Synthesis and relationship of stability and biological activity of new DSS and TMP conjugates

Sun, Ying; Tan, Zicheng; Li, Zhibin; Wang, Liang; Shan, Luchen; Yu, Pei; Lee, Simon Ming‐Yuen; Wang, Yuqiang

doi:10.1039/c4md00448e

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…In our previous study, ADTM, aconjugate of DSS and TMP, was synthesized, which is more potent than its parental compounds in protecting against t-BHP-induced H9c2 cells injury in vitro [9]. Furthermore, we have found that the stability and activities of ADTM may improve after increasing bulky groups between DSS and TMP [24]. Based on these findings, DT-010 was synthesized by substitution with two allyl groups at the linkage position between DSS and TMP.…”

Section: Discussionmentioning

confidence: 99%

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

et al. 2016

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The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

et al. 2016

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“…As the results demonstrate, analysis of the pharmacokinetic parameters of DSS after iv administration of ADTM indicated longer half-life but lower drug exposure in the plasma (129.421 ± 15.203 min•mg/L). In our opinion, there are several probable reasons for this finding: Previous studies have indicated that the Chinese medicine combination consisting of SRR and CR significantly affects both the in vivo efficacy, as well as component distribution and excretion [25]. However, there were no significant differences in the pharmacokinetic parameters of TMP-OH when used alone or in combination with DSS.…”

Section: Discussionmentioning

confidence: 79%

Concurrent Determination of Danshensu and Hydroxyl Ligustrazine in Rat Plasma Using High-Performance Liquid Chromatography and its Application to the Pharmacokinetic Study of ADTM, DSS and TMP-OH Following Intravenous Administration

Li¹,

Sheng

Zhang³

et al. 2019

BJSTR

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R)- (3,5,6-trimethylpyrazinyl) methyl-2-acetoxy-3- (3,4-diacetoxyphenyl) propanoate (named as ADTM), a novel Danshensu (DSS)/ Tetramethylpyrazine (TMP) derivative, exerts cardio-protective and anti-thrombolytic effects both in vitro and in vivo. However, ADTM is metabolized into (R)-3,4-Dihydroxyphenyllactic acid (DSS) and (3,5,6-Trimethylpyrazin-2-yl) methanol (TMP-OH) too rapidly to describe its pharmacokinetic behavior accurately. In this study, a rapid, sensitive, and simple high-performance liquid chromatography-ultraviolet detection method was developed and validated for concurrent DSS and TMP-OH determination, to quantify and evaluate ADTM pharmacokinetic behavior and compare the differences therein between three administration modes: a) Single intravenous (iv) ADTM administration; b) Combined sodium DSS and TMP-OH iv administration; c) Single sodium DSS or TMP-OH iv administration for the same dosage. The assay was validated according to the Food and Drug Administration guidelines and found to be suitable for the determination of plasma levels of therapeutic drugs. This method was successfully applied to DSS and TMP-OH pharmacokinetic studies after iv administration of ADTM, DSS, and TMP-OH in rats. Pharmacokinetic parameters showed significant differences in DSS but not TMP-OH between the three groups. These preclinical data will be useful for the design of subsequent trials of DSS derivatives.

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“…Although some compounds displayed higher cardioprotective effects than ADTM in cultured cells, their protective effects were not as good as that of ADTM in a rat model of acute myocardial ischemia (data not shown). 19) Recently, we have reported several novel conjugates incorporating DSS, TMP and hydrogen sulfide donors. 20) Some of these compounds displayed higher activities in preventing cells from oxidative insult, unfortunately, all of them have poor water solubility.…”

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Synthesis and Biological Evaluation of Danshensu and Tetramethylpyrazine Conjugates as Cardioprotective Agents

Wang¹,

Zhang²,

Xu³

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Myocardial ischemia is a primary cause of sudden death worldwide. Numerous active ingredients of traditional Chinese medicines including danshensu (DSS) and tetramethylpyrazine (TMP) have been widely used for the treatment of myocardial ischemia. To enhance their therapeutic efficacy and improve their drugability, in this work, we designed new DSS and TMP conjugates. Their water solubility and protective effects were studied in vitro and in experimental animal models. The new compounds demonstrated higher activities than the positive control agents acetylated danshensu and tetramethylpyrazine conjugate (ADTM) and salvianolic acid B (SAB) in preventing cells from oxidative insult. Among the new compounds, 14, bearing two glycine moieties, was more water soluble. In addition, compound 14 was much more potent in preventing cells from oxidative injury, at least 10-and 20-fold as potent as ADTM and SAB, respectively. The protective effects of compound 14 may be attributed to its anti-radical activity and anti-apoptotic activity. These results suggest that compound 14 is a promising candidate for the treatment of myocardial ischemia.Key words danshensu; tetramethylpyrazine; synthesis; water solubility; myocardial ischemia Myocardial ischemia is a primary cause of sudden death worldwide. Myocardial ischemia results from a decreased blood flow to the heart, preventing the heart from receiving adequate supply of oxygen. The reduced blood flow is usually the result of a partial or complete blockade of the arteries. Traditional treatments focus on restoring blood supply, such as by pass-graft surgery, dilation of coronary artery and coronary thrombolysis, and etc.

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Synthesis and relationship of stability and biological activity of new DSS and TMP conjugates

Abstract: A series of novel conjugates of danshensu (DSS) and tetramethylpyrazine (TMP) were designed and synthesized.

Cited by 4 publications

References 16 publications

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

Concurrent Determination of Danshensu and Hydroxyl Ligustrazine in Rat Plasma Using High-Performance Liquid Chromatography and its Application to the Pharmacokinetic Study of ADTM, DSS and TMP-OH Following Intravenous Administration

Synthesis and Biological Evaluation of Danshensu and Tetramethylpyrazine Conjugates as Cardioprotective Agents

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