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The University of Southampton

Research project: Whitby: Synthesis of Bioactive compounds: Ligands for Nuclear Receptors and Neuroactive amines

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Nuclear receptors are proteins which act to regulate gene expression, typically controlled by binding of small molecules (often hormones).

There are a number of nuclear receptors identified first in the human genome, for which the natural ligands are not know - described as ‘Orphan Nuclear Receptors'. In order to define the roles of these receptors small molecule ligands which can bind to the active sites (Fig 1) and regulate activity provide a crucial biological tool. We have recently reported the first known ligands (1) of the ONR's Liver Receptor Homologue-1 (LRH-1) and Steroidogenic Factor-1 (SF-1).[1] These receptors are known to be important in many aspects of development and homeostasis and molecules which can regulate them are likely to form the basis of useful pharmaceuticals.

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Although the ligands appear complex, they are assembled in one step using zirconium chemistry (Scheme), or three steps using cobalt chemistry. We are developing the biology of these compounds in collaboration with the Faculty of Medicine.

Figure 1. Binding in LRH-1 active site.


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Synthesis of agonists for the Orphan Nuclear Receptors LRH-1 and SF-1.




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We also have an interest in molecules designed to be active in the central nervous system, typically by incorporating the β- or γ-aryl-amine motif found in many neurotransmitters (e.g. dopamine, 5-hydroxytryptamine). Recent examples include efficient novel routes to azepins 2,[2] opioids such as 3, and 3-benzylpyrrolidines 4, including the first use of zirconium mediated reactions on a solid support.[3]

[1] Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1. Whitby, R. J.; Dixon, S.; Maloney, P. R.; Delerive, P.; Goodwin, B. J.; Parks, D. J.; Willson, T. M. J. Med. Chem. 2006, 49, 6652-6655.

[2] Zirconium-mediated synthesis of azepanes and benzazepanes
Macfarlane, D. P. S.; Norton, D.; Whitby, R. J.; Tupper, D.
Synlett 2006, 3439-3442.

[3] Organozirconium-mediated solution- and solid-phase synthesis of 3-benzyl pyrrolidines and other potentially neuroactive amines
Hunter, R. A.; Macfarlane, D. P. S.; Whitby, R. J.
Synlett 2006, 3314-3318.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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