A focus on the NF-kB signaling cascade
Identify
inhibitors of
NF-kB
activation
Inhibitors already
known...
arthritis, sceptic shock,
inflammatory bowel
disease
In collaboration with
Prof. Ron Hay FRS
Life Sciences
Dundee
Chemical library
in place
Robust HT screen
Hit Identification
chemical
tool
Chemical and
biological validation
Used to study
Potential
biological
therapeutic
processes
Bremner and Heinrich, 2002, J. Pharmacy and Pharmacol., 54, 453-46 72
A focus on the NF-kB signaling cascade
Identify
inhibitors of
NF-kB
activation
Natural Product collection from
Professor Alan Harvey, SIDR
University of Strathclyde
Chemical library
in place
Robust HT screen
Hit Identification
Chemical and
biological validation
NF-kB
Luc
Luciferase based
Reporter gene assay
Raquel Frade, Ron Hay
Nick Westwood
Used to study
Potential
biological
therapeutic
processes
A focus on the NF-kB signaling cascade
Identify
inhibitors of
NF-kB
activation
Natural Product collection from
Professor Alan Harvey, SIDR
University of Strathclyde
Chemical library
in place
Tanacetum parthenium
extract purification
Raquel Frade
Robust HT screen
Hit Identification
Chemical and
biological validation
Luciferase based
reporter gene assay
Raquel Frade, Prof Ron Hay FRS
Nick Westwood
structure assignment
Dr Tomas Lebl
Used to study
Potential
biological
therapeutic
processes
A sesquiterpene lactone?
?
solvent
?
H
H
H
O
O
H
Assignment of the structure of the major component
in the purified bioactive extract
(1H)
(13C)
1
-
-
204.9
2
2.68
2.17
45.4
3
4.62 (4.65)
-
71.8 (72.0)
4
-
-
175.6
5
-
-
138.0
6
4.94
-
77.2
7
3.11
-
43.4
8
1.91
1.77
28.4
9
2.46
-
40.8
10
-
-
209.0
11
-
-
140.9
12
-
-
171.4
13
6.18
5.67
122.1
14
2.06
-
30.5
15
2.12
-
14.4
MS : 279 [M + H]+
Tomas Lebl
Structurally related compounds
O
O
R
R1
O
O
R = b-OAc (S), R1 = H
R = a-OAc (R), R1 = H
R = b-OMe (S), R1 = H
R = a-OMe (R), R1 = H
R = b-OH (S), R1 = OH
R = a-OH (S), R1 = OH
R = b-OAc (S), R1 = OH
R = a-OAc(S), R1 = OH
Cl
O
O
O
O
HO
H
Me
O
O
O
O
R = b-OH (S), R1 = H
iso-secotanapartholide
From Artemisia rutifolia
no report of a-OH isomer
Zdero, Bohlmann et al., 1986, Phytochem., 25, 883-889; Jia et al., 1991, Phytochem., 30,
3033-3035; Oksuz, 1990, Phytochem., 29, 887-890; Toth et al., 2003, Tet., 59, 3729-3735.
Structurally related compounds
R = b-OAc (S), R1 = H
R = a-OAc (R), R1 = H
R = b-OMe (S), R1 = H
R = a-OMe (R), R1 = H
O
O
R
R1
Cl
O
O
O
O
HO
R = b-OH (S), R1 = OH
R = a-OH (S), R1 = OH
R = b-OAc (S), R1 = OH
R = a-OAc(S), R1 = OH
O
O
H
Me
O
O
O
O
R = b-OH (S), R1 = H
iso-secotanapartholide
HO
HO
O
O
O
OH
H
H
H
O
O
O
HO
O
O
O
O
O
O
secotanapartholides
Knight et al., 1996, J.Chem.Soc., Perkin Trans. 1, 1979-1986 and references therein.
A focus on the NF-kB signaling cascade
Identify
inhibitors of
NF-kB
activation
Synthesis of authentic material
to clarify stereochemistry issues at C3
Chemical library
in place
Robust HT screen
Hit Identification
14
10
2
HO
O
O
1
9
3
8
4
5
6
7
15
11
O
13
Chemical and
biological validation
Used to study
Potential
biological
therapeutic
processes
12
O
Edward Makiyi, Susan Cobb
Proposed biosynthesis of the secotanapartholides
OH
OH
O
O
O
O
HO
H
H
O
O
O
O
O
O
and b-isomer
and b-isomer
OH
O
O
H
O
O
Bohlmann and Zdero, 1982, Phytochem., 21, 2543-2549; Knight et al., 1996, J.Chem.Soc.,
Perkin Trans. 1, 1979-1986; Rucker et al., 1992, Planta Med., 58, 293.
Proposed biosynthesis of secotanapartholide
OH
O
H
O
O
O
HO
[BF3.OEt2]
H
O
O
O
O
Bohlmann and Zdero, 1982, Phytochem., 21, 2543-2549; Knight et al., 1996, J.Chem.Soc.,
Perkin Trans. 1, 1979-1986; Rucker et al., 1992, Planta Med., 58, 293.
A biomimetic approach to iso-secotanapartholides?
OH
O
O
O
H
O
O
Artabsin
Geissman and Winters, 1968, Tet. Lett., 27, 3145-3147.
A biomimetic approach to iso-secotanapartholides?
(1H)
1
-
-
2
2.32, 2.69
2.32, 2.65
3
4.30
4.32
4
-
-
5
-
-
6
4.98
4.94
7
3.06
3.15
8
1.88, 1.96
1.87, 1.96
9
2.54, 2.61
2.52, 2.58
10
-
-
11
-
-
12
-
-
13
5.67, 6.35
5.66, 6.35
14
2.15
2.15
15
2.15
2.13
OMe
3.41
3.41
O
H
O
MeO
OH
O
O
O
MeO
O
O
O
H
O
O
Ji et al., 1991, Phytochem., 30, 583-587.
An alternative semi-synthesis approach
late stage oxidative cleavage
with no protecting groups
Synthesis of diastereomeric diols
H
OAc
OH
O
conc. H2SO4 O
H
O
cat. OsO4, NMO
97%
H
O
O
O-acetylisophotosantonic lactone
Prof. Alex Slawin
O
THF, H2O
87%
OH
O
H
O
O
3:1 inseparable mixture
Buchi et al., 1966,J. Am. Chem. Soc.,
88, 3403-3408.
... and then diastereomeric triols
Prof. Alex Slawin
... and then diastereomeric triols
Synthesis of 3b-OH-iso-secotanapartholide
Greico et al., 1974, J.Org.Chem., 39, 119-120
Synthesis of epi-3a-iso-secotanapartholide
.. and then for the comparison with the natural material
Thanks to Professors Todorova, Marco, Lee, Ryu and Saliba
Does anyone have any seco-tanapartholide?
A comparison of iso-secotanapartholides
with our isolated natural material
500MHz, CD3CN
synthetic
epi-3a-OH
3b-OH
Natural
source
A focus on the NF-kB signaling cascade
Identify key
biological
process
Chemical library
in place
and 3b-isomer
Robust HT screen
Hit Identification
Chemical and
biological validation
NF-kB
Luc
Used to study
Potential
biological
therapeutic
processes