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Current
Bioactive Compounds
Current Bioactive Compounds
Volume 3, Number 3, September 2007
Contents
Review Articles
Inhibitors of Trypanosoma brucei 6-Phosphogluconate
Dehydrogenase Pp. 161-169
S. Hanau, K. Montin, I.H. Gilbert, M.P. Barrett and F.
Dallocchio
[Abstract]
Study on the Molecular Structure and Bio-Activity
(DNA Polymerase Inhibitory Activity, Anti-Inflammatory Activity
and Anti Oxidant Activity) Relationship of Curcumin Derivatives
Pp. 171-177
Yoshiyuki Mizushina, Toshifumi Takeuchi, Kouji Kuramochi,
Susumu Kobayashi, Fumio Sugawara, Kengo Sakaguchi and Hiromi
Yoshida
[Abstract]
Polyamine Analogues and Derivatives as Potential Anticancer
Agents Pp. 179-191
Lynda Ralton, Charles S. Bestwick and Paul Kong Thoo Lin
[Abstract]
Bone Modulating Bioactive Natural Compounds: Review
Pp. 193-200
Kanji Mori, Dominique Heymann and Ronan Le Bot
[Abstract]
Recent Advances in Methodologies for the Discovery
of Antimycobacterial Drugs Pp. 201-208
Todd P. Primm and Scott G. Franzblau
[Abstract]
Bioactive Compounds
Anti-Cancer/Anti-Tumor Pp. 209-218
Anti-Viral Pp. 219
Anti-Inflammatory Pp. 220-221
Anti-Microbial Pp. 222-224
Anti-Bacterial Pp. 225-226
Anti-Oxidant Pp. 227
Central Nervous System Related Pp. 228-229
Anti-HIV Pp. 230-231
Enzyme Inhibition Pp. 232-235
Other Activities Pp. 236-238
Abstracts
[Back to top]
Inhibitors of Trypanosoma brucei 6-Phosphogluconate
Dehydrogenase
S. Hanau, K. Montin, I.H. Gilbert, M.P. Barrett and F.
Dallocchio
6-Phosphogluconate dehydrogenase (6PGDH) is the third enzyme
of the pentose phosphate pathway. It converts 6-phosphogluconate
to ribulose 5-phosphate and concomitantly provides NADPH required
for many biosynthetic and detoxification reactions. Its presence
has been shown to be essential for growth of bloodstream form
Trypanosoma brucei, a parasite responsible for African
trypanosomiasis and it may be considered a validated drug
target in this protozoan. The structure of the enzyme is known
from X-ray crystallographic studies. There appears to be relatively
little difference between the active sites of the trypanosomal
and human enzymes, although pharmacological analysis shows
that selective inhibition of an extensive nature is possible.
Work has been carried out on the design of several classes
of inhibitors for the T. brucei enzyme that are selective
over the same enzyme from mammalian liver. One class comprises
sugar derivatives, which mimic the substrate of the catalysed
reaction. A second class of more potent inhibitors mimic the
transition-state and high-energy intermediates of the enzymatic
reaction of 6PGDH. 4-Phospho-D-erythronohydroxamate with a
Ki = 10 nM is the compound
with the highest affinity for the T. brucei 6PGDH
reported to date, and the selectivity of 254-fold over the
sheep enzyme is also the highest found. A third class of inhibitors
are triphenylmethane derivatives, examples of which also show
very pronounced anti-trypanosomal activity.
[Back to top]
Study on the Molecular Structure and Bio-Activity
(DNA Polymerase Inhibitory Activity, Anti-Inflammatory Activity
and Anti Oxidant Activity) Relationship of Curcumin Derivatives
Yoshiyuki Mizushina, Toshifumi Takeuchi, Kouji Kuramochi,
Susumu Kobayashi, Fumio Sugawara, Kengo Sakaguchi and Hiromi
Yoshida
We found that phenolic compounds, petasiphenol and curcumin
(diferuloylmethane), were selective inhibitors of DNA polymerase
λ (pol
λ)
in vitro. In this review, we described the molecular
structure and bio-activity (i.e., pol inhibitory activity,
anti-inflammatory activity and anti-oxidant activity) relationship
of phenolic compounds such as petasiphenol, curcumin and 13
chemically synthesized derivatives of curcumin. The inhibitory
effect on pol λ
(full-length, i.e. intact pol λ
including the BRCA1 C-terminus (BRCT) domain) by some derivatives
was stronger than that by curcumin, and monoacetylcurcumin
(compound (13)) was the strongest pol λ
inhibitor of all the compounds tested, achieving 50% inhibition
at a concentration of 3.9 μM.
Compound (13) did not inhibit the activity
of the C-terminal catalytic domain of pol λ
including the pol β-like
core, in which the proline-rich region and BRCT domain were
deleted from its N-terminal region. These curcumin derivatives
had anti-12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
inflammatory activity with the same tendency as pol λ
inhibitory activity, but compound (13) had
no anti-oxidant activity (i.e., DPPH radical-scavenging activity).
This compound did not influence the activities of replicative
pols such as α,
δ and
ε,
and had no effect on repair-related pol activity such as pol
β,
although the three-dimensional structure of pol β
is thought to be highly similar to that of pol λ.
Based on these results, the pol λ-inhibitory
mechanism of compound (13) and the structure-activity
relationship of anti-inflammation are discussed.
[Back to top]
Polyamine Analogues and Derivatives as Potential Anticancer
Agents
Lynda Ralton, Charles S. Bestwick and Paul Kong Thoo Lin
Polyamines exert an essential role in cell proliferation and
development. The cellular concentration of these small organic
molecules is tightly regulated and their cellular uptake actively
modulated via the polyamine transporters (PAT). The apparent
critical influence of polyamines on cell development and survival
and their recognition by the PAT have both led to polyamines
being increasingly considered for the development of a range
of chemotherapeutic agents. In this review, we discuss how
polyamine chains attached to cytotoxic molecules have been
used to aid their transport into tumour cells. Furthermore,
the ability of polyamine analogues and derivatives to modulate
polyamine biosynthesis and apoptosis induction is assessed.
Specifically, novel intercalating naphthalimido compounds
bearing an amino or polyamine chains are highlighted.
[Back to top]
Bone Modulating Bioactive Natural Compounds: Review
Kanji Mori, Dominique Heymann and Ronan Le Bot
Up to date, it has been reported that several bioactive natural
compounds can modulate bone metabolism. It has been also disclosed
that some of them simultaneously modulate the immune response.
Thus, understanding the molecular mechanisms surrounding bone
metabolism has moved bone research into a new era and recently
the term “osteoimmunology” is coined to describe
new interdisciplinary field of bone and immunology. Now, therefore
bone research is one of the hot spots designing novel drugs.
Notably, the role of phytoestrogens represented by isoflavones
in the bone health was frequently reviewed; however only a
few reviews thoroughly cover the field of bioactive natural
compounds in bone metabolism.
In this review, we summarize current status of representative
bioactive natural compounds that modulate bone metabolism
and present new therapeutic approaches in the near future
by focusing on three classes of compounds phytoestrogens,
polyunsaturated fatty acids and lactoferrin.
[Back to top]
Recent Advances in Methodologies for the Discovery
of Antimycobacterial Drugs
Todd P. Primm and Scott G. Franzblau
Mycobacteria, especially M. tuberculosis, have remained
a worldwide dominant cause for human morbidity (~10 million
annual cases) and mortality (3 million deaths annually) since
ancient times. An estimated one-third of living humans are
latently infected with M. tuberculosis. Despite this,
there have been no new drugs specifically developed against
mycobacteria since the 1960s. Because of a slow growth rate,
biosafety concerns, and other issues, drug discovery by in
vitro screening of natural and synthetic compounds has
been limited in the past. However, a number of new techniques
and technologies for whole cell antimycobacterial screening
have been developed recently. This review examines and compares
these methods, discusses common issues in screening with mycobacteria,
and considers potential future developments in the field. |
