In recent years, small organic molecules
have
attracted a great deal of interests of
scientists
in new drug design targeting
biological
macro-molecules, such as
proteins, enzymes,
receptors and nucleic
acids (DNA and RNA).
The interactions of drug with DNA comprise
noncovalent binding and covalent bonding.
The former one is reversible but the later one
is irreversible. Most of the interactions between
drugs and DNA belong to reversible binding,
except for aristolochic acids in some toxic
herbs from Aristolochiaceae which damage
DNA
irreversibly.
Prof. Jiang’s studies revealed that some
anti-cancer
alkaloids, such as berberine and its
synthesized dimer, chelerythrine,
sanguinarine
and nitidine can specifically interact with DNA
through an intercalating mode. In order to
clarify their molecular mechanism of
anti-cancer
activities, Prof. Jiang employed a combination
of spectrometric and biomedical techniques,
including mass spectrometry, fluorometric
analysis, spectrophotomeric titration,
ethidium
displacement, DNA polymerase stop assay
etc., to intensively investigate the noncovalent
irreversible binding of these alkaloids to several
types of DNA, such as double-stranded,
bulged and G-quadruplex DNA. The studies
covered, for example, measurement of binding
constants to designed DNA with different
sequences and discussion of structure-activity
relationship of these alkaloids. In addition, a
series of dimeric berberines were synthesized,
which were found to be much stronger
DNA-binding
agents.
|
|
"Our data provided concrete evidence for the
most reasonable arrangement of
"Beads-on-a-String" structure of human telomeric DNA.
Furthermore, a novel model for the binding
of sanguinarine to "Beads-on-a-String" human
telomeric DNA was established for the first
time. This novel binding model supplied
important guidance for structure-based anti-cancer
drug design targeting human telomeric
DNA, "Professor Jiang addressed particularly
the results from the studies on the interaction
between sanguinarine and G-quadruplex
DNA which exists in telomere of human
chromosome. "The alkaloid berberine is the
main component of some common Chinese
herbs, such as Rhizoma Coptidis ("Huang-
Lian") and Cortex Phellodendri ("Huang-Bai"),
whereas, sanguinarine and nitidine are being
used as anti-microbial and
anti-inflammatory
agents in toothpaste and mouthwashes. The
strong DNA-binding activities of berberine,
sanguinarine and nitidine alert us to the
safety concern of daily-used hygiene products
containing these herbal alkaloids," Prof.
Jiang
commented from another angle on the
significance of their DNA-binding research.
Prof Jiang, Zhi-Hong
School of Chinese Medicine
Hong Kong Baptist University
zhjiang@hkbu.edu.hk
|