Synthesis of Thromboxane and Monofluorinated Analogues

• Applicant: Dr. Hannah Baars
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation ; Pharmacology
• Term: from 2016 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329283583

Prostanoids consisting of prostaglandins, prostacyclins, and thromboxane are a very important class of local hormone-like chemical messengers. The Aggarwal group recently reported a dramatically short synthesis of one prostaglandin (PGF2alpha). The route is based on an organocatalyzed cascade reaction in which an enal intermediate is formed which is perfect placed to access all of the other prostanoids very efficiently. Among them, especially thromboxane is an interesting target and will be addressed in this project. Thromboxane A2 plays a critical role in thrombosis and cardiovascular diseases. A first-line treatment for this diseases is aspirin (blocks TxA2 synthesis by targeting cyclooxygenase (COX) and therefore all prostanoids). Its use is associated with undesirable adverse effects and resistance is a common clinical problem. For these reasons, there is considerable interest in addressing the TxA2 pathway directly. One new approach is the development of humanised antibody-based drug targeting TxA2. Since TxA2 is very unstable, a monofluorinated analogue is proposed as an ideal candidate to raise antibodies against TxA2. The synthesis strategy of the monofluorinated TxA2 builds on the expertise gained from the synthesis of PGF2alpha, latanoprost and bimatoprost, and involves in the beginning an organocatalyzed cascade forming enal as building block. Another key step will be the fluorination and three different strategies will be pursued. A cooperation partner, the Bristol Platelet Group (School of Physiology and Pharmacology), will utilize the generated stable TxA2 analogues then to develop the therapeutic antibody-based drug that removes TxA2 for the treatment of cardiovascular disease.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Varinder Kumar Aggarwal, Ph.D.