Synthesis, cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Mostoufi, Azar; Baghgoli, Raheleh; Fereidoonnezhad, Masood

doi:10.1016/j.compbiolchem.2019.03.008

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…CA4 is a very potent cytotoxic agent with low nM IC 50 values in all the cancer cell lines and is about 1000-fold more potent than cisplatin. In contrast, the second axial ligands (Val, Oct, and PhB) are not cytotoxic on their own and have IC 50 values in the mM range against various cancer cell lines, 14,26,28,30 and the IC 50 values for DCA were reported as >100 μM. 27,31,32 All the Pt(IV)-CA4 conjugates also exhibited low nM cytotoxicity (<10 nM) in all cancer cell lines with the exception of HT-29, where IC 50 values varied between 101 and 1100 nM (Table 2).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

et al. 2021

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: "Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC 50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH 3 ) 2 (PhB)(CA4)Cl 2 ] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

et al. 2021

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“…375 Å spacing. Binding interactions between docked ligand and the enzyme were analyzed using the Autodock tools program (ADT, Version 1.5.6) [46,47] . The best binding mode was selected based on the lowest binding energy conformation.…”

Section: Methodsmentioning

confidence: 99%

Novel Hydrazone Derivatives of 3‐Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies

Beygi

Mostoufi

Mojaddami

2022

Chemistry & Biodiversity

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A series of 3‐bromopyruvate (3‐BP) derivatives were synthesized to develop new potent anticancer agents. The chemical structures of the compounds were characterized using FT‐IR, 1H‐, 13C‐NMR spectroscopy, and elemental analysis (CHN). Their cytotoxic activities were investigated against four cancer cell lines, including colon (SW1116), breast (MDA‐MB‐231), lung (A549), and liver (HepG2) cancer cell lines. Among the synthesized compounds, 3b showed promising cytotoxic activity compared to 3‐BP, with IC50 values of 16.3 μM, 19.1 μM, 27.8 μM, and 14.5 μM against A549, MDA‐MB‐231, SW1116 and, HepG2 cell lines, respectively. Furthermore, the effect of these compounds on MCF‐10A (a normal breast cell lines) was investigated to determine their selectivity between tumorigenic and non‐tumorigenic cells. Since the 3‐BP inhibits hexokinase II (HK II), molecular docking of 3‐BP derivatives was carried out using AutoDock 4.2. The binding energies of these derivatives were greater than 3‐BP, indicating that they had a higher affinity for HK II. For validation of docking, a 40 ns MD simulation was performed. SwissADME was used to predict pharmacokinetics, drug‐likeness, and ADME parameters of the screened compounds. The results demonstrated that these derivatives are suitable candidates for developing orally potent HK II inhibitors.

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“…The molecular docking of these compounds on histone deacetylase complex confirmed their high affinity to the zinc-ion in the active site of the enzyme. Further results suggested that B9 can effectively induce apoptosis in breast cancer cells in a dose-dependent manner (38).…”

Section: Butyric Propionic and Phenylbutyric Acidmentioning

confidence: 99%

“…Chemical structures of valproic acid (VPA) and other short-chain fatty acids (SCFAs). acid (BA) B15 according to Ref 38. …”

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confidence: 99%

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

2020

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Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant inhibition of cancer cell proliferation by modulating multiple signaling pathways. First of all, they act as histone deacetylase (HDAC) inhibitors (HDIs), being involved in the epigenetic regulation of gene expression. Afterward, VPA is shown to induce apoptosis and cell differentiation, as well as regulate Notch signaling. Moreover, it up-regulates the expression of certain G protein-coupled receptors (GPCRs), which are involved in various signaling pathways associated with cancer. As a consequence, some pre-clinical and clinical trials were carried out to estimate anticancer effectiveness of VPA, in monotherapy and in new drug combinations, while other SCFAs were tested in pre-clinical studies. The present manuscript summarizes the most important information from the literature about their potent anticancer activities to show some future perspectives related to epigenetic therapy.

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Synthesis, cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Cited by 6 publications

References 31 publications

Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

Novel Hydrazone Derivatives of 3‐Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

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