Reference - Detail
| RRC ID | 54898 |
|---|---|
| Author | Ali TFS, Ciftci HI, Radwan MO, Koga R, Ohsugi T, Okiyama Y, Honma T, Nakata A, Ito A, Yoshida M, Fujita M, Otsuka M. |
| Title | New SIRT2 inhibitors: Histidine-based bleomycin spin-off. |
| Journal | Bioorg Med Chem |
| Abstract |
Bleomycin is considered to exert its antitumor activity via DNA cleavage mediated by activated oxygen generated from the iron complex in its chelator moiety. Spin-offs from this moiety, HPH-1Trt and HPH-2Trt, with anti-cancer activities were recently synthesized. In this paper, we developed inhibitors of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of Sirtuin protein (SIRT2), based on HPH-1Trt/HPH-2Trt, and aimed to generate new anti-cancer drugs. HPH-1Trt and HPH-2Trt had in vitro anti-SIRT2 inhibitory activity with 50% inhibitory concentration (IC50) values of 5.5 and 8.8 μM, respectively. A structural portion of HPH-1Trt/HPH-2Trt, a tritylhistidine derivative TH-1, had stronger activity (IC50 = 1.7 μM), and thus, fourteen derivatives of TH-1 were synthesized. Among them, TH-3 had the strongest activity (IC50 = 1.3 μM). Selective binding of TH-3 in the pocket of SIRT2 protein was confirmed with a molecular docking study. Furthermore, TH-3 strongly lowered viability of the breast cancer cell line MCF7 with an IC50 of 0.71 μM. A structure-activity relationship study using cell lines suggested that the mechanism of TH-3 to suppress MCF7 cells involves not only SIRT2 inhibition, but also another function. This compound may be a new candidate anti-cancer drug. |
| Volume | 27(9) |
| Pages | 1767-1775 |
| Published | 2019-5-1 |
| DOI | 10.1016/j.bmc.2019.03.003 |
| PII | S0968-0896(19)30219-6 |
| PMID | 30885568 |
| MeSH | Antineoplastic Agents / chemical synthesis Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Binding Sites Bleomycin / chemistry* Bleomycin / metabolism Bleomycin / pharmacology Catalytic Domain Cell Survival / drug effects Histidine / chemistry* Histone Deacetylase Inhibitors / chemistry* Histone Deacetylase Inhibitors / metabolism Histone Deacetylase Inhibitors / pharmacology Humans MCF-7 Cells Molecular Docking Simulation Sirtuin 2 / antagonists & inhibitors* Sirtuin 2 / metabolism Structure-Activity Relationship |
| IF | 2.802 |
| Times Cited | 7 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | MCF7(RCB1904) |