Current Programs in Medicinal/Biological Chemistry 1. Nitric oxide mimetic drug discovery • Alzheimer’s and neurodegenerative disorders • Colon cancer chemoprevention 2. Selective estrogen receptor modulators • chemical toxicology & cancer promotion/prevention • postmenopausal antidepressants (inc. botanical) NIH/NCI CA 102590 NIH/NCCAM AT002299 NIH/NIA AG027425
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Current Programs in Medicinal/Biological Chemistry 1.Nitric oxide mimetic drug discovery Alzheimer’s and neurodegenerative disorders Colon cancer chemoprevention.
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Current Programs in Medicinal/Biological Chemistry
1. Nitric oxide mimetic drug discovery• Alzheimer’s and neurodegenerative disorders
• Colon cancer chemoprevention
2. Selective estrogen receptor modulators• chemical toxicology & cancer promotion/prevention
• postmenopausal antidepressants (inc. botanical)
NIH/NCI CA 102590NIH/NCCAM AT002299
NIH/NIA AG027425Institute for Study of Aging-Elan Pharmaceuticals
A Brief Presentation of Research from the Thatcher Group
Better Living Through ChemistryBetter Living Through Chemistry
Biological activity mimics NO: bioactivation to NO in vivo?
►NO biology: Nobel Prize 1998 Medicine: “NO sex; NO wonder; NO way”NO signaling ubiquitous (diffusible free radical gas binds to Fe-heme)Endogenous NO: from Arg +NO synthase (NOS)
nNOS: neurotransmission, learning & memoryNO is essential for normal physiological function in the CNS, including learning & memory, & is compromised in disease states including neurodegenerative disorders
RONO2 + 3e- + 3H+ NO
Better Living Through ChemistryBetter Living Through Chemistry
GT 1061 in Phase 1 clinical trials for Alzheimer’s (FDA approved IND)GT 1061 in Phase 1 clinical trials for Alzheimer’s (FDA approved IND)
NO is essential for normal physiological function in the CNS, including learning & memory, & is compromised in disease states including neurodegenerative disorders
Better Living Through ChemistryBetter Living Through Chemistry
2. Selective estrogen receptor modulators-tissue specific estrogen agonist effect: bone and lipids
-tissue specific antiestrogen effect: mammary and uterine -Anti-osteoporosis; hormone replacement therapy (HRT); chemopreventive; -anticancer; antiinflammatory
-endometrial cancer; breast cancer; thrombosis + strokeRisk: long-term use in healthy (menopausal) women
► SERMs are polyaromatic phenols: oxidative metabolism by oxidase/peroxidase
Are oxidative metabolites responsible for toxicity or therapeutic activity?
Can new SERMs be designed to improve efficacy and safety profile?
Common Themes & VisionCommon Themes & Vision1. Nitric oxide mimetic drug discovery
2. Selective estrogen receptor modulators
• both families are reactive molecules; metabolism is important for activity and potentially toxicity; these are good drugs clinically proven over decades or a century
• NO signaling and biological redox systems are intrinsic to the actions of both families
Aims► Molecules hitting multiple targets; diseases are multifactorial► Moderate potency, multiple mechanisms, high safety► Translational research: bench-to-bedside
Tools of the Trade Tools of the Trade
1. Synthetic organic chemistry: drug candidates; model compounds; reactive intermediates; novel biological probes Examples
3. Cell biology and proteomics: Perturbation of cell growth and protein/gene biomarkers; ROS and NOx production; LC-MS-MS Examples
4. Animal models- cancer*, cardio** and cerebrovascular**: murine tissue pathology; immunohistochemistry; ex vivo function Examples
5. Animal models- behavior: antidepressant; cognition enhancement; anxiolytic; spatial working and reference memory; transgenics** Examples
* extradepartmental collaborations at UIC** extramural collaborations
Br
OH
OH
i. HNO3, H2SO4, DCM
ii. Na2S2O3, CH3OH
iii. H2O2, H2SO4ONO2
ONO2
S S
ONO2
ONO2
GT 015
i, ii, iii
SH
CO2H
1. EtOH, PTSA,
2. Allyl bromide,3. AgNO3, I2, CH3CN
ONO2
ONO2
EtO2C
S
ONO2
EtO2C
S
O2NO
SH
CO2Et
Toluene, reflux
K2CO3, Acetone
S
CO2Et
+
GT 947
GT 794
1 2 3
SH
CO2H
1. LiAlH4, THF 2. HNO3, (CH3CO)2OS S
ONO2
ONO2
GT 4294
SH
OH
H3CO SH+
Br
BrO
KOH
EtOH-AcOEtH3CO S
O
Br
PPA
SH3COBr
SH3COBr
Brbromoacetamide
DCM-EtOH
H2O2
DCM-TFA SH3COBr
BrOH O
N
NaH, DMF
SH3COBr
O
O
N
O
O
SH3COBr
O
O
N
PPh3, TMSCl1) HCl
2) BBr3
SHOBr
O
O
N
5M NaOCH3, AcOEtCuI, DMF-MeOH, 120oC
SHOOMe
O
O
N
SHOSO2Me
O
O
N
CuI, proline, NaOHCH3SO2Na, DMSO
120oC
1Return
2Return
HPLC Chromatogram of raloxifene (0.05 mM), rat liver microsomes (1.0 nmol P450/mL), GSH (0.5 mM), and a NADPH generating system in 50 mM phosphate buffer ( 37 °C , 30 min). For control incubations, either GSH or NADP+ was omitted.
SOH
HO
O(H2C)5N(H2C)2OPh
SOH
O
O(H2C)5N(H2C)2OPh
O
SO
O
O(H2C)5N(H2C)2OPh
SOH
HO
O(H2C)5N(H2C)2OPh
Raloxifene
HO
OH
TyrP450 P450
TyrP450
MAJORMINOR
GSHnucleoside
conjugatesadducts
GSHnucleoside
conjugatesadducts
R1R
2
R3
TS1 TS2TS3
R
a
P
a
RbPb/R2
TSaTSb
R1 TS1 R2 TS2 TS3 R310
15
20
25
30
G
(kcal/
mo
l)
Ra TSa Pa R2 TSb Rb0
5
10
15
20
25
G
(kcal/
mo
l)
3Return
1.25 1.35 1.45 1.55 1.65 1.75 1.85 1.95 2.050
25
50
75
100
log ([GT094], uM)
rel.
in
cres
e in
cel
ln
um
ber
as
%
Fig 9. Concentration response of cell number with GT094 in Caco-2 cell (48hr) assayed by sulforhodamine B dye staining: EC50 = 40 μM.