ORGANIC
LETTERS
2012
Vol. 14, No. 24
6126–6129
Convenient Method for the Synthesis of
a Flexible Cyclic Polyamide for Selective
Targeting of c‑myb G‑quadruplex DNA
Qiang Zhang, Xiaojie Cui, Sen Lin, Jiang Zhou, and Gu Yuan*
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department of
Chemical Biology, College of Chemistry and Molecular Engineering, Peking University,
Beijing 100871, China
Received August 27, 2012
ABSTRACT
A convenient efficient method for synthesis of a flexible cyclic polyamide (cβ, 1) was developed through cyclodimerization. Electrospray
ionization mass spectrometry and nuclear magnetic resonance results showed that 1 selectively binds to the c-myb G-quadruplex with high
affinity, and there was no binding with the ILPR, bcl-2, and c-kit G-quadruplexes. This is the first time that a flexible cyclic polyamide was found to
have high selectivity for the c-myb G-quadruplex.
Over the past few decades, G-quadruplexes involved
in telomeres and promoter regions were found to play
important roles in cell cycle, apoptosis, gene transcription,
and gene expression.1 The c-myb gene has critical influence
on the proliferation, differentiation and survival of hema-
topoietic stem cells.2 The expression of c-myb is normally
restricted to very low levels in normal cells, while it has
been shown to have high levels in some solid tumors and
leukemias.3 A GGA repeat was found in the promoter of
c-myb. NMR studies revealed that the G-quadruplex of
this region was formed by stacking two double-layer
G-quadruplexes in a tetrad:heptad:heptad:tetrad (T:H:H:T)
structure.4 Thus far, macrocyclic molecules such as tel-
omestatin, porphyrins, and their derivatives have been
reported as G-quadruplex ligands (structures shown in
Figure S1, Supporting Information).5 These rigid macro-
cyclic skeletons provide expanded planar surfaces that
interact with the terminal G-quartets by πꢀπ stacking
with high affinity. However, this kind of ligand does not
usually show high selectivity even though an expanded
porphyrin molecule was reported as a specific ligand to
bind to the single-loop hybrid G-quadruplex.6 The
remarkable cytotoxicity and side effects of these compounds
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10.1021/ol302918f
Published on Web 12/04/2012
2012 American Chemical Society