The rise of diversity-oriented synthesis in drug discovery

Molecular diversity is a crucial feature in bioactive compound libraries. This makes sense as it would expand the chemical space around the studied biological targets or processes and therefore increase the chance to find hit compounds. During the 1990S and early 2000S, combinatorial chemistry was very popular within big pharmas as a privileged method to quickly generate diversity by simultaneously preparing multiple compound libraries; especially using the solid-phase synthesis techniques (i.e., functionalized lanterns and Merrifield resin beads).1 Yet, the major drawback is the lack of structural diversity (i.e., poor scaffold diversity) within the chemical series. Without throwing the baby out with the bathwater, combinatorial chemistry greatly contributes to fuel up many high-throughput screening campaigns and could be useful to assess quickly structure-activity relationships of different compounds having similar backbones. However, how can we efficiently achieve scaffold diversity? How can we navigate simultaneously into different regions of biologically relevant chemical space?

In my opinion, diversity-oriented synthesis (DOS) could be a potential answer to those questions.

The DOS approach considers the efficient and simultaneous synthesis of structurally different compounds with the purpose to probe large portions of the bioactive small molecules space.2 Compared to the target-oriented synthesis where each step is performed sequentially to yield a final product, DOS starts from simple and similar building blocks towards complex and diverse compounds, usually in few steps (Fig. 1). To be fruitful, four parameters have to be considered to create high molecular diversity: i) the building blocks, ii) the stereochemistry, iii) the functional groups and iv) the molecular skeleton, which is the most important criterion.

MB 1

Figure 1. Synthetic approach in combinatorial synthesis and DOS.

Obviously, DOS heavily depends on reliable, atom-economic and high-yielding reactions and must work on a wide range of susbtrates as well as functional groups. Reactions such as multicomponent reactions (Ugi, Passerini, Petasis), tandem/domino and pericyclic processes as well as ring-closing metathesis (RCM) amongst others are now widely used in DOS. Recently, Nielsen and Schreiber have noticed that several DOS methodologies followed three distinct phases: Build/Couple/Pair (B/C/P).3 The Build part correspond to the synthesis of the starting materials, the Couple part refer to coupling reactions to form linear precursors. Finally, the Pair phase refer to folding reactions that trigger intramolecular pairing between compatible functional groups.

As a good example, Marcaurelle et al. have reported an aldol-based B/C/P strategy for the generation of structurally diverse macrocyclic histone deacetylase (HDAC) inhibitors.4 Using different asymmetric syn– and anti-aldol reactions in the Build phase, four stereoisomers of a Boc-protected g-amino acid were generated. On the other hand, chiral amine partners consisted in both stereoisomers of O-PMB-protected alaninol. Thus, in the Couple phase, eight chiral amides were prepared by coupling the chiral acid and amine starting materials. The resulting amides were then reduced to generate the related secondary amines. The fun part starts in the Pair phase where three different reactions – a nucleophilic aromatic substitution (SNAr), a [3+2] azide-alkyne cycloaddition and a ring-closing metathesis (RCM) – were used to greatly diversify the whole matrix, thus providing a variety of macrocycles of different size (8- to 14-membered rings, Figure 2). Finally, the combinatorial diversification of the scaffolds resulting from the RCM reaction, further yielded a 14 400 macrolactams library. This has led to the discovery of a novel class of HDAC inhibitors.

MB 2

Figure 2. Aldol-based DOS strategy towards novel macrolactams inhibiting the HDAC enzyme by Marcaurelle et al.

Hence, by pushing the synthetic boundaries always further, DOS could serve as the perfect tool to rapidly interrogate the medicinally relevant chemical space.

Blog written by Mohamed Benchekroun


(1)          Carroll, J. Will Combinatorial Chemistry Keep Its Promise? Biotechnol. Healthc. 2005, 2 (3), 26–32.

(2)          Galloway, W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Diversity-Oriented Synthesis as a Tool for the Discovery of Novel Biologically Active Small Molecules. Nat. Chem. 2010, 1, 80.

(3)          Nielsen, T. E.; Schreiber, S. L. Towards the Optimal Screening Collection: A Synthesis Strategy. Angew. Chem. Int. Ed. 2008, 47 (1), 48–56.

(4)          Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M. D.; Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.; Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-N.; Haggarty, S. J.; Palmer, M.; Foley, M. A. An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors. J. Am. Chem. Soc. 2010, 132 (47), 16962–16976.


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