A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

Parker, J.; Nimir, Hassan; Griffith, Darren M.; Duff, B.G.; Chubb, Anthony J.; Brennan, Marian; Morgan, Maria P.; Egan, Denise A.; Marmion, Celine J.

doi:10.1016/j.jinorgbio.2013.03.011

Cited by 27 publications

(13 citation statements)

References 26 publications

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“…Similar levels of enzyme inhibition have previously been reported for these two compounds against different human HDAC isoforms (HDAC1, 2, 3, 4, 6, 7, 8 and 9) ( Khan et al., 2008 ). However, unlike this study where similar P. falciparum growth inhibition was obtained ( Table 1 ), in proliferation inhibition studies with mammalian cells, belinostat has been shown to be up to 11-fold more active than vorinostat ( Khan et al., 2008; Andrews et al., 2012a; Sumanadasa et al., 2012; Parker et al., 2013 ). While it is tempting to try to correlate the nuclear extract deacetylase inhibition data with the P. falciparum growth inhibition data generated in this study, differences in compound uptake, access to cellular targets following uptake, drug stability, and variations in off-target effects will impact activity and make these direct comparisons difficult.…”

Section: Discussioncontrasting

confidence: 44%

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Engel

Jones

Avery

et al. 2015

International Journal for Parasitology: Drugs and Drug Resistan

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Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat®), romidepsin (Istodax®) and belinostat (Beleodaq®), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10–200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4.

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Section: Discussioncontrasting

confidence: 44%

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Engel

Jones

Avery

et al. 2015

International Journal for Parasitology: Drugs and Drug Resistan

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“…Marmion and coworkers developed platinum(II) complexes with HDAC inhibitory ligands. They reported enhanced selectivity for cisplatin complexes of functionalized suberoylanilide hydroxamic acid [29,30] and belinostat [31] and enhanced cytotoxicity of transplatin complexes of valproate compared to cisplatin [32]. Brabec and coworkers studied platinum(IV) prodrugs of oxaliplatin with axial valproate ligands [33].…”

Section: Introductionmentioning

confidence: 99%

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Almotairy

Gandin

Morrison

et al. 2017

Journal of Inorganic Biochemistry

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Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by H andPt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH)(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH)(PBA)] (2), cis,trans-[Pt(CBDCA)(NH)(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH)(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH))(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells.

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“…Successful applications such as development of Bcl-2xL agents [80], topoisomerase I and II inhibitors [123], COX-2/5-LOX dual inhibitors [124], Rac1 agents [125], inhibitors of Hsp90 [126], inhibitors of Tip 60 [127], mTOR [128], histone deacetylase inhibitors [129], hTERT inhibitors [130,131] and CDK [29] agents highlight the importance of this virtual docking technique ( Table 2). These, like many other targets involved in cellular events such as cell growth, differentiation and proliferation, could serve as potential targets for drug discovery directed towards various types of cancer.…”

Section: Virtual Screening and Virtual Docking Methodsmentioning

confidence: 99%

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

Vucicevic

Nikolić

Mitchell

2019

CMC

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Background: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Results: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. Conclusion: In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

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A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

Cited by 27 publications

References 26 publications

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

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