2 research outputs found
G‑Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
Synthetic
lethality is a genetic concept in which cell death is
induced by the combination of mutations in two sensitive genes, while
mutation of either gene alone is not sufficient to affect cell survival.
Synthetic lethality can also be achieved “chemically”
by combination of drug-like molecules targeting distinct but cooperative
pathways. Previously, we reported that the small molecule pyridostatin
(PDS) stabilizes G-quadruplexes (G4s) in cells and elicits a DNA damage
response by causing the formation of DNA double strand breaks (DSB).
Cell death mediated by ligand-induced G4 stabilization can be potentiated
in cells deficient in DNA damage repair genes. Here, we demonstrate
that PDS acts synergistically both with NU7441, an inhibitor of the
DNA-PK kinase crucial for nonhomologous end joining repair of DNA
DSBs, and BRCA2-deficient cells that are genetically impaired in homologous
recombination-mediated DSB repair. G4 targeting ligands have potential
as cancer therapeutic agents, acting synergistically with inhibition
or mutation of the DNA damage repair machinery
A-Ring Dihalogenation Increases the Cellular Activity of Combretastatin-Templated Tetrazoles
The combretastatins have been investigated for their
antimitotic
and antivascular properties, and it is widely postulated that a 3,4,5-trimethoxyaryl
A-ring is essential to maintain potent activity. We have synthesized
new tetrazole analogues (<b>32</b>–<b>34</b>),
demonstrating that 3,5-dihalogenation can consistently increase potency
by up to 5-fold when compared to the equivalent trimethoxy compound
on human umbilical vein endothelial cells (HUVECs) and a range of
cancer cells. Moreover, this increased potency offsets that lost by
installing the tetrazole bridge into combretastatin A-4 (<b>1</b>), giving crystalline, soluble compounds that have low nanomolar
activity, arrest cells in G<sub>2</sub>/M phase, and retain microtubule
inhibitory activity. Molecular modeling has shown that optimized packing
within the binding site resulting in increased Coulombic interaction
may be responsible for this improved activity