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Asymmetric synthesis and evaluation of danshensu-cysteine conjugates as novel potential anti-apoptotic drug candidates.

Pan LL, Wang J, Jia YL, Zheng HM, Wang Y, Zhu YZ - Int J Mol Sci (2014)

Bottom Line: We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent.Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities.Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. panlilong@fudan.edu.cn.

ABSTRACT
We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

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Effects of Danshensu-cysteine conjugates on H2O2-induced cellular injury in SH-SY5Y cells. SH-SY5Y cells were incubated with Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM) or N-acetyl-l-cysteine (NAC, 5 mM) for 4 h, then stimulated with H2O2 (200 μM) for 12 h, the cell viability (A) and lactate dehydrogenase (LDH) (B) release were measured, respectively. Data shown are means ± SEM, &p < 0.05 compared with unstimulated cells, * p < 0.05, ** p < 0.01 compared with H2O2-stimulated cells. Data were from at least three independent experiments, each performed in duplicate. Representative picture shows cell morphology (C) and nuclear morphology (D) detected by microscope or fluorescence microscope (magnification, 200×), respectively.
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ijms-16-00628-f003: Effects of Danshensu-cysteine conjugates on H2O2-induced cellular injury in SH-SY5Y cells. SH-SY5Y cells were incubated with Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM) or N-acetyl-l-cysteine (NAC, 5 mM) for 4 h, then stimulated with H2O2 (200 μM) for 12 h, the cell viability (A) and lactate dehydrogenase (LDH) (B) release were measured, respectively. Data shown are means ± SEM, &p < 0.05 compared with unstimulated cells, * p < 0.05, ** p < 0.01 compared with H2O2-stimulated cells. Data were from at least three independent experiments, each performed in duplicate. Representative picture shows cell morphology (C) and nuclear morphology (D) detected by microscope or fluorescence microscope (magnification, 200×), respectively.

Mentions: Consistent with our previous study [6], H2O2 (200 μM) stimulation for 12 h significantly decreased cell viability, accompanied by serious lactate dehydrogenase (LDH) release (Figure 3A,B). However, pretreatment with the three Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM), showed similar protective effects on H2O2-induced cell death and LDH release in SH-SY5Y cells. Meanwhile, we also checked the effects of these three compounds on H2O2-induced changes of cellular morphology and nuclear morphological changes. As shown in Figure 3C,D, pretreatment with the three derivatives (DSC, 2 and 3) (all at 50 μM) also showed similar protective effects on H2O2-induced cellular morphological changes and nuclear morphological changes. As a positive control, N-acetyl-l-cysteine (NAC, 5 mM) could markedly attenuate H2O2-mediated cellular events mentioned above. Collectively, DSC and its two diastereoisomers (2 and 3) showed similar protective effects in H2O2-induced cellular injury in SH-SY5Y cells.


Asymmetric synthesis and evaluation of danshensu-cysteine conjugates as novel potential anti-apoptotic drug candidates.

Pan LL, Wang J, Jia YL, Zheng HM, Wang Y, Zhu YZ - Int J Mol Sci (2014)

Effects of Danshensu-cysteine conjugates on H2O2-induced cellular injury in SH-SY5Y cells. SH-SY5Y cells were incubated with Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM) or N-acetyl-l-cysteine (NAC, 5 mM) for 4 h, then stimulated with H2O2 (200 μM) for 12 h, the cell viability (A) and lactate dehydrogenase (LDH) (B) release were measured, respectively. Data shown are means ± SEM, &p < 0.05 compared with unstimulated cells, * p < 0.05, ** p < 0.01 compared with H2O2-stimulated cells. Data were from at least three independent experiments, each performed in duplicate. Representative picture shows cell morphology (C) and nuclear morphology (D) detected by microscope or fluorescence microscope (magnification, 200×), respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307265&req=5

ijms-16-00628-f003: Effects of Danshensu-cysteine conjugates on H2O2-induced cellular injury in SH-SY5Y cells. SH-SY5Y cells were incubated with Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM) or N-acetyl-l-cysteine (NAC, 5 mM) for 4 h, then stimulated with H2O2 (200 μM) for 12 h, the cell viability (A) and lactate dehydrogenase (LDH) (B) release were measured, respectively. Data shown are means ± SEM, &p < 0.05 compared with unstimulated cells, * p < 0.05, ** p < 0.01 compared with H2O2-stimulated cells. Data were from at least three independent experiments, each performed in duplicate. Representative picture shows cell morphology (C) and nuclear morphology (D) detected by microscope or fluorescence microscope (magnification, 200×), respectively.
Mentions: Consistent with our previous study [6], H2O2 (200 μM) stimulation for 12 h significantly decreased cell viability, accompanied by serious lactate dehydrogenase (LDH) release (Figure 3A,B). However, pretreatment with the three Danshensu-cysteine conjugates (DSC, 2 and 3) (all at 50 μM), showed similar protective effects on H2O2-induced cell death and LDH release in SH-SY5Y cells. Meanwhile, we also checked the effects of these three compounds on H2O2-induced changes of cellular morphology and nuclear morphological changes. As shown in Figure 3C,D, pretreatment with the three derivatives (DSC, 2 and 3) (all at 50 μM) also showed similar protective effects on H2O2-induced cellular morphological changes and nuclear morphological changes. As a positive control, N-acetyl-l-cysteine (NAC, 5 mM) could markedly attenuate H2O2-mediated cellular events mentioned above. Collectively, DSC and its two diastereoisomers (2 and 3) showed similar protective effects in H2O2-induced cellular injury in SH-SY5Y cells.

Bottom Line: We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent.Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities.Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. panlilong@fudan.edu.cn.

ABSTRACT
We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.

Show MeSH
Related in: MedlinePlus