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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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Article information


Submitted
26 Oct 2012
Accepted
05 Dec 2012
First published
07 Dec 2012

Chem. Sci., 2013,4, 1046-1052
Article type
Edge Article

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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