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What can a chemist learn from nature’s macrocycles? – A brief, conceptual view

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Abstract

Macrocyclic natural products often display remarkable biological activities, and many of these compounds (or their derivatives) are used as drugs. The chemical diversity of these compounds is immense and may provide inspiration for innovative drug design. Therefore, a database of naturally occurring macrocycles was analyzed for ring size, molecular weight distribution, and the frequency of some common substructural motifs. The underlying principles of the chemical diversity are reviewed in terms of biosynthetic origin and nature’s strategies for diversity and complexity generation in relation to the structural diversity and similarities found in the macrocycle database. Finally, it is suggested that synthetic chemists should use not only nature’s molecules, but also nature’s strategies as a source of inspiration. To illustrate this, the biosynthesis of macrocycles by non-ribosomal peptide synthetases and terpene and polyketide cyclases, as well as recent advances of these strategies in an integrated synthesis/biotechnology approach are briefly reviewed.

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Abbreviations

ACE:

angiotensin converting enzyme

ACP:

acyl carrier protein

AT:

acyl transferase

C:

condensation

6-dEB:

6-deoxyerythronolide B

DEBS:

deoxyerythronolide B synthase

E:

epimerization (domain)

GGPP:

geranylgeranyl diphosphate

KR:

ketoreductase (domain)

KS:

ketosynthase (domain)

M:

N-methylation (domain)

Nic:

nicotinoyl

NRPS:

non-ribosomal peptide synthetase

PCP:

peptidyl carrier protein

PKS:

polyketide synthase

QSAR:

quantitative structure-activity relationships

TE:

thioesterase

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  1. Department of Bioorganic Chemistry, Weinberg 3, Leibniz-Institute of Plant Biochemistry, D-06120 Halle (Saale), Germany

    Ludger A. Wessjohann, Eelco Ruijter, Daniel Garcia-Rivera & Wolfganf Brandt

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  1. Ludger A. Wessjohann
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Wessjohann, L.A., Ruijter, E., Garcia-Rivera, D. et al. What can a chemist learn from nature’s macrocycles? – A brief, conceptual view. Mol Divers 9, 171–186 (2005). https://doi.org/10.1007/s11030-005-1314-x

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