The overexpression of α-synuclein
(α-syn) and its aggregation
is the hallmark of Parkinson’s disease. The α-syn aggregation
results in the formation of Lewy bodies that causes neuronal cell
death. Therefore, the small molecules that can protect neuronal cells
from α-syn toxicity or inhibit the aggregation of α-syn
could emerge as anti-Parkinson agents. Herein, a library of methoxy-stilbenes
was screened for their ability to restore the cell growth from α-syn
toxicity, using a yeast strain that stably expresses two copies of
a chromosomally integrated human α-syn gene. Tetramethoxy-stilbene
4s
, a nonantioxidant, was the most capable of restoring cell
growth. It also rescues the more toxic cells that bear three copies
of wild-type or A53T-mutant α-syn, from cell growth block. Its
EC
50
values for growth restoration of the 2-copy wild-type
and the 3-copy mutant α-syn strains are 0.95 and 0.35 μM,
respectively. Stilbene
4s
mitigates mitochondrial membrane
potential loss, negates ROS production, and prevents nuclear DNA-fragmentation,
all hallmarks of apoptosis. However,
4s
does not rescue
cells from the death-inducing effects of Bax and βA4, which
suggest that
4s
specifically inhibits α-syn-mediated
toxicity in the yeast. Our results signify that simultaneous use of
multiple yeast-cell-based screens can facilitate revelation of compounds
that may have the potential for further investigation as anti-Parkinson’s
agents.
Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes. The most active human CYP1B1 inhibitors were further studied for their selectivity against human CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. The meta-chloro-substituted biphenyl urea 5h was the most potent inhibitor of CYP1B1 with IC value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC >10 μM in the four CYP assays, indicating >2000-fold selectivity). Similarly, two methoxy-substituted biphenyl ureas 5d and 5e also displayed potent and selective inhibition of CYP1B1 with IC values of 69 and 58 nM, respectively, showing >62 and >98-fold selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. In order to probe if the relatively insoluble biphenyl ureas were cell permeable and if they could at all be used for future cellular studies, their CYP1B1 inhibition was investigated in live recombinant human and yeast cells. Compound 5d displayed the most potent inhibition with ICs of 20 nM and 235 nM, respectively, in the two cell-based assays. The most potent and selective CYP1B1 inhibitor (compound 5h) from Sacchrosomes, also displayed potent inhibition in live cell assays. Molecular modeling was performed to understand the trends in potency and selectivity observed in the panel of five CYP isoenzymes used for the in vitro studies.
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