Volume 6 Issue 10, October 2014

Volume 6 Issue 10

The success of natural products and their derivatives as drugs has encouraged researchers to seek further inspiration from nature in the discovery of novel bioactive small molecules. Two Articles in this issue describe attempts to mimic aspects of natural-product biosynthesis in the preparation of diverse molecules for screening. The cover is an illustrative metaphor for the connection between nature and drug discovery. The honeycomb, prevalent in nature, represents a vast array of reactions, with the highlighted cells representing those reactions that yield products with specific biological activity.

Editorial p841; Interviews p845, 846; News & Views p851; Articles p872, 877




  • Editorial |

    A collection of articles in this issue focuses on attempts to mimic aspects of natural-product biosynthesis for the identification of new drugs.



  • Interview |

    Adam Nelson and Stuart Warriner, from the University of Leeds, talk with Nature Chemistry about their work to develop viable synthetic strategies for preparing new chemical structures in parallel with the identification of desirable biological activity.

  • Interview |

    Jeffrey Bode from ETH Zürich talks with Nature Chemistry about his group's work on synthetic fermentation, and how he hopes it could bring the power of chemical synthesis into the hands of citizen scientists.

Research Highlights


News and Views

  • News & Views |

    The generation of chemical libraries for screening is a key part of the drug discovery process. Now, two studies describe attempts to combine features of natural product biosynthesis into the creation of libraries with the aim of mimicking nature's success at the production of bioactive molecules.

    • Derek B. Lowe
  • News & Views |

    A synthetic compound that transports chloride across membranes can kill both normal cells and cancer cells in vitro. The transporter works together with sodium channels to move NaCl into the cells, which triggers cell death.

    • Jeffery T. Davis
  • News & Views |

    A better understanding of electron transfer through molecules could provide the basis for many technological breakthroughs. Now, the rate of electron transfer has been enhanced in a family of molecules by making them more rigid, and this phenomenon may be explained by the loss of electronic energy to vibrations.

    • John R. Miller
  • News & Views |

    Bicyclic peptides that are cell-permeable and can inhibit an intracellular target have been developed. These peptides consist of two rings: one enables the peptide to pass through the membrane, the other can inhibit the target.

    • Rob M. J. Liskamp
  • News & Views |

    Self-assembled cylinders can generally be extended only from their ends — growth that is considered to be 'one-dimensional'. Now, platelet-like structures with controlled size and composition have been constructed by growth in two dimensions of self-assembled structures, starting from crystallite seed micelles.

    • Chunhua Cai
    •  & Jiaping Lin


  • Review Article |

    A critical overview and analysis of contemporary screening approaches toward the discovery of new reactivity is provided. A breakdown of each approach in terms of strategy, practicality and utility from the perspective of a synthetic chemist is also given, as well as considerations on the future of high-throughput screening in reaction discovery.

    • Karl D. Collins
    • , Tobias Gensch
    •  & Frank Glorius


  • Article |

    A discovery approach termed activity-directed synthesis is described; it exploits arrays of reactions whose outcome is critically dependent on the conditions used, and prioritizes reactions that yield bioactive product mixtures. The discovery of both bioactive small molecules and associated synthetic routes thus occurs in parallel.

    • George Karageorgis
    • , Stuart Warriner
    •  & Adam Nelson
  • Article |

    The production of biologically active compounds by microbial fermentation has proved highly successful in drug discovery. Now, a method that mimics this process has been used to prepare unnatural peptides from small building blocks without the need for additional reagents, and in a fashion that is immediately compatible with biological screening.

    • Yi-Lin Huang
    •  & Jeffrey W. Bode
  • Article |

    Anion transporters that disrupt cellular ion homeostasis could represent a new approach for generating therapeutic lead compounds. Now, two pyridine diamide-strapped calix[4]pyrroles have been shown to induce coupled chloride anion and sodium cation transport in liposomal models and cells. These compounds promote cell death by increasing intracellular chloride and sodium ion concentrations.

    • Sung-Kyun Ko
    • , Sung Kuk Kim
    • , Andrew Share
    • , Vincent M. Lynch
    • , Jinhong Park
    • , Wan Namkung
    • , Wim Van Rossom
    • , Nathalie Busschaert
    • , Philip A. Gale
    • , Jonathan L. Sessler
    •  & Injae Shin
  • Article |

    Self-assembly is commonly used to construct complex nanostructures from soft matter. Now, using the living crystallization-driven self-assembly approach, controlled nanostructure growth in both one and two dimensions has been achieved. Uniform lenticular multiblock platelets, as well as hierarchical structures analogous to nanoscale single- and double-headed arrows and spears have been prepared with controlled sizes in two dimensions.

    • Zachary M. Hudson
    • , Charlotte E. Boott
    • , Matthew E. Robinson
    • , Paul A. Rupar
    • , Mitchell A. Winnik
    •  & Ian Manners
  • Article |

    The relationship between electron-transfer properties and the structure of molecular electronics is still not fully understood. Now, a rigid and flat molecular wire has been shown to significantly enhance the rate of electron transfer compared with conventional flexible molecular wires. This enhancement is attributable to both conjugation-induced electronic coupling and inelastic electron tunnelling-enabled electron–vibration coupling.

    • Junpei Sukegawa
    • , Christina Schubert
    • , Xiaozhang Zhu
    • , Hayato Tsuji
    • , Dirk M. Guldi
    •  & Eiichi Nakamura
  • Article |

    Obtaining precise structural information for metal-centred reactions that take place within the pores of metal–organic frameworks continues to be an elusive goal. Now, a flexible framework has been synthesized that enables the direct elucidation of the products of post-synthetic metallation reactions and subsequent chemical transformations by single-crystal X-ray crystallography. Camera image: © boyoglu/iStock/Thinkstock

    • Witold M. Bloch
    • , Alexandre Burgun
    • , Campbell J. Coghlan
    • , Richmond Lee
    • , Michelle L. Coote
    • , Christian J. Doonan
    •  & Christopher J. Sumby
  • Article |

    Analysing the dynamic adsorption of small molecules in porous materials is a significant challenge. Now, in situ single-crystal X-ray diffraction has shown that molecular adsorption in a crystalline nanochannel occurs through multiple steps. Transient states during the process were also visualized, demonstrating the potential of X-ray analysis for probing non-covalent adsorption processes.

    • Ryou Kubota
    • , Shohei Tashiro
    • , Motoo Shiro
    •  & Mitsuhiko Shionoya
  • Article |

    Multi-electron redox chemistry is important in transition-metal-mediated processes, but is rarely observed with uranium due to its propensity to undergo single-electron reactions. Now, uranium can use its electrons, coupled with those stored in redox-active ligands, to perform multi electron reduction of organoazides and form uranium tris(imido) derivatives.

    • Nickolas H. Anderson
    • , Samuel O. Odoh
    • , Yiyi Yao
    • , Ursula J. Williams
    • , Brian A. Schaefer
    • , John J. Kiernicki
    • , Andrew J. Lewis
    • , Mitchell D. Goshert
    • , Phillip E. Fanwick
    • , Eric J. Schelter
    • , Justin R. Walensky
    • , Laura Gagliardi
    •  & Suzanne C. Bart
  • Article |

    FeS clusters are a universal motif in organisms and are central to many processes, including nitrogen fixation and respiration. By carrying out the first many-electron calculation of the [2Fe-2S] and [4Fe-4S] clusters, they are shown to have an unusual set of closely packed energy levels, which are key to understanding their reactivity.

    • Sandeep Sharma
    • , Kantharuban Sivalingam
    • , Frank Neese
    •  & Garnet Kin-Lic Chan
  • Article |

    Non-haem iron(III)-peroxo complexes that bind redox-inactive metal ions are synthesized to investigate the role of the Ca2+ ion in the oxidation of water to dioxygen in photosystem II. The electrochemical properties and reactions of these compounds with an electron donor and an acceptor are found to be markedly dependent on the Lewis acidity of redox-inactive metal ions.

    • Suhee Bang
    • , Yong-Min Lee
    • , Seungwoo Hong
    • , Kyung-Bin Cho
    • , Yusuke Nishida
    • , Mi Sook Seo
    • , Ritimukta Sarangi
    • , Shunichi Fukuzumi
    •  & Wonwoo Nam

In Your Element

  • In Your Element |

    From rubies to Rolls-Royce, Anders Lennartson explores the colourful history of chromium and its coordination compounds.

    • Anders Lennartson




  • Focus |

    Biomimetic drug discovery

    Natural products and their derivatives have long been a significant source of pharmaceuticals. A collection of articles in this Focus highlights efforts to mimic some aspects of the way in which these compounds are made in nature with the aim of improving the processes by which synthetic drug leads are identified.