研究领域

Synthesis

Research in the group ranges across the total synthesis of biologically active natural products and structural analogues to the discovery and development of new synthetic methods. Stereocontrolled Synthesis of Bioactive Natural Products and Structural Analogues Representative targets include rare anticancer polyketides of both marine and terrestrial origin such as 1-4 below. For example, dictyostatin (1) shares the same microtubule-stabilising mechanism as the clinically important anticancer drug Taxol, while spirastrellolide A (2) is a potent inhibitor of protein phosphatase 2A. Likewise, chivosazole A (3) and reidispongiolide A (4) are novel actin-interacting macrolides isolated from myxobacteria and marine sponges respectively, which also represent challenging synthetic targets. In all these cases, the initial uncertainty over the stereochemistry, combined with their natural scarcity, has adversely affected their development. Efficient and flexible synthetic routes for the modular construction of these and other complex polyketide natural products are being pursued to establish their full configurations and provide a sustainable supply for detailed biological evaluation. A parallel objective is to design simplified analogues and hybrids that retain the exceptional cancer cell growth inhibitory properties whilst increasing their synthetic accessibility. New Synthetic Methods There is a need for new and more efficient methods of synthesis, particularly ones that achieve high levels of stereochemical control, where the development of asymmetric aldol methodology is of particular interest. These new methods are being applied to the synthesis of a wide variety of biologically important natural products.

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Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues JH Pereira, C Petchprayoon, AC Hoepker, NW Moriarty, SJ Fink, G Cecere, I Paterson, PD Adams, G Marriott – ChemMedChem (2014) 9, 2286 (DOI: 10.1002/cmdc.201402150) Total synthesis of jiadifenolide. I Paterson, M Xuan, SM Dalby – Angew Chem Int Ed Engl (2014) 53, 7286 (DOI: 10.1002/anie.201404224) Molecular Recognition of Epothilones by Microtubules and Tubulin Dimers Revealed by Biochemical and NMR Approaches A Canales, L Nieto, J Rodríguez-Salarichs, PA Sánchez-Murcia, C Coderch, A Cortés-Cabrera, I Paterson, T Carlomagno, F Gago, JM Andreu, KH Altmann, J Jiménez-Barbero, JF Díaz – ACS Chem Biol (2014) 9, 1033 (DOI: 10.1021/cb400673h) Total synthesis of the antimitotic marine macrolide (-)-leiodermatolide I Paterson, KK Ng, S Williams, DC Millican, SM Dalby – Angew Chem Int Ed Engl (2014) 53, 2692 (DOI: 10.1002/anie.201310164) The Impact of the Mukaiyama Aldol Reaction in Total Synthesis SB Kan, KK Ng, I Paterson – Angew Chem Int Ed Engl (2013) 52, 9097 (DOI: 10.1002/anie.201303914) MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications. KR Brunden, NM Gardner, MJ James, Y Yao, JQ Trojanowski, VM Lee, I Paterson, C Ballatore, AB Smith – ACS Med Chem Lett (2013) 4, 886 (DOI: 10.1021/ml400233e) Total synthesis of aplyronine C. I Paterson, SJ Fink, LY Lee, SJ Atkinson, SB Blakey – Organic Letters (2013) 15, 3118 (DOI: 10.1021/ol401327r) Total synthesis of (+)-spirastrellolide A methyl ester: Challenges and discoveries I Paterson, P Maltas, EA Anderson – Pure and Applied Chemistry (2013) 85, 1133 (DOI: 10.1351/PAC-CON-13-01-01) Total Synthesis of (-)-Rhizopodin SM Dalby, J Goodwin-Tindall, I Paterson – Angew Chem Int Ed Engl (2013) 52, 6517 (DOI: 10.1002/anie.201301978) Studies toward the total synthesis of madeirolide A GW Haslett, CI MacGregor, SP Fearnley, I Paterson – ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY (2013) 245 Studies towards the total synthesis of Leiodermatolide KK-H Ng, S Williams, I Paterson – ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY (2013) 245 Total synthesis of alotaketal A M Xuan, I Paterson, S Dalby – ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY (2013) 245 Synthesis of the C1-C11 western fragment of madeirolide A. I Paterson, GW Haslett – Organic Letters (2013) 15, 1338 (DOI: 10.1021/ol400280b) Total synthesis of alotaketal A. M Xuan, I Paterson, SM Dalby – Organic Letters (2012) 14, 5492 (DOI: 10.1021/ol302570k) The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments I Paterson, EA Anderson, SM Dalby, JH Lim, P Maltas, O Loiseleur, J Genovino, C Moessner – Org Biomol Chem (2012) 10, 5861 (DOI: 10.1039/c2ob25100k) The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis. I Paterson, EA Anderson, SM Dalby, JH Lim, P Maltas – Org Biomol Chem (2012) 10, 5873 (DOI: 10.1039/c2ob25101a) A Second-Generation Total Synthesis of Spirastrellolide A Methyl Ester I Paterson, P Maltas, SM Dalby, JH Lim, EA Anderson – Angew Chem Int Ed Engl (2012) 51, 2749 (DOI: 10.1002/anie.201108594) Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones I Paterson, VASN Doughty, MD McLeod, T Trieselmann – Tetrahedron (2011) 67, 10119 (DOI: 10.1016/j.tet.2011.09.012) Insights into the interaction of discodermolide and docetaxel with tubulin. Mapping the binding sites of microtubule-stabilizing agents by using an integrated NMR and computational approach. A Canales, J Rodríguez-Salarichs, C Trigili, L Nieto, C Coderch, JM Andreu, I Paterson, J Jiménez-Barbero, JF Díaz – ACS Chem Biol (2011) 6, 789 (DOI: 10.1021/cb200099u) Synthesis of the macrocyclic core of leiodermatolide. I Paterson, T Paquet, SM Dalby – Organic Letters (2011) 13, 4398 (DOI: 10.1021/ol2017388)