Facile strategy for the creation of complex and diverse compounds


High-throughput screening (HTS) of synthetic chemical libraries, containing mainly small molecules, is widely used in drug discovery programmes, both in industry and academia.

HTS has provided many drug leads, but mainly for biological targets that can be modulated by low molecular weigh and planar compounds. For more complex biological targets, HTS will fail due to the nature of the composition of the screening library. A recent study (J. Med. Chem. 2011, 6405) has shown that medicinal chemists have been synthesizing, over the last 50 years, compounds with lower than ideal Fsp3 (fraction of sp3-hybridised carbons) values and higher than ideal ClogP values, the former attributed to the increasing ease of sp2-sp2 coupling reactions. Therefore there is an interest in creating new libraries of complex compounds with better “druglike” features.

Hergenrother and co-workers (Nature Chemistry, 2013, 195) describe a ring-distortion strategy to rapidly (≤5 synthetic steps) generate collections of complex and diverse small molecules from readily available polycyclic natural products. An important consequence of starting with natural products is that all the intermediates generated are complex structurally and worth of inclusion in the final library.

They demonstrate this strategy for three complex natural products, gibberellic acid, adrenosterone and quinine using combinations of ring-cleavage, ring expansions, ring-fusions and ring rearrangements reactions (Fig 1-3).

cv4Figure 1. Ring-distortion approach on gibberellic acid.

cv5Figure 2. Ring-distortion approach on adrenosterone.

cv6Figure 3. Ring-distortion approach on quinine.

The average Fsp3 values for Hergenrother compounds was found to be 0.59, considerably higher than the 0.23 average found for a ChemBridge commercial collection of 150,000 compounds, while the ClogP was 2.90, 1.1 log units lower that that in the commercial collection, corresponding to a 12-fold reduction in hydrophobicity. Moreover, a chemoinformatic analysis (Tanimoto coefficients) revealed very low similarity between all of the compounds synthesized in this way which is a much superior derivatisation strategy than the conventional modification of peripheral functionalities.

Screening this library should definitely be of great interest to medicinal chemists.

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