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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: 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.

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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The structures of Danshensu, l-cysteine and their conjugated derivatives (1–3). (A) Danshensu; (B) l-Cysteine; (C) N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC); (D) (2R,2'R)-diastereoisomer of DSC; (E) (2S,2'R)-diastereoisomer of DSC.
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ijms-16-00628-f001: The structures of Danshensu, l-cysteine and their conjugated derivatives (1–3). (A) Danshensu; (B) l-Cysteine; (C) N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC); (D) (2R,2'R)-diastereoisomer of DSC; (E) (2S,2'R)-diastereoisomer of DSC.

Mentions: Salvia miltiorrhiza Bunge (Danshen in Chinese) or S. miltiorrhiza, a perennial herbal plant of the Labiatae family, is widely used for the treatment of coronary heart disease and other cardiovascular disorders, blood circulation diseases, and menstrual disorders in Eastern countries for hundreds of years [8,9]. Danshensu ((R)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid, Figure 1A), a hydrophilic bioactive component of Danshen, attracts considerable interest due to its salubrious biological activities, such as coronary artery dilatation, microcirculation improvement, myocardial protection and anti-platelet aggregation [6,10]. However, the chemical instability of phenolic hydroxyl groups of danshensu results in poor cellular permeability, bioavailability, lipophilicity and low pharmacological potency, which limits its further therapeutic development for clinical use [11]. Many synthetic Danshensu compounds with modified groups have emerged, laying the foundation of exploring and improving the biological activity of Danshensu.


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)

The structures of Danshensu, l-cysteine and their conjugated derivatives (1–3). (A) Danshensu; (B) l-Cysteine; (C) N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC); (D) (2R,2'R)-diastereoisomer of DSC; (E) (2S,2'R)-diastereoisomer of DSC.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00628-f001: The structures of Danshensu, l-cysteine and their conjugated derivatives (1–3). (A) Danshensu; (B) l-Cysteine; (C) N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC); (D) (2R,2'R)-diastereoisomer of DSC; (E) (2S,2'R)-diastereoisomer of DSC.
Mentions: Salvia miltiorrhiza Bunge (Danshen in Chinese) or S. miltiorrhiza, a perennial herbal plant of the Labiatae family, is widely used for the treatment of coronary heart disease and other cardiovascular disorders, blood circulation diseases, and menstrual disorders in Eastern countries for hundreds of years [8,9]. Danshensu ((R)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid, Figure 1A), a hydrophilic bioactive component of Danshen, attracts considerable interest due to its salubrious biological activities, such as coronary artery dilatation, microcirculation improvement, myocardial protection and anti-platelet aggregation [6,10]. However, the chemical instability of phenolic hydroxyl groups of danshensu results in poor cellular permeability, bioavailability, lipophilicity and low pharmacological potency, which limits its further therapeutic development for clinical use [11]. Many synthetic Danshensu compounds with modified groups have emerged, laying the foundation of exploring and improving the biological activity of Danshensu.

Bottom Line: 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.

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