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  • 1
    Online Resource
    Online Resource
    High Antiproliferative Activity of Hydroxythiopyridones over Hydroxypyridones and Their Organoruthenium Complexes
    MDPI AG ; 2021
    In:  Biomedicines Vol. 9, No. 2 ( 2021-01-27), p. 123-
    Details
    In: Biomedicines, MDPI AG, Vol. 9, No. 2 ( 2021-01-27), p. 123-
    Abstract: Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a–1c and 3-hydroxy-4-thiopyridones 1d–1f as well as their Ru(η6-p-cymene)Cl complexes 2a–2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d–1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low μM range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines9020123
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2720867-9
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  • 2
    Online Resource
    Online Resource
    Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 10 ( 2021-10-04), p. 1020-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 10 ( 2021-10-04), p. 1020-
    Abstract: Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14101020
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    Thiourea-Derived Chelating Ligands and Their Organometallic Compounds: Investigations into Their Anticancer Activity
    MDPI AG ; 2020
    In:  Molecules Vol. 25, No. 16 ( 2020-08-11), p. 3661-
    Details
    In: Molecules, MDPI AG, Vol. 25, No. 16 ( 2020-08-11), p. 3661-
    Abstract: Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [MII(cym)(L)Cl]X (cym = η6-p-cymene) or [MIII(Cp*)(L)Cl] X (Cp* = η5-pentamethylcyclopentadienyl), where X = Cl− or PF6−, and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules25163661
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2008644-1
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  • 4
    Online Resource
    Online Resource
    Impact of the Metal Center and Leaving Group on the Anticancer Activity of Organometallic Complexes of Pyridine-2-carbothioamide
    MDPI AG ; 2021
    In:  Molecules Vol. 26, No. 4 ( 2021-02-05), p. 833-
    Details
    In: Molecules, MDPI AG, Vol. 26, No. 4 ( 2021-02-05), p. 833-
    Abstract: RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the 1H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules26040833
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2008644-1
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  • 5
    Online Resource
    Online Resource
    Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 2 ( 2021-01-29), p. 103-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 2 ( 2021-01-29), p. 103-
    Abstract: Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14020103
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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