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.
Highlights
S-trityl-l-cysteine (STLC) (Figure 1) has been identified as an ATP-noncompetitive and reversible inhibitor of human mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent [1,2,3,4].STLC has been reported as a potent anticancer agent in an NCI 60 tumor cell line screen
The amphiphilic character of STLC results in poor water solubility and reduced permeability that affect its bioavailability [10]. Addressing this issue by alkylation or acylation of the STLC free primary amine resulted in loss of activity [4]
Based on our previous findings, we sought to design STLC-like compounds incorporating different substitutions on the primary amine group that may imitate the trityl histidine structure
Summary
S-trityl-l-cysteine (STLC) (Figure 1) has been identified as an ATP-noncompetitive and reversible inhibitor of human mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent [1,2,3,4]. STLC has been reported as a potent anticancer agent in an NCI 60 tumor cell line screen (half maximal tumor growth inhibition concentration of 1.3 μM). Thereafter, the in and carboxyl groups for better pharmacokinetics may necessitate repurposing towards another valid vitro SIRT2 inhibitory activities of these synthesized compounds were examined using target because such modifications may compromise its Eg5 ATPase inhibition effect. SIRT2 inhibitors showed antiproliferative effects against different cancer cell lines studies. Based on our previous findings, we sought to design STLC-like compounds incorporating different substitutions on the primary amine group that may imitate the trityl histidine structure. This study aimed to confer STLC with novel bioactivities against SIRT2 by enhancing its pharmacokinetic profile via modification of its terminal amine and carboxyl groups
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