Design and synthesis of P-selectin inhibitors targeting cancer growth and metastasis and microwave assisted radio-fluorodenitration and pharmacological studies of (4-[18F]-fluorophenyl)-triphenylphosphonium nitrate (18F-PTPP) as a cardiac positron emission tromography tracer
Graham B. Jones
George O'Doherty, Michael P. Pollastri, Zhaohui S. Zhou
Date of Award
Doctor of Philosophy
Department or Academic Unit
Collge of Science. Department of Chemistry and Chemical Biology.
metastasis, inhibitors, coronary artery disease
Chemistry | Organic Chemistry
Selectins are adhesion receptors that bind to the carbohydrate structure of sialyl Lewisx (sLex) and sialyl Lewisa (sLea) and are over-expressed on tumor cells. P-selectin is a member of the selectin family of cell adhesion molecules (CAM). Increased interaction between P-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) promotes cancer cell metastasis, and over expression of cell surface sialic acid, which is associated with tumor progression and metastatic spread. Sialyl molecules on the surface of tumor cells interact with platelets, leukocytes and endothelium through the selectins. Sialic acids are conjugated to the carbohydrate moieties of Sialyl Lewisx (sLex ) on PSGL-1 and are important in cellular functions. Sialyl molecules on the surface of on carcinoma cells interact with platelets, leukocytes and endothelium through the selectin of CAM. Therefore, a small molecule inhibitor could inhibit the interaction of P-selectin mediated platelet binding of tumor cells during the early stages of the metastatic process.
Our strategy was to design novel, therapeutically effective sLex mimetic selectin inhibitors on the basis of structure-based and calculated physicochemical properties approach. Non-carbohydrate inhibitors have shown better properties over sugar-based inhibitors with respect to absorption, distribution, metabolism and excretion (ADME). A structure-based approach has been used to replace the sugar moiety of sLex with fused tricyclic, heterocycles or constrained bicyclic molecules which could block the formation of cover, enabling tumor cell interaction with platelets. Molecular modeling was used to define a diverse collection of non-carbohydrate small and constrained mimics as central scaffolds in the design of new sLex analogues. Synthetic protocols for the efficient introduction of C-8 substituents were developed and used to synthesize a set of C-8 substituted pyrazoloquinolinone analogues. In addition, different substituted azepine and diazepine derivatives were generated. Novel, potentially effective inhibitors of P-selectin were prepared utilizing structure-based design and these may be useful as anti-cancer agents.
Coronary artery disease (CAD) results in reduced blood flow to the heart due to the rupture of an atherosclerotic plaque. Therefore, quantitative myocardial blood flow measurements are needed. A non-invasive imaging technique such as positron emission tomography (PET) is a useful method for quantitation of myocardial blood flow under various physiological conditions. Fluorine-18 has the best imaging characteristics with low positron energy and a half-life of 110 min. Fluorine-18 is useful for complex synthesis and affords a longer time for in vivo analysis. To develop a fluorine-18 labeled PET radiotracer for cardiac imaging, a fluorinated compound (4-[18F]-fluorophenyl)triphenylphosphonium nitrate) (18F-PTPP) was synthesized. The compound was designed such that the fluorine atom is conveniently introduced in a short period of time to allow a one-step radiosynthesis with fluorine-18. The microwave-assisted, one step radio-fluorodenitration of 18F-PTPP via nucleophilic aromatic substitution was used.
The time needed for synthesis, purification and formulation of 18F-PTPP was 53 min with an average radiochemical yield 93%. Tissue distribution studies in Sprague-Dawley (SD) rats showed that heart has moderate uptake relative to liver and the uptake ratio between these tissues was found to be 3.3:1. This novel PET imaging modality could be a useful imaging technique that may benefit patients with coronary artery disease.
Molecular modeling methods were used to design pyrazoloquinolinone, azepine and diazepine analogs that may be useful as anti cancer agents. A fast efficient method for the microwave-assisted, one step radiosynthesis of 18F compounds was developed, which could be useful diagnostic technique that may in the future be beneficial for cardiology patients.
Afroze, Roushan, "Design and synthesis of P-selectin inhibitors targeting cancer growth and metastasis and microwave assisted radio-fluorodenitration and pharmacological studies of (4-[18F]-fluorophenyl)-triphenylphosphonium nitrate (18F-PTPP) as a cardiac positron emission tromography tracer" (2012). Chemistry Dissertations. Paper 45. http://hdl.handle.net/2047/d20002718
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