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Open AccessArticle

Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement

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Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-Ku, Kumamoto 8620976, Japan
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Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Japan
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Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo 12622, Egypt
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Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
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Department of Biochemistry Science, Faculty of Pharmacy, Al-Azhar University (Girls), Nasr City, Cairo 11651, Egypt
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Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
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Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
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School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan
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Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 1138657, Japan
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Authors to whom correspondence should be addressed.
Academic Editors: Nazim Sekeroglu, Anake Kijjoa and Sevgi Gezici
Molecules 2019, 24(18), 3295; https://doi.org/10.3390/molecules24183295
Received: 29 July 2019 / Revised: 5 September 2019 / Accepted: 6 September 2019 / Published: 10 September 2019
(This article belongs to the Special Issue Selected Papers from the Joint Symposia of MESMAP-5 & ISPBS-5)
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. View Full-Text
Keywords: STLC; SIRT2; anticancer; molecular docking; solubility STLC; SIRT2; anticancer; molecular docking; solubility
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MDPI and ACS Style

Radwan, M.O.; Ciftci, H.I.; Ali, T.F.S.; Ellakwa, D.E.; Koga, R.; Tateishi, H.; Nakata, A.; Ito, A.; Yoshida, M.; Okamoto, Y.; Fujita, M.; Otsuka, M. Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement. Molecules 2019, 24, 3295.

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