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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
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New SIRT2 inhibitors: Histidine-based bleomycin spin-off
Taha F S Ali1, Halil I Ciftci2, Mohamed O Radwan3
1Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Bioorganic & Medicinal Chemistry
|March 20, 2019
Summary
Researchers developed novel anti-cancer drugs by inhibiting Sirtuin protein 2 (SIRT2). The compound TH-3, derived from bleomycin analogs, effectively reduced breast cancer cell viability, showing promise as a new therapeutic candidate.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Bleomycin's antitumor activity involves DNA cleavage via activated oxygen.
- Newly synthesized HPH-1Trt and HPH-2Trt compounds exhibit anti-cancer properties.
- Sirtuin protein 2 (SIRT2) is a target for cancer drug development.
Purpose of the Study:
- To develop novel SIRT2 inhibitors based on HPH-1Trt/HPH-2Trt structures.
- To identify potent anti-cancer drug candidates with improved efficacy.
- To investigate the mechanism of action for novel compounds against cancer cells.
Main Methods:
- Synthesis of tritylhistidine derivatives (TH-1 and its analogs) from HPH-1Trt/HPH-2Trt.
- In vitro assessment of SIRT2 inhibitory activity using IC50 values.
- Molecular docking studies to confirm selective binding to SIRT2.
- Evaluation of cell viability in MCF7 breast cancer cell line.
- Structure-activity relationship (SAR) studies.
Main Results:
- HPH-1Trt and HPH-2Trt showed in vitro SIRT2 inhibitory activity (IC50: 5.5 and 8.8 μM).
- Tritylhistidine derivative TH-1 exhibited enhanced activity (IC50: 1.7 μM).
- TH-3 demonstrated the strongest SIRT2 inhibition (IC50: 1.3 μM) and selective binding.
- TH-3 significantly reduced MCF7 cell viability (IC50: 0.71 μM).
Conclusions:
- TH-3 is a potent inhibitor of SIRT2 and a promising anti-cancer agent.
- The mechanism of TH-3 involves SIRT2 inhibition and potentially other pathways.
- Further investigation is warranted for TH-3 as a candidate anti-cancer drug.
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