The G protein-coupled estrogen receptor (GPER, GPR30) represents a promising target for the treatment of estrogen receptor α and β negative breast cancers. Previously reported agonists of GPER have shown that activation of GPER inhibits breast cancer cell proliferation. We report herein a new GPER agonist scaffold based upon in silico pharmacophore screening. Three of these compounds were found to increase cAMP at similar levels as the known GPER-selective agonist G-1. Compound was found to be selective for GPER (over estrogen receptor α and β) and inhibit breast cancer cell proliferation at levels consistent with G-1. Docking studies go on to suggest that both 5 and G-1 bind within the same binding pocket in GPER and point to possible key residues that are important in GPER activation.
Photodeoxygenation of dibenzothiophene S-oxide and its derivatives have been used to generate atomic oxygen [O( 3 P)] to examine its effect on proteins, nucleic acids, and lipids. The unique reactivity and selectivity of O( 3 P) have shown distinct oxidation products and outcomes in biomolecules and cell-based studies. To understand the scope of its global impact on the cell, we treated MDA-MB-231 cells with 2,8-diacetoxymethyldibenzothiophene S-oxide and UV-A light to produce O( 3 P) without targeting a specific cell organelle. Cellular responses to O( 3 P)-release were analyzed using cell viability and cell cycle phase determination assays. Cell death was observed when cells were treated with higher concentrations of sulfoxides and UV-A light. However, significant differences in cell cycle phases due to UV-A irradiation of the sulfoxide were not observed. We further performed RNA-Seq analysis to study the underlying biological processes at play, and while UVirradiation itself influenced gene expression, there were 9 upregulated and 8 downregulated genes that could be attributed to photodeoxygenation.
Opportunistic fungal
infections caused by Cryptococcus
neoformans are a significant source of mortality in
immunocompromised patients. They are challenging to treat because
of a limited number of antifungal drugs, and novel and more effective
anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic
agent for the treatment of topical fungal infections for more than
two decades. It is a fungicide, with broad activity across multiple
fungal species. We synthesized 10 N-hydroxypyridone
derivatives to develop an initial structure–activity understanding
relative to efficacy as a starting point for the development of systemic
antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight
of the ten show inhibition at 1–3 μM concentration (0.17–0.42
μg per mL) in both Cryptococcus species and in C. albicans, but poor
activity in the Malassezia species.
In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either
fluconazole or amphotericin B, and are synergistic with multiple inhibitors
of the mitochondrial electron transport chain. They appear to function
primarily by chelating iron within the active site of iron-dependent
enzymes. This preliminary structure–activity relationship points
to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and
six as sites where further substitution may be tolerated. These molecules
provide a clear starting point for future optimization for efficacy
and target identification.
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