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Synlett 2012(2): 163-170  
DOI: 10.1055/s-0031-1290125
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

Reduce to the Maximum: Truncated Natural Products as Powerful Modulators of Biological Processes

Jean-Yves Wacha,b, Karl Gademann*a
a Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
e-Mail: karl.gademann@unibas.ch;
b Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
Further Information

Publication History

Received 7 September 2011
Publication Date:
22 December 2011 (online)

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Abstract

This account describes several examples from the literature, as well as from our own work, of efforts to reduce the structural complexity of natural products through truncation by organic synthesis. This process, sometimes called diverted total synthesis or function oriented synthesis, also aims to deliver improved compounds for clinical evaluation. The discussed examples from the literature of this type of chemical editing are the truncation of halichondrin B to E7389/eribulin, bryostatin 1 to the bryologs, migrastatin to the migrastatin core, macfarlandin E, and somatostatin (SRIF14) to L-363,301 and octreotide. From our work, efforts on the truncation of anguinomycin/leptomycin, farinosone C to tyrosinol propionamide, and anachelin to the anachelin chromophore are discussed. A hypothesis as to why nature retains apparently nonfunctional appendages on biologically active core structures (related to the pharmacophore) in such ‘less than perfect’ natural products is presented. It is proposed that such appendages are generated to increase chemotype plasticity, and that such plasticity might eventually lead to secondary benefits, such as improved physicochemical properties or additional bioactivity.

Key words

natural products - anticancer agents - truncation - chemical biology

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