Current Drug Discovery Approaches using
Molecular Diversity and Chemical Biology
Sung-Chan Lee, Sung Kon Ko, Hwan Jong Jang, Heeseon An, and Seung Bum Park*
Department of Chemistry, Seoul National University, Seoul, 151-747 Korea
Diversity-oriented synthesis (DOS), which aims to
populate the chemical space with skeletally and
stereochemically diverse small molecules with high
appending potentials, has been proven to be an
essential tool for the discovery of bioactive small
molecules. The incorporation of privileged
substructural motifs has become an essential
element in DOS pathways. A multistep, practical
solid-phase strategy for the synthesis of natural
product-like diaza-bridged heterocycles was
developed. A key step in the library synthesis is
tandem acidolytic cleavage with subsequent in situ
iminium formation followed by the Pictet-Spengler
intramolecular cyclization. The Key steps were
regioselective and diastereoselective to give Afinal
products as single diastereomers in exceptional
yields and purities, which was confirmed by NMR O
structural study and LC/MS analysis. This
R
approach is exemplified by the preparation of a 2 O
384-member library fused with indole and R
dihydroxybenzene and diversified at two bridging N
nitrogen atoms, using the solid-phase parallel
R
synthetic methodology without further purification. O
1
sbpark@snu.ac.kr
In addition, our group reported the construction of
22 discrete, novel core skeletons embedded with a
privileged benzopyran substructure through a
branching DOS strategy. In that paper, we
emphasized the maximization of skeletal diversity
in 3-D space and we confirmed the importance of
core skeletons by showing dramatic differences in
the biological activities of compounds sharing the
same appendices but having different 3-D
structures. After the successful demonstration of
skeletal diversity with the privileged benzopyran
substructure, we turned our attention to the
importance of charge distribution.To emphasize the
importance of diverse charge distributions in DOS
O
pathways, we designed and synthesized
R
benzopyran-embedded
small molecules merged
O
1
with diverse
heterocycles
different
O
N having
O
orientations
of
polar
charge;
and
these
compounds
OH
R
R
O
O
could have quite
different 4biological
functions due
3
R
to diversity in polar Rsurface charge
distributions,
O
R
N
which
might
become
a
new
diversity
element for
R R
N
N
N N
N
N
DOS.
R
4
2
R
I
B I
II
5
6
3
R
O
II
O
O
III
IV
III
IV
Scheme 1.
1.
2.
3.
4.
Park, J.; Lee, H.Y.; Cho, M.-H.; Park, S. B.* Angew. Chem. Int. Ed. 2007, 46, 2018-2022.
Ko, S. K.; Jang, H. J.; Kim, E.; Park, S.B.* Chem. Commun. 2006, 28, 2962-2964.
Lee, S. -C.; Park, S. B.* Chem. Commun. 2007, 3714-3716.
Lee, S. -C.; Park, S. B.* J. Comb. Chem. 2007, 9, 828-835.
Seung Bum Park
朴 勝范, b 1970 in Seoul Korea.
Yonsei Univ. (B.S 1993), Yonsei Univ. (M.S. 1997)
Texas A&M Univ. (Ph.D 2001, Prof. R. F. Standaert)
Postdoc. Harvard Univ. (Prof. S. L. Schreiber, 2001-2004)
Assistant Professor at Seoul National Univ. (2004-present)
Research filed: Chemical Biology, Diversity-oriented Synthesis, Combinatorial
Chemistry, Bioorganic/Organic Chemistry, Medicinal Chemistry, High Throughput
Screening, NanoBioTechnology