New SIRT2 inhibitors: Histidine-based bleomycin spin-off.

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.

• Authors: Taha F S Ali, Halil I Ciftci, Mohamed O Radwan, Ryoko Koga, Takeo Ohsugi, Yoshio Okiyama, Teruki Honma, Akiko Nakata, Akihiro Ito, Minoru Yoshida, Mikako Fujita, Masami Otsuka
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 27 Issue 9 Pg. 1767-1775 (05 01 2019) ISSN: 1464-3391 [Electronic] England
• PMID: 30885568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Bleomycin
• Histidine
• Sirtuin 2

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Bleomycin (chemistry, metabolism, pharmacology)
• Catalytic Domain
• Cell Survival (drug effects)
• Histidine (chemistry)
• Histone Deacetylase Inhibitors (chemistry, metabolism, pharmacology)
• Humans
• MCF-7 Cells
• Molecular Docking Simulation
• Sirtuin 2 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship