Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib - impact of the organometallic group on the antimitotic activity.

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.

Towards understanding antimicrobial activity, cytotoxicity and the mode of action of dichapetalins A and M using in silico and in vitro studies.

Dichapetalum madagascariense Poir (Dichapetalaceae) is traditionally used to treat bacterial infections, jaundice, urethritis and viral hepatitis in Africa. Its root contains a broad spectrum of biologically active dichapetalins. To evaluate the plant's effect on human MCF-7 cells and its' antibacterial and antiparasitic potentials, we isolated and identified the known dichapetalins A and M from the roots. Both dichapetalins were tested on six bacterial strains (Shigella flexneri, Bacillus cereus, Salmonella paratyphi B, Listeria monocytogenes, Escherichia coli, Staphylococcus aureus) and two parasite strains; Trypanosoma brucei brucei, and Leishmania donovani using the Alamar Blue assay system. Dichapetalins A and M were more potent against B. cereus with IC50 values of 11.15 and 3.15 µg/ml, respectively, compared to the positive control ampicillin (IC50 = 19.50 µg/ml). Dichapetalins A (IC50 = 74.22 µg/ml) and M (IC50 = 72.34 µg/ml) were less active against T. b. brucei, compared to the standard Suramin (IC50 = 4.96 µg/ml). Dichapetalin M showed moderate activity against L. donovani (Amphotericin B: IC50 = 0.21 µg/ml) with an IC50 of 16.80 µg/ml. In human MCF-7 cells expressing the NR1I2 receptor, the activity of dichapetalin M was higher (IC50 = 4.71 µM and 3.95 µM) for 48 and 72 h of treatment, respectively compared to Curcumin with IC50 of 17.49 µM and 12.53 µM for 48 and 72 h of treatment, respectively. Results from in vitro expression studies with qPCR confirmed an antagonistic effect of dichapetalin M on PXR (NR1I2) signaling; supporting the PXR signaling pathway as a possible mode of action of dichapetalin M as predicted by in silico results. These findings confirm previous studies that D. madagascariense can be a source of potential lead compounds for development of novel antibiotic, antiparasitic and anticancer medicines, and provide further insights into the mechanism of action of the dichapetalins.

From Catalysis to Cancer: Toward Structure-Activity Relationships for Benzimidazol-2-ylidene-Derived N-Heterocyclic-Carbene Complexes as Anticancer Agents.

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.