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FP6

SPIROTENUIPESINES Sintesi della relazione

Project ID: 40386
Finanziato nell'ambito di: FP6-MOBILITY
Paese: United Kingdom

Final Activity Report Summary - SPIROTENUIPESINES (Total Synthesis of the Potent Neurotrophic Factors Spirotenuipesine A and B)

Naturally occurring polypeptidyl neurotrophic factors play a critical role in neuronal survival and growth, a decreased level of neurotrophic support is a common caracteristic of a variety of neurodegenrative disorders. Drug availability problems associated with the polypeptidic neurotrophins known so far are a serious impediment to their development in prospective human settings; therefore the Danishefsky group has selected a number of small molecules which exhibit activity as non-peptidyl neurotrophic factors (NPNF) in the neurite outgrowth assay. In some interesting cases, these new compounds have shown extremely potent submicromolar activity as low as a hundred nanomolar. During the outgoing phase of the fellowship, the researcher has initiated the work on the biomimetic total synthesis of the neurotrophic factor (-)-11-O-debenzoyltashironin by collecting all the necessary background information and the relevant literature. (-)-11-O-debenzoyltashironin promotes neurite outgrowth in foetal rat cortical neurons at concentrations as low as 0.1 uM. It needs to be highlighted that since the mechanism of action of these naturally-derived non-peptidyl factors has not been established yet, the synthesis of significant amounts of these compounds, otherwise scarcely available from natural sources, would allow ground-breaking investigations on their activity.

This new class of molecules would also provide a significant difference in the mode of administration, as they would be able to cross the blood-brain barrier, crucially not requiring direct microinjection to the brain. This work has provided a great platform to explore novel methodologies and investigate the chirality transfer in domino Diels-Alder processes. The syntheses of the target natural compound in both enantiopure forms and their analogues has been completed as planned in the first year of the fellowship and in the following period the researcher has liaised with a team of biologists who are screening the activity of the compounds in vitro.

The fellow has planned and suggested structural modifications to improve the activity of the compounds under the guidance of her supervisor. Initial biological investigations carrier out in the laboratories of Dr Li at Memorial Sloan Kettering Cancer Centre have confirmed the neurothrophic acivity of (-)-11-O-debenzoyltashironin at concentrations as low as 30uM. This work has allowed the fellow to strengthen her synthetic skills focusing on molecules with a biologically relevant profile in a multidisciplinary environment. During this time the fellow has supervised 2 first year PhD students and worked at Columbia University as an Organic Chemistry Lecturer for Science Honor Program, designing and leading a weekly 2.5hr course covering the theoretical and practical aspects of general organic chemistry.

As a postdoctoral fellow in the laboratories of Professor Balasubramanian, the fellow has been involved in a number of projects centred on the synthesis of small natural molecules targeting nucleic acids. This has complimented her training as well as expand her expertise in new scientific areas and in particular in novel druggable targets in the nucleic acids field. The opportunity to work in chemical biology focussed project areas has allowed the fellow to learn new and complementary practical techniques. As initially proposed, the return phase of the fellow has concentrated on the transfer of expertise to the return host and application of the new gained skills within drug development programmes.

Moreover, as initially proposed, the fellow has attended lectures and workshops to develop medicinal chemistry skills and share knowledge gained during PhD and outgoing phase. She has given great focus to provide guidance to less experienced scientists continuing the development of teamwork, leadership and inter-personal skills. The lecturing and tutoring undergraduate and graduate students in organic chemistry and medicinal chemistry disciplines has offered an outstanding possibility to promote science.

Contatto

Balasubramanian SHANKAR, (Reader)
Tel.: +44 1223 336347
Fax: +44 1223 336362
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