New SIRT2 inhibitors: Histidine-based bleomycin spin-off

被引：18

作者：

Ali, Taha F. S. ^{[1
,2
]}

Ciftci, Halil I. ^{[1
,3
]}

Radwan, Mohamed O. ^{[1
,3
,4
]}

Koga, Ryoko ^{[1
]}

Ohsugi, Takeo ^{[5
]}

Okiyama, Yoshio ^{[6
]}

Honma, Teruki ^{[6
]}

Nakata, Akiko ^{[7
]}

Ito, Akihiro ^{[8
,9
]}

Yoshida, Minoru ^{[7
,8
,10
]}

Fujita, Mikako ^{[11
]}

Otsuka, Masami ^{[1
]}

机构：

[1] Kumamoto Univ, Fac Life Sci, Dept Bioorgan Med Chem, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan

[2] Menia Univ, Dept Med Chem, Fac Pharm, Al Minya 61519, Egypt

[3] Sci Farm Ltd, Dept Drug Discovery, Chuo Ku, 1-7-30 Kuhonji, Kumamoto 8620976, Japan

[4] Natl Res Ctr, Chem Nat Cpds Dept, Pharmaceut & Drug Ind Res Div, Cairo 12622, Egypt

[5] Rakuno Gakuen Univ, Dept Lab Anim Sci, Sch Vet Med, 582 Bunkyodai Midorimachi, Ebetsu, Hokkaido 0698501, Japan

[6] RIKEN, Ctr Biosyst Dynam Res, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[7] RIKEN, Seed Cpds Exploratory Unit Drug Discovery Platfor, Ctr Sustainable Resource Sci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[8] RIKEN, Chem Genom Res Grp, Ctr Sustainable Resource Sci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[9] Tokyo Univ Pharm & Life Sci, Sch Life Sci, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan

[10] Univ Tokyo, Dept Biotechnol, Grad Sch Agr & Life Sci, Bunkyo Ku, 1-1-1 Yayoi, Tokyo 1138657, Japan

[11] Kumamoto Univ, Sch Pharm, Res Inst Drug Discovery, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 09期

关键词：

METAL BINDING-SITE; RNA-EDITING ENZYME; MECHANISM; COMPOUND; KINASE;

D O I：

10.1016/j.bmc.2019.03.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bleomycin is considered to exert its antitumor activity via DNA cleavage mediated by activated oxygen generated from the iron complex in its chelator moiety. Spinoffs 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 mu M, respectively. A structural portion of HPH-1Trt/HPH-2Trt, a tritylhistidine derivative TH-1, had stronger activity (IC50 = 1.7 mu M), and thus, fourteen derivatives of TH-1 were synthesized. Among them, TH-3 had the strongest activity (IC50, = 1.3 mu M). 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 mu M. 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.

引用

页码：1767 / 1775

页数：9

共 42 条

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