Presentation on theme: "Current Programs in Medicinal/Biological Chemistry 1.Nitric oxide mimetic drug discovery Alzheimer’s and neurodegenerative disorders Colon cancer chemoprevention."— Presentation transcript:
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 Institute for Study of Aging-Elan Pharmaceuticals A Brief Presentation of Research from the Thatcher Group
Better Living Through Chemistry 1.Nitric oxide mimetic drug discovery ►Clinical drugs: nitroglycerin (GTN); isosorbide dinitrate (ISDN); organic nitrates -angina (1874); CHF; cardioprotection (2005) 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) eNOS: smooth muscle relaxation, anti-atherogenic iNOS: immune response; antibacterial nNOS: neurotransmission, learning & memory NO is essential for normal physiological function in the CNS, including learning & memory, & is compromised in disease states including neurodegenerative disorders RONO 2 + 3e - + 3H + NO
Better Living Through Chemistry 1.Nitric oxide mimetic drug discovery ►Clinical drugs: nitroglycerin (GTN); isosorbide dinitrate (ISDN); organic nitrates -angina (1874); CHF; cardioprotection (2005) 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 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 + stroke Risk: 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 & Vision 1.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 1.Synthetic organic chemistry: drug candidates; model compounds; reactive intermediates; novel biological probes ExamplesExamples 2.Physical - Mechanistic organic chemistry: reaction mechanisms; kinetics; identification of reaction intermediates; computational methodsExamplesExamples 3.Cell biology and proteomics: Perturbation of cell growth and protein/gene biomarkers; ROS and NOx production; LC-MS-MS ExamplesExamples 4.Animal models- cancer*, cardio** and cerebrovascular**: murine tissue pathology; immunohistochemistry; ex vivo function Examples Examples 5.Animal models- behavior: antidepressant; cognition enhancement; anxiolytic; spatial working and reference memory; transgenics** Examples Examples *extradepartmental collaborations at UIC **extramural collaborations
2 Return 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. R1R1 R2R2 R3R3 TS 1 TS 2 TS 3 RaRa PaPa RbRb Pb/R 2 TS a TS b
3 Return Return Fig 9. Concentration response of cell number with GT094 in Caco-2 cell (48hr) assayed by sulforhodamine B dye staining: EC 50 = 40 μM. Time, h06121824 % G136 ± 0.717.0 ± 6.428.5 ± 6.939.1 ± 2.326.4 ± 7.0 % S48.8 ± 2.555.0 ± 4.638.1 ± 2.536.5 ± 17.361.0 ± 5.6 % G2-M14.9 ± 3.128.1 ± 1.833.5 ± 9.424.6 ± 15.112.7 ± 1.5 Figure 8. Cell cycle FACS analysis of propidium bromide treated Caco- 2 cells incubated with GT 094 (100 uM, 48 h). Cell cycle and proliferation Proteomic identification of modified proteins in rat liver
Colon Cancer Chemoprevention Aberrant Crypt Foci (ACF) correlate with progression to tumors in animal models 1.GT094 significantly reduces ACFs compared to no drug and ASA treatment. 2.GT 094 significantly reduces colon cell proliferation (p27 elevated) and tumor weight and multiplicity in a 30 week AOM study 4 Return Return
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