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Issue 3, 2013
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Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry

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Abstract

A combination of molecular modelling and rational biosynthetic engineering of the rapamycin polyketide synthase was used to generate rapalogs lacking O- and C-linked methyl groups at positions 16 and 17 respectively. These rapalogs displayed enhanced inhibition of cancer cell lines and were produced at titres close to those of the parent strain. By recapitulating these experiments in higher-producing rapamycin strains, combined with the ectopic expression of gene products acting late in the biosynthetic pathway in order to minimise the accumulation of intermediates, gram-quantities of novel rapalogs bearing multiple structural changes were produced.

Graphical abstract: Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry

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Publication details

The article was received on 26 Oct 2012, accepted on 05 Dec 2012 and first published on 07 Dec 2012


Article type: Edge Article
DOI: 10.1039/C2SC21833J
Citation: Chem. Sci., 2013,4, 1046-1052
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    Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry

    M. A. Gregory, A. L. Kaja, S. G. Kendrew, N. J. Coates, T. Warneck, M. Nur-e-Alam, R. E. Lill, L. S. Sheehan, L. Chudley, S. J. Moss, R. M. Sheridan, M. Quimpere, M. Zhang, C. J. Martin and B. Wilkinson, Chem. Sci., 2013, 4, 1046
    DOI: 10.1039/C2SC21833J

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