Antiproliferative <i>S</i>-Trityl-<span style="font-variant: small-caps">l</span>-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement
Mohamed O. Radwan,
Halil I. Ciftci,
Taha F. S. Ali,
Doha E. Ellakwa,
Ryoko Koga,
Hiroshi Tateishi,
Akiko Nakata,
Akihiro Ito,
Minoru Yoshida,
Yoshinari Okamoto,
Mikako Fujita,
Masami Otsuka
Affiliations
Mohamed O. Radwan
Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-Ku, Kumamoto 8620976, Japan
Halil I. Ciftci
Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-Ku, Kumamoto 8620976, Japan
Taha F. S. Ali
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Doha E. Ellakwa
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Ryoko Koga
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Hiroshi Tateishi
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Akiko Nakata
Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
Akihiro Ito
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
Minoru Yoshida
Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
Yoshinari Okamoto
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Mikako Fujita
Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
Masami Otsuka
Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-Ku, Kumamoto 8620976, Japan
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.
