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Citation: Liu Zhanxiong, Yuan Jing, Zhang Zhenfeng, Yan Deyue, Zhang Wanbin. Design, Synthesis and Antitumor Activity of 1-Monosubstituted 1H-Naphtho[2, 3-d]imidazole-4, 9-diones and 1H-Anthra[2, 3-d]imidazole-4, 11-diones[J]. Chinese Journal of Organic Chemistry, ;2018, 38(12): 3302-3317. doi: 10.6023/cjoc201807019 shu

Design, Synthesis and Antitumor Activity of 1-Monosubstituted 1H-Naphtho[2, 3-d]imidazole-4, 9-diones and 1H-Anthra[2, 3-d]imidazole-4, 11-diones

a.
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240
b.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240

Corresponding author: Zhang Zhenfeng, zhenfeng@sjtu.edu.cn Zhang Wanbin, wanbin@sjtu.edu.cn
Received Date: 9 July 2018
Revised Date: 3 August 2018
Available Online: 14 December 2019
Fund Project: the National Natural Science Foundation of China 21572131Project supported by the National Key Research and Development Plan (No. 2016YFA0201500) and the National Natural Science Foundation of China (No. 21572131)the National Key Research and Development Plan 2016YFA0201500

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In order to further expand the molecular diversity of quinone-fused imidazoles as anticancer agents, a number of 1-monosubstituted 1H-naphtho[2, 3-d]imidazole-4, 9-diones and 1H-anthra[2, 3-d]imidazole-4, 11-diones were designed, synthesized and biologically evaluated. The structure-activity relationships were studied in vitro against three human cancer cell lines (human breast carcinoma cell line MCF-7, human cervical carcinoma cell line Hela and human lung carcinoma cell line A549) and one normal cell line (mouse fibroblast cell line L929). Among them, 1-methyl-1H-anthra[2, 3-d]imidazole-4, 11-dione, which bears a large π-system and a small N-substituent in the imidazole segment, showed good antiproliferative activity against MCF-7 and A549 (IC₅₀ values are 7.4 and 1.6 μmol·L^-1, respectively) and almost no cytotoxicity to L929 (IC₅₀ is 150 μmol·L^-1).
- anthraquinone,
- naphthoquinone,
- imidazole,
- antitumor
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Figure 1. Design of 1-monosubstituted 1H-naphtho[2, 3-d]imidazole-4, 9-diones

Scheme 1. Synthesis of 1-monosubstituted 1H-naphtho[2, 3-d]imidazole-4, 9-diones

Reaction conditions: (a) N₂H₄·H₂O, 80 ℃, 4 h, 82% yield; (b) HCOOH, reflux, 6 h, 99% yield; (c) KOH, RX (X＝Br or I), DMSO; (d) cyclopropylamine, CHCl₃, 5 h, 69% yield; (e) N₂H₄·H₂O, 80 ℃, used directly for next step; (f) triethyl orthoformate, reflux, 3 h, 38% yield; (g) RNH₂, Et₃N, THF, 8~26 h, 75~87% yield; (h) N₂H₄·H₂O, 80~85 ℃, 40 min~2 h, 29~45% yield; (i) triethyl orthoformate, reflux 0.5~8 h, 40%~90% yield.

Scheme 2. Synthesis of other 1-monosubstituted 1H-benzo[d]imidazole-4, 7-dione derivatives

Reaction conditions: (a) NaH, MeI, THF, reflux, 2 h, 50% yield; (b) HBr (48 wt%), reflux, 3 h, 88% yield; (c) aq. FeCl₃, r.t., 79% yield; (d) HBr (48 wt%), reflux, 3 h, 99% yield; (e) aq. FeCl₃, r.t., 78% yield; (f) conc. HNO₃, conc. HCl, 85~90 ℃, 2 h, then r.t., 3 h, 78% yield; (g) KOH, MeI, DMSO, r.t., 66% yield; (h) cyclopenta-1, 3-diene, MeOH, r.t., 97% yield; (i) KOH, MeI, DMSO, r.t., 20% yield; (j) conc. H₂SO₄, fuming HNO₃, 0 ℃, then r.t., 69% yield; (k) H₂, Pd/C (10%), MeOH, 50 ℃, then HCl, 77% yield; (l) FeCl₃·6H₂O, r.t., then HCl, 95% yield; (m) KOH, MeI, DMSO, r.t., 41% yield.

Scheme 3. Synthesis of 1H-anthra[2, 3-d]imidazole-4, 11-diones

Reaction conditions: (a) HCOOH, reflux, 6 h, 99% yield; (b) KOH, MeI, DMSO, r.t., 24%~99% yield; (c) CH₃COOH, reflux, 74% yield; (d) KOH, MeI, DMSO, r.t., 25%~52% yield.

Figure 2. X-ray structures of 4b, 4m, and 4o

Figure 3. (A) Distribution of different cell states and (B) the quantification of cell apoptosis

Cells were treated with 2, 4 and 8 μmol·L^－1 of compound 4t for 24 h.

Figure 4. Effects of 4t on the cell cycle distribution of A549 cells

Cells were treated with 2, 4 and 8 μmol·L^－1 of compound 4t for 24 h. Cell cycle was determined by PI (propidium iodide) staining and cell cytometry