A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

Huang, Ding; Liu, Qingwang; Zhang, Maojie; Guo, Yizhen; Cui, Zhiying; Li, Tao; Luo, Dong; Xu, Biao; Huang, Chao; Guo, Jingjie; Tam, Kin Yip; Zhang, Min; Zhang, Shaolin; He, Yun

doi:10.1021/acs.jmedchem.2c00640

Cited by 13 publications

(3 citation statements)

References 40 publications

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“…Conversely, excessive ROS production causes oxidative damage to biomolecules and poses detrimental effects on the overall sperm quality (DNA integrity, membrane stability, energy production, motility, capacitation) [42][43][44]. In this study, the increase in the ATP levels was followed by an abnormal increase in ROS after the DCA or 4-PBA treatment similar to studies conducted on cancer cells [45][46][47]. Interestingly, Zhao et al [48] found that DCA can relieve oxidative stress through the PDK2-PDH-Nrf2 channel.…”

Section: Discussionsupporting

confidence: 73%

Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3

Guo,

Zhang,

Huang

et al. 2023

IJMS

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Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate dehydrogenase complex component X (PDHX) was demonstrated to be associated with sperm metabolism and affected the boar sperm viability, motility, and fertility. Pyruvate Dehydrogenase Kinases (PDKs) are the key metabolic enzymes that regulate pyruvate dehydrogenase complex (PDHC) activity and also the conversion from glycolysis to oxidative phosphorylation. In the present study, two PDK inhibitors, Dichloroacetate (DCA) and Phenylbutyrate (4-PBA), were added to an extender and investigated to determine their regulatory roles in liquid-stored boar sperm at 17 °C. The results indicated that PDK1 and PDK3 were predominantly located at the head and flagella of the boar sperm. The addition of 2 mM DCA and 0.5 mM 4-PBA significantly enhanced the sperm motility, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), and ATP content. In addition, DCA and 4-PBA exerted their effects by inhibiting PDK1 and PDK3, respectively. In conclusion, DCA and 4-PBA were found to regulate the boar sperm metabolic activities via PDK1 and PDK3. These both can improve the quality parameters of liquid-stored boar sperm, which will help to improve and optimize liquid-stored boar semen after their addition in the extender.

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Section: Discussionsupporting

confidence: 73%

Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3

Guo,

Zhang,

Huang

et al. 2023

IJMS

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“…Compound 1 was synthesized as described in the literature [49]. In brief, tris (15 g, 0.124 mol) and SOCl2 (39 mL, 0.519 mol) were placed in a 250 mL flask and stirred at 0 °C.…”

Section: The Synthetic Route Of Compoundmentioning

confidence: 99%

“…Compound 1 was synthesized as described in the literature [49]. In brief, tris (15 g, 0.124 mol) and SOCl 2 (39 mL, 0.519 mol) were placed in a 250 mL flask and stirred at 0 • C. After pyridine (5 mL, 0.062 mol) was added dropwise to the reaction solution, the reaction temperature was raised slowly to 100 °C.…”

Section: Synthesis Of Compound 9 311 the Synthetic Route Of Compoundmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Biotin-SN38-Valproic Acid Conjugates

Zhang

et al. 2023

Molecules

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Despite the strong anticancer activity of SN38 (7-ethyl-10-hydroxy-camptothecin), the severe side effects and loss of anticancer activity caused by the lack of selectivity to cancer cells and hydrolysis of ring E prevent its clinical application. To address the issue, herein a multifunctional SN38 derivative (compound 9) containing biotin (tumor-targeting group) and valproic acid (histone deacetylase inhibitor, HDACi) was synthesized via click chemistry and evaluated using MTT assay. The in vitro cytotoxicity study showed that compound 9 exhibited superior cytotoxicity than irinotecan against human cervical cancer HeLa cells, albeit it was inferior to SN38. More significantly, compound 9 significantly reduced toxicity in mouse embryonic fibroblast NIH3T3 cells, indicating that compound 9 had the capacity to enhance tumor targeting due to its cell selectivity. Further studies demonstrated that, compared with irinotecan, compound 9 induced similar apoptosis of cancer cells. Consequently, compound 9 can not only improve its tumor-targeting ability mediated by biotin but also exert potent anticancer activity through the effect of SN38 and valproic acid, indicating that the design concept is an effective strategy for the structural modification of SN38.

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Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode

Sun,

Xu,

Zhang

et al. 2024

Bioorganic Chemistry

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A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

Cited by 13 publications

References 40 publications

Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3

Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3

Synthesis and Antitumor Evaluation of Biotin-SN38-Valproic Acid Conjugates

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode

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