scholarly journals Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions

2018 ◽  
Vol 19 (7) ◽  
pp. 2050 ◽  
Author(s):  
Salvatore Savino ◽  
Cristina Marzano ◽  
Valentina Gandin ◽  
James Hoeschele ◽  
Giovanni Natile ◽  
...  
Keyword(s):  
Lipoic Acid ◽  
Pyruvate Dehydrogenase ◽  
Human Cancer ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Human Cancer Cell Lines ◽  
Target Dna ◽  
Leaving Groups ◽  
New Compounds

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.

scholarly journals Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4104-4113 ◽  
Author(s):  
Britta M. Stenson ◽  
Mikael Rydén ◽  
Knut R. Steffensen ◽  
Kerstin Wåhlén ◽  
Amanda T. Pettersson ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Tissue Mass ◽  
Metabolic Complications ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
White Adipocytes ◽  
X Receptors

Abstract Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

scholarly journals Synthesis of Novel Benzamide- piperazine-sulfonamide Hybrids as Potential Anticancer Agents

2019 ◽  
Vol 92 (3) ◽  
pp. 393-402
Author(s):  
B. Ramalingeswara Rao ◽  
Mohana Rao Katiki ◽  
Dileep Kommula ◽  
SaiShyam Narayanan ◽  
Ruby John Anto ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Human Cancer ◽  
In Vitro Cytotoxicity ◽  
Sensitive Cell Line ◽  
Human Cancer Cell Lines ◽  
Ic50 Values ◽  
Different Origins ◽  
New Compounds ◽  
A549 Lung

The synthesis of a series of substituted hippuric acid (2-benzamidoacetic acid) derivatives containing arylsulfonylpiperazine nucleus (3a–j, 4a–j) is described. The compounds were synthesized by coupling hippuric/4-fluorohippuric acid with various arylsulfonylpiperazines using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI). The structures of all the new compounds were confirmed by IR, NMR and MS spectral data. All the synthesized compounds have been evaluated for their in vitro cytotoxicity towards five human cancer cell lines of different origins viz. HeLa (Cervical), A549 (Lung), A375 (Skin), MD-AMB-231(Breast) and T98G (brain) and their IC50 values were determined. Among the compounds tested, 3b, 3d, 3g, 4c and 4e displayed significant cytotoxic activity (IC50 = 24.2–38.2 µM). T98G was the most sensitive cell line towards the compounds studied followed by HeLa, A375, A549 and MD-AMB-231.

scholarly journals Asp295 Stabilizes the Active-Site Loop Structure of Pyruvate Dehydrogenase, Facilitating Phosphorylation of Ser292 by Pyruvate Dehydrogenase-Kinase

2011 ◽  
Vol 2011 ◽  
pp. 1-13
Author(s):  
Tripty A. Hirani ◽  
Alejandro Tovar-Méndez ◽  
Ján A. Miernyk ◽  
Douglas D. Randall
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Loop Structure ◽  
Hybrid Analysis ◽  
Mutant Proteins ◽  
Variable Substrate ◽  
Two Hybrid

We have developed an in vitro system for detailed analysis of reversible phosphorylation of the plant mitochondrial pyruvate dehydrogenase complex, comprising recombinant Arabidopsis thaliana α2β2-heterotetrameric pyruvate dehydrogenase (E1) plus A. thaliana E1-kinase (AtPDK). Upon addition of MgATP, Ser292, which is located within the active-site loop structure of E1α, is phosphorylated. In addition to Ser292, Asp295 and Gly297 are highly conserved in the E1α active-site loop sequences. Mutation of Asp295 to Ala, Asn, or Leu greatly reduced phosphorylation of Ser292, while mutation of Gly297 had relatively little effect. Quantitative two-hybrid analysis was used to show that mutation of Asp295 did not substantially affect binding of AtPDK to E1α. When using pyruvate as a variable substrate, the Asp295 mutant proteins had modest changes in kcat, Km, and kcat/Km values. Therefore, we propose that Asp295 plays an important role in stabilizing the active-site loop structure, facilitating transfer of the γ-phosphate from ATP to the Ser residue at regulatory site one of E1α.

scholarly journals Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 712 ◽  
Author(s):  
Choong-Hwan Kwak ◽  
Jung-Hee Lee ◽  
Eun-Yeong Kim ◽  
Chang Woo Han ◽  
Keuk-Jun Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pyruvate Dehydrogenase ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
In Vitro Assays ◽  
In Vivo Models

Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.

scholarly journals Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 737
Author(s):  
Elwira Chrobak ◽  
Maria Jastrzębska ◽  
Ewa Bębenek ◽  
Monika Kadela-Tomanek ◽  
Krzysztof Marciniec ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Cell Lines ◽  
Human Cancer ◽  
Amelanotic Melanoma ◽  
Human Cancer Cell Lines ◽  
Ic50 Values ◽  
C 32 ◽  
New Compounds ◽  
Derivatives Of

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 μM, and, for 7b, they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.

Synthesis of Diaryl Pyrrolones Derivatives as Combretastatin A-4

2013 ◽  
Vol 652-654 ◽  
pp. 689-692 ◽  
Author(s):  
Li Wei ◽  
Guo Yuan Lu
Keyword(s):  
Double Bond ◽  
Antitumor Activity ◽  
Natural Product ◽  
13C Nmr ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
New Compounds ◽  
Cis Isomer

Combretastatins-A4 (CA-4) is a natural product with anticancer activity. However, only the cis-isomer exhibits strong antitubulin activity, but the cis-isomer tends to isomerize to the inactive trans-isomer. Thus, this paper reports that an additional pyrrolidone ring was used to replace the cis double bond to arrest the cis-conformation, and a series of 3,4-diaryl pyrrolediones and 3,4-diaryl pyrrolones as CA-4 analogues were synthesized via a four steps reaction from 3,4-dimethoxyacetophenone and 3-fluoro-4-methoxy acetophenone. The structure of the new compounds was confirmed by 1H NMR, 13C NMR, ESI-MS and elemental analysis. The in vitro activities of CA-4 analogues against HL-60, SMMC-7721 and A549 human cancer cell lines were tested using colorimetric MTT assay and the results indicate that they show significant antitumor activity.

scholarly journals Five New Cucurbitane-Type Triterpenoid Glycosides from the Rhizomes of Hemsleya penxianensis with Cytotoxic Activities

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2937
Author(s):  
De-Li Chen ◽  
Xu-Dong Xu ◽  
Rong-Tao Li ◽  
Bo-Wen Wang ◽  
Meng Yu ◽  
...  
Keyword(s):  
Human Cancer ◽  
Normal Liver ◽  
2D Nmr ◽  
Cytotoxic Activities ◽  
Human Cancer Cell Lines ◽  
Ic50 Value ◽  
Low Cytotoxicity ◽  
Triterpenoid Glycosides ◽  
New Compounds

Five new cucurbitane-typetriterpenoid glycosides, named Xuedanoside F–J (1–5), were obtained from the rhizomes of Hemsleya penxianensis (Xue dan), which belongs to the family of Cucurbitaceae. These new compounds were elucidated byspectroscopic analysis, including 1D, 2D NMR, and HR-ESI-MS spectra. Additionally, all the isolates were evaluated for cytotoxicity against three human cancer cell lines (Hela, MCF-7, and A-549) with the IC50 ranging from 2.25 to 49.44 µM in vitro with treatment 48 h and showed low cytotoxicity in human normal liver L-02 cells (IC50 > 50 µM). Compound 5 showed the most significant cytotoxic activity with the IC50 value of 2.25, 4.72, and 5.33 µM in 48 h, respectively.

scholarly journals Chromone-Derived Polyketides from the Deep-Sea Fungus Diaporthe phaseolorum FS431

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 182 ◽  
Author(s):  
Heng Guo ◽  
Zhao-Ming Liu ◽  
Yu-Chan Chen ◽  
Hai-Bo Tan ◽  
Sai-Ni Li ◽  
...  
Keyword(s):  
Deep Sea ◽  
Human Cancer ◽  
Electron Capture Detection ◽  
Cytotoxic Activities ◽  
Ionization Mass ◽  
Chemical Transformations ◽  
Human Cancer Cell Lines ◽  
Diaporthe Phaseolorum ◽  
New Compounds

Five new chromone-derived polyketides phaseolorins A-F (1–5), together with nine known compounds, were isolated from the deep-sea derived fungus Diaporthe phaseolorum FS431. The structures of new compounds were determined by analysis of their NMR and high-resolution electrospray ionization mass spectroscopy (HRESIMS) spectroscopic data. The absolute configurations were confirmed by chemical transformations, extensively experimental electron capture detection (ECD) calculations, or X-ray crystallography. Among them, compound 2 represented the first example for a new family of chromone derivative possessing an unprecedented recombined five-member γ-lactone ring. Moreover, the new compounds (1–5) were evaluated for in vitro cytotoxic activities against a panel of human cancer cell lines.

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