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Kinesin spindle protein (KSP) inhibitors are one of the most promising anticancer agents developed in recent years. Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium. Conjugation of 7-chloroquinazolin-4(3H)-one with the pyridine-2-ylmethylimine group and the organometallic moiety resulted in up to a 36-fold increased cytotoxicity with IC50 values in the micromolar and nanomolar range also toward drug-resistant cells. All studied conjugates increased the percentage of cells in the G2/M phase, simultaneously decreasing the number of cells in the G1/G0 phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action.

Kinesin-5 inhibitors offer cancer cell-targeted approach, thus securing reduced systemic toxicity compared to other antimitotic agents. By modifying the 1,4-dihydropyridine-based kinesin-5 inhibitor CPUYL064 with a ferrocenyl moiety (Fc), we designed and prepared a series of organometallic hybrids that show high antiproliferative activity, with the best compounds exhibiting up to 19-fold increased activity. This enhanced activity can be attributed to the presence of the ferrocenyl moiety. [ABSTRACT FROM AUTHOR]

Antimitotic agents are among the most important drugs used in anticancer therapy. Kinesin spindle protein (KSP) was proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its (S)-enantiomer. Conjugation of the organometallic moiety with ispinesib and its (S)-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC50 values in the nanomolar range. The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation. [ABSTRACT FROM AUTHOR]

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Children without asthma symptoms, and any antiasthma treatment during last year, including fall-winter season 2020, were defined as I patients without asthma symptoms i (Figure 1C). In the fall-winter 2020 season, asthma symptoms and/or antiasthma therapy were reported in 31(27.9%) children (Figure 1C). [Extracted from the article]

Background: Innate immunity response to local dysbiosis seems to be one of the most important immunologic backgrounds of chronic rhinosinusitis (CRS) and concomitant asthma. We aimed to assess clinical determinants of upper‐airway dysbiosis and its effect on nasal inflammatory profile and asthma risk in young children with CRS. Methods: We recruited one hundred and thirty‐three children, aged 4‐8 years with doctor‐diagnosed CRS with or without asthma. The following procedures were performed in all participants: face‐to‐face standardized Sinus and Nasal Quality of Life questionnaire, skin prick test, taste perception testing, nasopharynx swab, and sampling of the nasal mucosa. Upper‐airway dysbiosis was defined separately by asthma‐specific microbiome composition and reduced biodiversity. Multivariate methods were used to define the risk factors for asthma and upper‐airway dysbiosis and their specific inflammatory profile of nasal mucosa. Results: The asthma‐specific upper‐airway microbiome composition reflected by the decreased ratio of Patescibacteria/Actinobacteria independently of atopy increased the risk of asthma (OR:8.32; 95%CI: 2.93‐23.6). This asthma‐specific microbiome composition was associated with ≥ 7/week sweet consumption (OR:2.64; 95%C:1.11‐6.28), reduced biodiversity (OR:3.83; 95%CI:1.65‐8.87), the presence of Staphylococcus strains in the nasopharynx (OR:4.25; 95%CI:1.12‐16.1), and lower expression of beta‐defensin 2, IL‐5, and IL‐13 in the nasal mucosa. The reduced biodiversity was associated with frequent antibiotic use and with a higher nasal expression of IL‐17 and T1R3 (sweet taste receptor). In asthmatic children, reduced sweet taste perception was observed. Conclusions: Specific upper‐airway dysbiosis related to frequent sweet consumption, frequent antibiotic courses, and altered nasal immune function increases the risk of asthma in young children with CRS. [ABSTRACT FROM AUTHOR]

Two‐step functionalization of 4‐diphenylphosphino benzoic acid with biotin afforded 2‐(biotinyloxy)ethyl 4‐(diphenylphosphanyl)benzoate (LP), that was subsequently used to synthesize the Ru(II) arene complexes [RuCl2(η6‐p‐cymene)(LP)] (1), [Ru(C2O4)(η6‐p‐cymene)(LP)] (2) and [Ru(curc)(η6‐p‐cymene)(LP)]NO3 ([3]NO3), the latter incorporating curcumin (curcH) as an additional bioactive fragment. [Ru(curc)(η6‐p‐cymene)(PPh3)]NO3 ([4]NO3) was also prepared as a reference compound. Compounds 2 and [3]NO3 exhibited excellent stability in water/DMSO solution while being slowly activated in the cell culture medium over 72 hours. Together with LP, they were therefore assessed for their antiproliferative activity towards a panel of cancer cell lines, with different levels of biotin transporter expression. The apparent affinity of the compounds towards avidin varies, and their antiproliferative activity does not correlate with biotin transporter expression, although it is systematically enhanced when biotin‐free cell culture medium is used. [ABSTRACT FROM AUTHOR]

[M(arene)(HQ)Cl] complexes (M = Ru II /Os II /Rh III /Ir III ; HQ = 8-hydroxyquinoline) have shown promise as anticancer agents. To assess the effect of conjugating biotin (vitamin B7) to such compounds and improve their tumor-targeting ability through interaction with the sodium-dependent multivitamin transporter (SMVT), the chlorido co-ligand was exchanged with biotinylated 6-aminoindazole. The complexes were characterized by NMR spectroscopy and mass spectrometry, and purity was determined by elemental analysis. The compounds were shown to be stable in aqueous solution but reacted in particular with biologically relevant nitrogen-donor ligands. The biotinylated organometallics were shown to be able to interact with the high-affinity biotin-binding protein streptavidin using molecular modelling. High antiproliferative activity of the biotinylated Rh complex (IC 50 = 1.1-10 μM) and its chlorido precursor (IC 50 = 2.1-7.0 μM) was demonstrated in human HCT116, NCI-H460, COLO 205, SW620, A2780 and A2780cis cancer cells, which feature differing levels of SMVT expression. While there was no clear relationship between the anticancer activity in cells and SMVT expression, the complexes showed similar activity in cisplatin-sensitive and -resistant cells. The most potent was the biotinylated Rh derivative which displayed low toxicity toward zebrafish embryos with >75% survival up to day 4 and after treatment with up to 32 μM complex.

Kinesin-5 inhibitors offer cancer cell-targeted approach, thus securing reduced systemic toxicity compared to other antimitotic agents. By modifying the 1,4-dihydropyridine-based kinesin-5 inhibitor CPUYL064 with a ferrocenyl moiety (Fc), we designed and prepared a series of organometallic hybrids that show high antiproliferative activity, with the best compounds exhibiting up to 19-fold increased activity. This enhanced activity can be attributed to the presence of the ferrocenyl moiety.

With the aim to combine more than one biologically-active component in a single molecule, derivatives of ispinesib and its (S) analogue were prepared that featured ferrocenyl moieties or bulky organic substituents. Inspired by the strong kinesin spindle protein (KSP) inhibitory activity of ispinesib, the compounds were investigated for their antiproliferative activity. Among these compounds, several derivatives demonstrated significantly higher antiproliferative activity than ispinesib with nanomolar IC 50 values against cell lines. Further evaluation indicated that the antiproliferative activity is not directly correlated with their KSP inhibitory activity while docking suggested that several of the derivatives may bind in a manner similar to ispinesib. In order to investigate the mode of action further, cell cycle analysis and reactive oxygen species formation were investigated. The improved antiproliferative activity of the most active compounds may be assigned to synergic effects of various factors such as KSP inhibitory activity due to the ispinesib core and ability to generate ROS and induce mitotic arrest., (© 2023 Wiley-VCH GmbH.)

Antimitotic agents are among the most important drugs used in anticancer therapy. Kinesin spindle protein (KSP) was proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its ( S )-enantiomer. Conjugation of the organometallic moiety with ispinesib and its ( S )-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC 50 values in the nanomolar range. The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation.