3 research outputs found
Molecular Basis of Structure–Activity Relationships between Salphen Metal Complexes and Human Telomeric DNA Quadruplexes
The first X-ray crystal structures of nickelÂ(II) and
copperÂ(II)
salphen metal complexes bound to a quadruplex DNA are presented. Two
structures have been determined and show that these salphen–metal
complexes bind to human telomeric quadruplexes by end-stacking, with
the metal in each case almost in line with the potassium ion channel.
Quadruplex and duplex DNA binding is presented for these two and other
related salphen complexes, all with side-chains terminating in pyrrolidino
end-groups and differing patterns of substitution on the salphen core.
The crystal structures are able to provide rationalizations for the
structure–activity data, and in particular for the superior
quadruplex-binding of the nickel complexes compared to that of the
copper-containing ones. The complexes show significant antiproliferative
activity for the compounds in a panel of cancer cell lines. They also
show telomerase inhibitory activity in the telomerase TRAP-LIG assay
Structure-Based Design and Evaluation of Naphthalene Diimide G‑Quadruplex Ligands As Telomere Targeting Agents in Pancreatic Cancer Cells
Tetra-substituted
naphthalene diimide (ND) derivatives with positively
charged termini are potent stabilizers of human telomeric and gene
promoter DNA quadruplexes and inhibit the growth of human cancer cells
in vitro and in vivo. The present study reports the enhancement of
the pharmacological properties of earlier ND compounds using structure-based
design. Crystal structures of three complexes with human telomeric
intramolecular quadruplexes demonstrate that two of the four strongly
basic <i>N</i>-methyl-piperazine groups can be replaced
by less basic morpholine groups with no loss of intermolecular interactions
in the grooves of the quadruplex. The new compounds retain high affinity
to human telomeric quadruplex DNA but are 10-fold more potent against
the MIA PaCa-2 pancreatic cancer cell line, with IC<sub>50</sub> values
of ∼10 nM. The lead compound induces cellular senescence but
does not inhibit telomerase activity at the nanomolar dosage levels
required for inhibition of cellular proliferation. Gene array qPCR
analysis of MIA PaCa-2 cells treated with the lead compound revealed
significant dose-dependent modulation of a distinct subset of genes,
including strong induction of DNA damage responsive genes CDKN1A,
DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere
maintenance, including hPOT1 and PARP1
Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets
Psammaplin A (<b>11c</b>) is a marine metabolite
previously
reported to be a potent inhibitor of two classes of epigenetic enzymes:
histone deacetylases and DNA methyltransferases. The design and synthesis
of a focused library based on the psammaplin A core has been carried
out to probe the molecular features of this molecule responsible for
its activity. By direct in vitro assay of the free thiol generated
upon reduction of the dimeric psammaplin scaffold, we have unambiguously
demonstrated that <b>11c</b> functions as a natural prodrug,
with the reduced form being highly potent against HDAC1 in vitro (IC<sub>50</sub> 0.9 nM). Furthermore, we have shown it to have high isoform
selectivity, being 360-fold selective for HDAC1 over HDAC6 and more
than 1000-fold less potent against HDAC7 and HDAC8. SAR around our
focused library revealed a number of features, most notably the oxime
functionality to be important to this selectivity. Many of the compounds
show significant cytotoxicity in A549, MCF7, and W138 cells, with
the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore,
compound treatment causes upregulation of histone acetylation but
little effect on tubulin acetylation. Finally, we have found no evidence
for <b>11c</b> functioning as a DNMT inhibitor