Synthesis and Antitumor Activity of Auranofin Derivatives †

doi:10.7503/cjcu20190246

Abstract

Abstract:

A new type of auranofin derivatives was synthesized and characterized by means of nuclear magne-tic resonance spectroscopy(NMR) and high resolution mass spectroscopy(HRMS). After treatment of tumor cells with target compounds, the effect of the target compound on cell viability was determined by MTS assay, apoptosis was detected by flow cytometry, Western blot was used to detect the effects of target compounds on total ubiquitinated protein(Ub-Prs), K48-linked polyubiquitinated protein and the expression of protease-specific substrate(GFPu) in vitro. The results showed that the auranofin derivative exerted a better antitumor effect by inhibiting the function of the proteasome.

Key words: Auranofin derivative, Proteasome, Antitumor activity

CLC Number:

O621

TrendMD:

ZHANG Peiquan,YANG Qianqian,LONG Huidan,CHEN Xin. Synthesis and Antitumor Activity of Auranofin Derivatives ^†[J]. Chem. J. Chinese Universities, 2019, 40(10): 2097.

Figures/Tables 5

Scheme 1 Synthetic routes of the AF derivatives

Fig.1 Cell viability of malignant A562(A, D), K549(B, E) and non-cancerous(LO2)(C, F) cells treated with Auranofin and derivatives at various concentrations for 24 h(A—C) and 48 h(D—F) a. DMSO; c/(μmol·L-1), b—f. 0.25, 0.5, 1, 2, 3. Cell viability was assessed by MTS assay. Mean±SD(n=3) are representative of three independent experiments. * P<0.05, versus DM treatment alone. Aur; AF-1; AF-2; AF-3.

Fig.2 Auranofin and derivatives induces cell apoptosis by Annexin-FITC(A1—A16) and A549 cells treated with AF, AF-1, AF-2 and AF-3 at the indicated doses for 24 h and apoptosis evaluated by flow cytometry(B) (B) Mean±SD(n=3) are representative of three independent experiments.*P<0.05, versus DMSO treatment alone. a. DMSO; c/(μmol·L-1): b. 0.25; c. 0.5; d. 1.

Fig.3 A549 cells incubated in presence of DMSO(a), AF(b), AF-1(c), AF-2(d) and AF-3(e)[0, 0.5(A1—A3) and 1(B1—B3) μmol/L] for 6 h Ub-prs., K48-linked poly-ubiquitinated proteins were assessed by immunoblot with GAPDH as a loading control. (A1, B1) Ub-Prs; (A2, B2) K48; (A3, B3) GAPDH.

Fig.4 GFPu-HEK293 cells obtained by stable transfection of HEK293 cells with GFPu(a surrogate proteasome substrate) incubated in presence of AF(a), AF-1(b), AF-2(c) and AF-3(d)(0, 0.25, 0.5, and 1 μmol/L) for 6 h, and GFPu amounts were assessed by immunoblot with GAPDH as a loading control (A1—C1) Ub-Prs; (A2—C2) GFPu; (A3—C3) GAPDH. c/(μmol·L-1): (A1—A3) 0.25; (B1—B3) 0.5; (C1—C3) 1.

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