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

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.

Scavenging neurotoxic aldehydes using lysine carbon dots

“…After washing with PBS, a Giemsa (Sigma) stock solution was diluted 1 : 10 in PBS and added to the fixed cells for 20 minutes in the dark. 29 Finally, cells were washed with water, dried, and imaged on a Leica DMI4000 B inverted microscope in bright field. In each field of view, the number of dark rounded cells per unit area (μm 2 ) was quantified.…”

Diosgenin: an important natural pharmaceutical active ingredient

“…In addition, the compound diosgenyl salicylate conjugates, obtained by the pyridine-catalyzed esterification of diosgenin with 2-acetoxybenzoyl chloride, showed the highest anti-inflammatory activity. (Cai et al, 2019) improved the solubility and physicochemical properties of diosgenin by introducing different amino acids at the C-3 position of diosgenin, due to the neuroprotective effect of amino acids, and a series of amino acid derivatives of diosgenin were synthesized, which were tested to show that most of the derivatives were better than the raw material, with 3β-(L-isoleucine)-diosgenin having neuro dual role of neuroprotection and angiogenesis. The synthetic pathway is shown in Figure 3.…”

“…Another study by (Wang et al, 2015b) summarized the current conformational relationships between diosgenin and its derivatives, obtaining the corresponding activities of different derivatives of this substance, different derivatives as intermediates of active ingredients of different drugs or final forms of activity presentation. In addition, it was shown that the amino acid derivatives of diosgenin have neurosynthetic and angiogenic effects, and their corresponding series of derivatives target enhanced neuroprotection compared to diosgenin, especially the compound DG-15, which has stronger activity and lower cytotoxicity than diosgenin, and is an important direction for the future development of drugs such as vascular activators (Cai et al, 2019). It has been studied that diosgenin-betulinic acid conjugates have the ability to enhance and/or alter the pharmacological properties of the substance's own components (Özdemir et al, 2020).…”

Neuroprotective Effect for Cerebral Ischemia by Natural Products: A Review

“…The neuroprotection of natural products has been discovered to modulate activities via multiple targets and signaling pathways with direct or indirect effects on enzymes, such as kinases, receptors and proteins ( Bagli et al, 2016 ). This wide band of pharmacological or biological activities has made them suitable candidates for the treatment of stroke ( Cai et al, 2019 ; Zhang, C. et al, 2020 ; Zhong et al, 2020 ). As a requirement of novel drug development for stroke, there is a focus on the neuroprotection of natural products via multi-targets.…”