression Regulation, Neoplastic / drug effects Humans Kinesins / chemistry Kinesins / genetics Neoplasms / drug therapy* Neoplasms / genetics Neoplasms / pathology Sirtuin 2 / antagonists & inhibitors* Sirtuin 2 / genetics Solubility Trityl Compounds / chemistry Trityl Compounds / pharmacology*
IF 3.267
引用数 2
リソース情報
ヒト・動物細胞 MCF7(RCB1904)