Limits...
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.

Show MeSH

Related in: MedlinePlus

The synthesis of target diastereoisomers 2 and 3.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4307265&req=5

ijms-16-00628-f002: The synthesis of target diastereoisomers 2 and 3.

Mentions: As outlined in Figure 2, the designed conjugates were synthesized efficiently using 3,4-dihydroxybenzaldehyde (4) as the starting material. The key intermediate 7 and l-cysteine derivatives 15 were synthesized according to the reported procedures [12,13]. The condensation of 4 with N-acetylglycine followed by hydrolysis in hydrochloric acid and protection of the hydroxyl groups in acetic anhydride afforded 7 in 33% total yield. Esterization of 7 with benzyl bromide in the presence of K2CO3 in acetone provided the thoroughly protected compound 8 in 90% yield. The asymmetric hydrogenation of 8 using 9/10 as the chiral ligand and [Rh(cod)2]BF4 as the catalyst precursor gave excellent enantioselectivities (>97% enantiomeric excess) and good yields (>89%) of compounds 11/12 respectively under the modified conditions of the literature procedures [14]. The deprotection of 11/12 by hydrogenolysis under the catalysis of 10% Pd-C in methanol attained (R)/(S)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoic acid (13/14) in >95% yields, which were then subjected to the condensation with S-benzyl-l-cysteine methyl ester (15) in the presence of 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and diisopropylethylamine (DIPEA) in CH2Cl2, affording the target amide conjugates 2/3 in 79% and 81% yields respectively.


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 synthesis of target diastereoisomers 2 and 3.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00628-f002: The synthesis of target diastereoisomers 2 and 3.
Mentions: As outlined in Figure 2, the designed conjugates were synthesized efficiently using 3,4-dihydroxybenzaldehyde (4) as the starting material. The key intermediate 7 and l-cysteine derivatives 15 were synthesized according to the reported procedures [12,13]. The condensation of 4 with N-acetylglycine followed by hydrolysis in hydrochloric acid and protection of the hydroxyl groups in acetic anhydride afforded 7 in 33% total yield. Esterization of 7 with benzyl bromide in the presence of K2CO3 in acetone provided the thoroughly protected compound 8 in 90% yield. The asymmetric hydrogenation of 8 using 9/10 as the chiral ligand and [Rh(cod)2]BF4 as the catalyst precursor gave excellent enantioselectivities (>97% enantiomeric excess) and good yields (>89%) of compounds 11/12 respectively under the modified conditions of the literature procedures [14]. The deprotection of 11/12 by hydrogenolysis under the catalysis of 10% Pd-C in methanol attained (R)/(S)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoic acid (13/14) in >95% yields, which were then subjected to the condensation with S-benzyl-l-cysteine methyl ester (15) in the presence of 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and diisopropylethylamine (DIPEA) in CH2Cl2, affording the target amide conjugates 2/3 in 79% and 81% yields respectively.

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