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. 2019 Nov 7;24(22):4025.
doi: 10.3390/molecules24224025.

Design, Synthesis and Biological Evaluation of Diosgenin-Amino Acid Derivatives with Dual Functions of Neuroprotection and Angiogenesis

Desheng Cai  1 , Jinchai Qi  1 , Yuqin Yang  1 , Wenxi Zhang  1 , Fei Zhou  1 , Xiaohui Jia  1 , Wenbo Guo  1 , Xuemei Huang  1 , Feng Gao  1 , Hongshan Chen  1 , Tong Li  1 , Guoping Li  1 , Penglong Wang  1 , Yuzhong Zhang  1 , Haimin Lei  1
Affiliations

Design, Synthesis and Biological Evaluation of Diosgenin-Amino Acid Derivatives with Dual Functions of Neuroprotection and Angiogenesis

Desheng Cai et al. Molecules. .

Abstract

Diosgenin, a natural product with steroidal structure, has a wide range of clinical applications in China. It also shows great potential in the treatment of blood clots and nerve damage. To enhance the bioavailability as well as efficacy of diosgenin, eighteen diosgenin-amino acid derivatives were designed and synthesized. The neuroprotective effects of these compounds were evaluated by SH-SY5Y cell line and the biosafety was evaluated by H9c2 cell line. The results displayed that part of the derivatives' activities (EC50 < 20 μM) were higher than positive control edaravone (EC50 = 21.60 ± 3.04 μM), among which, DG-15 (EC50 = 6.86 ± 0.69 μM) exhibited the best neuroprotection. Meanwhile, biosafety evaluation showed that DG-15 had no cytotoxicity on H9c2 cell lines. Interestingly, combined neuroprotective and cytotoxic results, part of the derivatives without their protecting group were superior to compounds with protecting group. Subsequently, Giemsa staining and DAPI (4',6-diamidino-2-phenylindole) staining indicated that DG-15 had a protective effect on damaged SH-SY5Y cells by reducing apoptosis. Moreover, DG-15 showed a higher role in promoting angiogenesis at high concentrations (4 mg/mL) on the chorioallantoic membrane model. This finding displayed that DG-15 had dual functions of neuroprotection and angiogenesis, which provided further insight into designing agent for the application in treatment of ischemic stroke.

Keywords: CAM model; angiogenesis; diosgenin-amino acids derivatives; neuroprotection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of the diosgenin-amino acids derivatives DG-1 to 18. Reagents and Conditions: (a) EDCI, DMAP, DCM, 12 h; (b) TFA, DCM, ice bath, 1 h (Boc protecting group); Pd(OH)2/C, H2, MeOH, r.t. 12 h (Cbz protecting group).
Figure 1
Figure 1
Cytotoxicity of diosgenin derivatives on H9c2 for 24 h. Data were expressed as cell viability based on three independent experiments (n = 3).
Figure 2
Figure 2
Giemsa staining on SH-SY5Y cells treated with compound DG-15 with different concentrations: (a) Control group; (b) TBHP treated cells; (c) 10 μM; (d) 20 μM; (e) 40 μM. The cell morphology was observed under the fluorescence microscope. The most representative fields were shown. Calibration bar: 200 μm.
Figure 3
Figure 3
DAP staining on SH-SY5Y cells treated with compound DG-15 with different concentrations: (a) Control group; (b) TBHP treated cells; (c) 10 μM; (d) 20 μM; (e) 40 μM. The cell morphology was observed under the fluorescence microscope. The most representative fields were shown. Calibration bar: 200 μm.
Figure 4
Figure 4
Compound DG-15 promoted angiogenesis in the CAM model with different concentrations: (a) Control group; (b) 1 mg/mL; (c) 4 mg/mL.
Figure 5
Figure 5
Compound DG-15 increased the number of blood vessels with different concentrations: 1 mg/mL; 4 mg/mL and Control group.
See this image and copyright information in PMC

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