Editorial: Diversity Oriented Synthesis
- 1Università di Genova, Italy
- 2Seoul National University, South Korea
Small molecules play an essential role in the fields of drug discovery and chemical biology, so it is fundamental to have synthetic methodologies able to assemble molecules characterized by innovative molecular frameworks, both in terms of skeleton and of stereochemistry. Diversity-oriented synthesis (DOS) aims to explore, through rapid and efficient synthetic methodologies, unexplored areas of the biology-relevant chemical space, to find new bioactive molecules, possibly towards new biological targets (Burke and Schreiber, 2004; Galloway et al., 2010).
One of the most successful approaches applied in DOS is the build/couple/pair approach. This approach has been used efficiently in the past by numerous research groups, and several success stories can be counted. Park et al (10.3389/fchem.2018.00507) in their short review illustrate how the build/couple/pair approach applied to the synthesis of natural product-like compounds and macrocycles. Since this thematic issue wants to look more to the future than to the past, Park also illustrates a more recent strategy, ring-distortion, which aims to achieve molecular diversity by altering pre-existing cyclic systems, through ring closures or openings, ring expansions or contractions, and other transformations. Through this approach the synthesis of natural product-like molecules, as well as macrocycles and benzannulated compounds, can be achieved.
Within this context, Spring et al (10.3389/fchem.2018.00460) demonstrate that the typical and well-tested build/couple/pair approach is currently used to produce DOS libraries as part of the fragment-based drug discovery (FBDD) (Erlanson and Jahnke, 2016), as opposed to the past, where DOS libraries were almost exclusively analyzed through HT screenings. Particularly interesting are those cases where new synthetic methodologies are introduced in the DOS strategy, as for example the C–H activation or the site-selective late-stage modifications of complex scaffolds. In fact, the use of these methodologies meets one of the requirements necessary for such molecules to be efficiently exploited in the FBDD, which is also one of the stated objectives of DOS, i.e. to escape from flatland (Lovering et al., 2009) and therefore to generate 3-dimensionally diversified molecules with a globular structure and abundance of chiral centers and sp3 carbons.
Other ways to assemble 3-dimensionally complex structures are presented by Lenci, Trabocchi et al (10.3389/fchem.2018.00522), who exploit morpholine skeletons rich in sp3 carbon atoms, derived from sugars and amino acids, and by Basso, Mang et al (10.3389/fchem.2018.00369), who exploit spiro-fused ring systems as scaffolds for the generation of three DOS libraries. Both groups benefit from chemoinformatic analysis of chemical space to gain insight into the detailed structure of the molecular scaffolds and to verify the validity of synthetic strategy. Specifically, calculation of the Principal Component Analysis was used by Lenci and Trabocchi to group the synthetized molecules into four main clusters depending on both their main skeletons and side-chain properties.
The work by Basso and Mang reveals, among other things, how multicomponent reactions, combining three or more diversomers in a single step, are useful to assemble DOS libraries in a straightforward manner. Along the same lines is the report by Wipf et al (10.3389/fchem.2018.00376) which, exploiting one of the oldest multicomponent reactions, the Biginelli reaction, manages to obtain fused polyheterocycles through a cascade process involving a hetero Diels-Alder reaction, in a stereoselective fashion.
The possibility to use the multicomponent Ugi reaction, followed by post-condensation cyclizations, to obtain polyheterocyclic systems is analyzed in detail by Van der Eycken et al (10.3389/fchem.2018.00557), who explore the various synthetic routes of assembling small/medium-sized rings, taking examples from the recent literature.
A comprehensive review is also published by Chebanov et al (10.3389/fchem.2018.00527) who, taking advantage of their expertise on the properties and reactivity of amino-azole derivatives, illustrate the strategies that can lead to DOS libraries from these compounds, both by exploiting two-component reactions as well as multicomponent processes. The synthesis of nitrogen-containing polyheterocycles, useful both in the field of drug-like substances and functional materials, is the subject of the article by Lei et al (). The authors show how the DOS approach can be used to generate imidazotriazole-based chemical probes able to identify the biological targets implied in epigenetic processes.
As was the case with combinatorial chemistry, which was initially developed in the field of drug discovery, but then found wide application in other fields, such as materials science, the same phenomenon is happening for DOS, and Müller et al (10.3389/fchem.2018.00579) demonstrate this with their studies on luminescent materials. The DOS approach developed herein enables a rapid assembly of dual emissive bichromophores, to be employed for accessing unimolecular white light emitters for OLED and biophysical analytics.
In conclusion, going back to the question made at the beginning of this thematic issue, i.e. whether the diversity-oriented synthesis approach is still valid or is experiencing a contraction, we can now answer that the concept of DOS is still validly applicable, and improvements and deviations from its original guidelines are taking DOS in new directions which are already showing very interesting results in various research fields.
Keywords: Diversity orientated synthesis, Multicomponent reactions (MCRs), Fragment based drug design, Chemoimformatics, Principal Component Analysis - PCA, Heterocycles
Received: 11 Dec 2018;
Accepted: 21 Dec 2018.
Edited by:Iwao Ojima, Stony Brook University, United States
Copyright: © 2018 Basso, Park and Moni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Andrea Basso, Università di Genova, Genoa, Italy, firstname.lastname@example.org
Prof. Seung Bum Park, Seoul National University, Seoul, 151-742, South Korea, email@example.com
Dr. Lisa Moni, Università di Genova, Genoa, Italy, firstname.lastname@example.org