RSC Medicinal Chemistry Blog

In this review from MedChemComm‘s forthcoming Natural Product themed issue, Vinayak Agarwal and Satish K. Nair (University of Illinois at Urbana-Champaign) review a number of small molecule natural products, that target aminoacyl tRNA synthetases, which are available for development into useful antibiotics. In particular Agarwal and Nair focus on three different chemical classes:

1. Molecules derived from polyketide precursors
2. Molecules that occur as phosphoramidate conjugates
3. Promising synthetic molecules with distinct modes of action to molecules of class 1 and 2

The factors that undermine the broad-based use of some of these molecules as effective antibiotics in humans are also discussed, as well as strategies to aid in directing development of derivatives with improved pharmacological properties.

Aminoacyl tRNA synthetases as targets for antibiotic development
Vinayak Agarwal and Satish K. Nair
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20032E

We will be bringing you more examples of work from this themed issue, guest edited by Professor Christopher T. Walsh andDr Sylvie Garneau-Tsodikova, over the next few weeks so make sure you check back for more.

In this review Ewa Maria Musiol and Tilmann Weber at Eberhard Karls University, Tübingen  present a summary of genetically and biochemically characterized in trans active ATs, which supply polyketide synthases assembly lines with building blocks and thus, might influence the polyketide structure by their substrate selectivity.

Included in this review are discussions on:

• MmpC involved in mupirocin biosynthesis
• OzmM and OzmC involved in oxazolomycin biosynthesis
• RhiG involved in rhizoxin biosynthesis
• VirI involved in virginiamycin biosynthesis
• TaV involved in myxovirescin biosynthesis
• BryP involved in bryostatin biosynthesis

…. and many more.

Discrete acyltransferases involved in polyketide biosynthesis
Ewa Maria Musiol and Tilmann Weber
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20048A

‘Natural products are an unsurpassed source of lead structures for drug discovery. However, these molecules, many of which fall into the beyond-rule-of-5 chemical space, are often difficult to optimize by chemical means because of their complex structures.’, explains Frank E. Koehn (Pfizer, Natural Products, Oncology Worldwide Medicinal Chemistry Groton, USA).

In this MedChemComm review article, Frank E. Koehn provides the reader with an overview on biosynthesis-oriented strategies to access analogues of natural products, which would be unattainable by chemical semisynthesis. Five relevant examples of distinct drugs, namely:

• salinosporamide
• geldanamycin
• FK506
• rapamycin
• epothilone

are described, for which libraries of analogues have been prepared via biosynthetic engineering approaches and which are under intensive biological investigation or already in clinical use.

This review is part of our forthcoming themed issue on Natural Products, guest edited by Professor Christopher T. Walsh and Dr Sylvie Garneau-Tsodikova – keep checking back for more hot research in this theme:

Biosynthetic medicinal chemistry of natural product drugs
Frank E. Koehn
Med. Chem. Commun., 2012, Review Article