New SIRT2 inhibitors: Histidine-based bleomycin spin-off. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: Ali, Taha F.S.; Ciftci, Halil I.; Radwan, Mohamed O.; Koga, Ryoko; Ohsugi, Takeo; Okiyama, Yoshio; Honma, Teruki; Nakata, Akiko; Ito, Akihiro; Yoshida, Minoru; Fujita, Mikako; Otsuka, Masami
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 9(2019)
• Page Start: 1767
• Page End: 1775
• Publication Date: 2019-05-01
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.03.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.